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Discovery of a new potent oxindole multi-kinase inhibitor among a series of designed 3-alkenyl-oxindoles with ancillary carbonic anhydrase inhibitory activity as antiproliferative agents

BMC Chemistry volume 17, Article number: 81 (2023) Cite this article

Abstract

An optimization strategy was adopted for designing and synthesizing new series of 2-oxindole conjugates. Selected compounds were evaluated for their antiproliferative effect in vitro against NCI-60 cell lines panel, inhibitory effect on carbonic anhydrase (CA) isoforms (hCAI, II, IX and XII), and protein kinases. Compounds 5 and 7 showed promising inhibitory effects on hCA XII, whereas compound 4d was the most potent inhibitor with low nanomolar CA inhibition against all tested isoforms. These results were rationalized by using molecular docking. Despite its lack of CA inhibitory activity, compound 15c was the most active antiproliferative candidate against most of the 60 cell lines with mean growth inhibition 61.83% and with IC50 values of 4.39, 1.06, and 0.34 nM against MCT-7, DU 145, and HCT-116 cell lines, respectively. To uncover the mechanism of action behind its antiproliferative activity, compound 15c was assessed against a panel of protein kinases (RET, KIT, cMet, VEGFR1,2, FGFR1, PDFGR and BRAF) showing % inhibition of 74%, 31%, 62%, 40%, 73%, 74%, 59%, and 69%, respectively, and IC50 of 1.287, 0.117 and 1.185 μM against FGFR1, VEGFR, and RET kinases, respectively. These results were also explained through molecular docking.

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Introduction

Designing new compounds through optimization and hybridization strategies continuously produces effective agents that can overcome many side effects and pharmacokinetics problems associated with the use of classical ones [1,2,3,4,5,6,7]. This approach depends on the identification of the essential pharmacophoric entities in two or more biologically active molecules with successive merging of them into one molecular construction utilizing pre-selected properties in the parent candidates [1]. According to the mechanism of action and the biological targets of the selected parent molecules, the newly designed hybrids could exert their biological activity through one or several mechanisms of action [8].

Carbonic anhydrases (CAs) (EC 4.2.1.1) are zinc metalloenzymes that catalyze the reversible interconversion between carbon dioxide and bicarbonate ion using zinc as a metal cofactor. In humans, only α-CA isoforms can be found with sixteen distinct isozymes have been reported to date. CAs I–III, VA, VB, VII, XIII, and XV are intracellular isoforms, whereas the CAs IV, VI, IX, XII, and XIV isoforms are extracellular. The rest CAs (VIII, X, and XI) are catalytically inactive due to the absence of one or more histidine residues that are essential for the CA catalytic activity, these isoforms are known as carbonic anhydrase related proteins [9, 10]. The transmembrane isoforms CA IX and CA XII play a key role in balancing the extracellular pH [11]. To survive the hypoxia-induced acidosis characterizing tumor microenvironment, cancer cells overexpress CA IX in response to hypoxia-inducible factor-1a (HIF-1α), which does not exist in normal tissues, promoting cancer cell survival and progression under these conditions [12]. Whereas, CA XII is overexpressed in a broad spectrum of solid tumors such as breast, cervical, and lung cancer [13]. Carbonic anhydrase inhibition is a promising strategy for cancer treatment, especially through the transmembrane isoforms hCA IX and hCA XII inhibition [5, 7].

There are five known main categories of CA inhibitors (CAIs); (1) Zinc binders which coordinate the catalytically essential Zn2+ ion in CA active site (e.g., sulfonamides and their isosteres, carboxylates and hydroxamates) [14], (2) Inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion (e.g., phenols, carboxylate and polyamines) [15], (3) CA active site entry blockers (e.g., coumarins and their isosteres) [16], (4) Molecules that bind out of the active site cavity (e.g., a carboxylic acid derivatives) [17, 18], and finally, (5) Molecules possessing unknown inhibition mechanism (e.g., Imatinib and nilotinib) [15].

Sulfonamide moiety (–SO2NH-R) and its isosteres (sulfamide, sulfamate and carboxylic group) such as compounds acetazolamide (AAZ, I), SCL-0111 (II), and III-V (Fig. 1) are reported metal ion binders that coordinate the catalytically crucial Zn2+ ion in the CA active site known as zinc binding group (ZBG) [14, 19]. Primary sulfonamide is the most commonly used ZBG in designing CAIs, as they possess the essential features required for Zn2+ ion chelation and its adjacent amino acids binding. The deprotonated SO2NH− moiety chelates the positively charged metal ion through its negative charge alternating the physiological zinc-bound nucleophile, moreover, the proton of the SO2NH− moiety forms a H-bond with Thr199 [18].

Fig. 1
figure 1

Structures of some reported anticancer CAIs, zinc binding groups are represented by pink color

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Furthermore, the tail approach has been identified as a successful strategy for the design and development of promising and selective CAIs [7, 20]. Where further stabilization of the enzyme-inhibitor complex is achieved through several Van der Waals interactions taking place between the aromatic/heteroaromatic scaffold carrying the sulfonamide group and its nearby residues. Emerging new chemical scaffolds as potential drug candidates targeting CA isozymes created a plausible rational for cancer treatment [21].

One of the main challenges in the development of new antitumor CAIs has been the lack of isoform-selectivity found in most of classical CAIs [22]. Although primary sulfonamide is the most effective ZBG for carbonic anhydrase inhibition, it results in a non-selective inhibition and so, many accompanying side effects. Secondary sulfonamides (e.g., compound VI) maintain the ligands capability to chelate the Zn2+ ion in their deprotonated form, as proved by X-ray crystallography [23]. A similar inhibition pattern has been reported for the cyclic secondary sulfonamide saccharin and its derivatives (e.g., compound VII), with effective and selective inhibition [24,25,26,27].

Moreover, heterocyclic compounds bearing both nitrogen and sulfur atoms have coordination potential towards various transition metal ions, thus, they are noticeably represented in many bioactive coordination compounds, among these compounds, several electron rich polyfunctional thiazole derivatives [28,29,30,31,32]. Furthermore, incorporating a thiazole moiety into the molecular structure of many lead compounds resulted in an improvement in the biological activities of the newly synthesized molecules (e.g., compound VIII) [33, 34].

Oxindole is a privileged scaffold that represents the core of various biologically and therapeutically important compounds and one of the most interesting heterocyclic classes that possesses a promising activity profile, in particular, multi-targeted antiproliferative activity with good tolerability in humans [35]. Specifically, 3-alkenyl-oxindole derivatives showed potent antiproliferative activity as CAIs [36, 37] and multi-kinase inhibitors [38, 39]. Several aromatic sulfonamide derivatives incorporating oxindole moieties showed interesting selectivity against specific hCA isoforms, especially tumor associated hCA IX with Ki values in the single digit nanomolar range [40]. Additionally, the presence of a spacer between the benzenesulfonamide and 2-oxindole scaffolds resulted in CA inhibition with diverse activity and selectivity profiles [41, 42]. Benzenesulfonamide-indole derivatives with ureido linkage, e.g., compound IX (Fig. 1), showed remarkable inhibitory results against a panel of hCA isoforms [43].

On the other hand, many oxindole derivatives showed antiproliferative activity through protein kinase inhibition (e.g., compounds X–XIV). Nintedanib (XI, Ofev®) is a potent 3-alkenyl-oxindole multi-kinase inhibitor for VEGFRI/II/III, FGFRI/II/III and PDGFR α/β with IC50 of 34, 13, 13, 69, 37, 108, 59, and 65 nM, respectively [44]. It is currently in phase III clinical trials for advanced ovarian cancer treatment [45]. In the same context, Sunitinib, (XII, Sutent®), is an oxindole-based multi-tyrosine kinase inhibitor that acts on VEGFRI/II, PDGFR β and c-Kit. It was approved by the FDA in 2006 for metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST) [46,47,48,49]. Moreover, Regorafenib (XIII, Stivarga ®) is a diphenyl urea based multi-tyrosine kinase inhibitor. It was FDA approved in 2012 for patients with metastatic colorectal cancer (CRC) [50], advanced GIST [51], and hepatocellular carcinoma (HCC) [52] (Fig. 2).

Fig. 2
figure 2

Structures of representative 2-oxindol and diphenyl urea multi-kinase inhibitors acting as anticancer drugs

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In the current research, we aimed to design and synthesize novel 3-alkenyl-oxindole derivatives as potent and selective CAIs for tumor-associated hCA isoforms knowing that indolin-2-one derivatives have a potential antiproliferative activity through different mechanisms including CA inhibition [53]. Our strategy is based on merging the essential key binding features in known CA inhibitor groups (sulfonamide, sulfonamide isosteres, or biologically active heterocycles) with diverse chemical properties and 3-alkenyl oxindole nucleus using different linkers producing three new series (4a–d), (5, 7), and (9a–c, 11a–c, 13a–c and 15a–c) (Fig. 3).

Fig. 3
figure 3

Design strategy for proposed CAIs compounds (4a–d, 5, 7, 9a–c, 11a–c, 13a–c and 15a–c)

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In the first series (4a–d), the oxindole nucleus was linked through 3-alkenyl (methylene) to the aromatic ring or heterocycles containing different groups that are reported to have antiproliferative activity along with CA binding affinity. In the second series (5, 7) a simple zinc binding group (sulfamide and sulfamate) was directly attached to the 3-alkenyl oxindole scaffold. As for the third series (9a–c, 11a–c, 13a–c, 15a–c) different linkers with hydrogen bonding ability were used to link the 3-alkenyl oxindole scaffold to the ZBGs (primary and secondary sulfonamides or aminothiazole heterocycle), as an optimizing strategy for studying their effect on selectivity and antiproliferative activity (Fig. 3).

The newly synthesized 3-alkenyl oxindole compounds were evaluated for their ability to inhibit hCA isoforms (CA I, II, IX, and XII) and their antiproliferative activity against NCI-60 cancer cell lines. This is followed by studying the binding mode of the most potent compounds through molecular modeling.

Results and discussion

Chemistry

The synthetic pathways adopted for the preparation of the target 3-(methylene)-indol-2-ones are depicted in Figs. 4, 5, and 6. In Fig. 4, the synthesis was initiated by the condensation of the active methylene group of 2-oxindole 1 with DMF/DMA to afford the N-methylene intermediate 2 [54], which was reacted with different aromatic amines (3a–d) in glacial acetic acid to give the target compounds 4a–d.

Fig. 4
figure 4

Synthesis of compounds 2 and 4a–d

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Fig. 5
figure 5

Synthesis of compounds 5–7

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Fig. 6
figure 6

Synthesis of compounds 9a–c, 11a–c, 13a–c, and 15a–c

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In Fig. 5, the 3-alkenyl oxindole derivative 5 was prepared by refluxing of the intermediate compound 2 with sulfamide in 1,4 dioxane [55]. The intermediate compound 6 could be prepared by hydrolyzing the intermediate compound 2 using NaOH. When intermediate compound 6 reacted with sulfamide in refluxing 1,4 dioxane, it afforded the sulfamate isosteric derivative 7.

In Fig. 6, four different linker intermediates were prepared 8a–c, 10a–c, 12a–c, 14a–c according to the reported methods [56,57,58,59,60,61,62,63,64] using a variety of reaction conditions then refluxed with the intermediate compound 2 in acetic acid using the general synthetic pathway adopted for the synthesis of compounds 4a–d to afford the target compounds 9a–c, 11a–c, 13a–c, 15a–c (Fig. 6).

The spectral data confirmed the structures of the target 3-methylene oxindoles (4a–d, 5, 7, 9a–c, 11a–c, 13a–c, and 15a–c). IR spectra revealed the presence of bands of the carbonyl group at 1656–1691 cm−1, the amino NH and the amidic NH stretching peaks were detected between 3100 and 3404 cm−1. Compound 4c showed broad band at 2500–3250 cm−1 corresponding to the carboxylic acid group. For compounds 4a–b, 4d, 5, 7, 9a–b, 11a–b, 13a–b, 15a–b, the observed bands between 1331–1396 cm−1 and 1157–1194 cm−1 are assigned to the asymmetric and symmetric stretching modes of the sulfoxide group. The 1H NMR spectra showed protons of the 3-methylene linkage as doublet signal, around δ range 7.5–7.8 ppm and the oxindole protons appeared as four signals around 6.90, 7.00, 7.09, and 8.50 ppm. Compound 4a showed two signals of saccharin protons at δ = 7.90–7.97 and 8.15 ppm, whereas compound 4c showed a broad exchangeable signal at δ = 12.50 ppm for the carboxylic acid group. In addition, 1H NMR spectra of 11a–c revealed a broad singlet signal at δ range 3.90–4.10 ppm due to benzylic CH2 protons. 1H NMR spectra of compounds 4d, 5, 6 and compounds 15a–c showed E/Z isomers mixtures. The presence of the E isomer was proved by the coupling constant of the olefinic hydrogens J = 12.0 Hz which calculated from the down-field doublet signal of E-vicinal protons at δ 7.76–7.79, and 8.12–8.30 ppm. Similarly, the presence of the Z isomer was confirmed by the coupling constant of the olefinic hydrogens with about J = 8 Hz which was elucidated from the up-field doublets of Z-vicinal protons at δ 5.68–6.30, 6.30–6.58 ppm with signals for vicinal protons in the range, Compounds 15a–c showed signals that appeared in the range of 8.80–9.33 ppm assignable to the urea exchangeable protons, for compounds 4b, 9b, 11b, 13b, and 15b, the pyrimidine protons appeared as two signals; the first one appeared as triplet for the proton at 4 position around 7.00 ppm and the second one appeared as a doublet for the protons at 3 and 5 positions around 8.40 ppm. On the other hand, the 1H NMR spectra of compounds 9c, 11c, 13c, and 15c showed two signals of the thiazole protons at range 7.26–7.40 and 7.35–7.50 ppm.

The 13C NMR spectra also confirmed the presence of signal attributable for carbonyl group of oxindole moiety at a range of 170.10–170.38 ppm, whereas signals for the other carbonyl groups in compounds 4c and 9a–c appeared at a range of 165.30–167.30 ppm. Elucidation of the urea moiety in compounds 15a–c showed signals at a range of 152.76–163.90 ppm. The carbonyl groups adjacent to the vinylic carbon in compounds 131a–c were detected at the expected chemical shift at a range of 189.19–189.22 ppm. Moreover, characteristic signals appeared at a range of 95.22–96.65 ppm in this series confirming the presence of the ethylene group (–C=C–C=O).

In vitro biological evaluation

In vitro antiproliferative activity assay against NCI 60-cell line panel

From the newly synthesized compounds, eleven compounds (4c, 4d, 5, 9a, 9b, 11a, 11b, 13b, 13c, 15b, and 15c) were selected by the National Cancer Institute (NCI) Developmental Therapeutics Program (DTP), Bethesda, Maryland, USA for the in vitro anti-proliferative activity evaluation [65]. The selected compounds were examined at 10 μM dose against the NCI 60-cell line panel. This panel consists of nine cell line groups of leukemia, non-small cell lung carcinoma (NSCLC), melanoma, colon, CNS, ovarian, renal, prostate, and breast cancers. The results are reported as mean-graph of the percent growth relative to control and presented as percentage growth inhibition (GI%), furthermore, mean GI% of each compound over all panel cell lines was calculated (Table 1; Additional file 1; S3: In vitro biological activity).

Table 1 % Cell growth inhibition of NCI 60 cancer cell lines exhibited by investigated final compounds (4c, 4d, 5, 9a, 9b, 11a, 11b, 13b, 13c, 15b, 15c)
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Investigation of the primary GI% data revealed that some of the newly synthesized compounds have a promising antiproliferative activity. The most potent compound showing remarkable growth inhibition percent was compound 15c with mean GI% of 61.83% overall the tested cell lines. Compound 15c was a broad spectrum inhibitor for most NCI cell lines such as, Leukemic cell lines (HL-60(TB), K-562, MOLT-4, and SR) with GI% range of 57.96–89.33%, nearly all Non-small cell lung cancer with GI% ranging from 43.44 to 83.16%, colon cancer cell lines (COLO205, HCT-116, HCT-15, HT29, KM12 and SW-620) with GI% range of 40.78–82.12%, CNS cancer cell lines (SF-539, SNB-19, SNB-75, and U251) with GI% of 66.38, 69.03, 66.62, and 58.05%, respectively, melanoma cell with GI% range of 37.92–152.70%, ovarian cancer cell lines with GI% ranging from of 39.57–84.64%, renal cancer cell lines with GI% range of 32.00–120.47, %, prostate cancer cell lines (PC-3 and DU-145) with GI% of 31.40 and 59.52%, respectively, and finally, breast cancer cell lines with GI% ranging from 52.05 to 102.25%.

Moreover, compound 11b showed potent inhibitory activity against the different NCI cell lines, namely, the leukemic (K-562 and SR) cancer cell lines with GI% of 32.81 and 42.22%, respectively. the colon cancer KM12 cell line with GI% of 77.28%, melanoma cancer MDA-MB-435 cell line with GI% of 31.96%, renal cancer cell lines (CAKI-1 and UO-31) with GI% 48.43 and 39.31%, respectively, and breast cancer cell line (MCF-7) with GI% of 37.23%.

Significant activity was also observed for compounds (4c, 9a, 9b, 11a, and 13c) against various cell lines such as leukemic, non-small cell lung cancer, colon, CNS, and renal cancer with growth inhibition % ranging between 30.80–59.02%. It was observed that the presence of the methylamino linkage in compounds 11a and 11b generally increased the antiproliferative activity over their analogues containing the amido linkage (9a and 9b). Among series (4a–d), compound 4c possessing free carboxylic acid showed inhibitory activity against NSCL (HOP-62), colon (KM12), CNS (SNB-75), renal (UO-31), and breast (BT-549) cancer cell lines ranging 32.04–49.71%. The combination between enaminone linkage and amino thiazole in compound 13c improved the antiproliferative activity against leukemic (RPMI-8226), colon (KM12) and renal (CAKI-1) cancer cell lines with inhibition ranging 30.8–59.02%.

In vitro five-dose assay on selected cell lines (MCT-7, HCT-116, and DU-145)

The preliminary screening results revealed that compound 15c showed prominent antiproliferative activity against several cell lines from the different NCI subpanels. Thus, compound 15c was further evaluated at five-dose assay (0.02–200 µM) on the most sensitive cell lines that are available to our laboratory. Compound 15c showed a potent growth inhibition 50% at a single digit nanomolar concentration against breast cancer (MCT-7), and prostate cancer (DU 145) cell lines, as well as a sub-nanomolar concentration against colon cancer (HCT-116) cell line with IC50 values of 4.39, 1.059, and 0.34 nM, respectively (Table 2; Additional file 1; S3: In vitro biological activity).

Table 2 In vitro cytotoxicity towards human MCT-7 (Breast), DU-145 (Prostate), and HCT-116 (Colon) cancer cell lines, expressed as mean growth inhibitory concentration 50% (IC50) values
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Carbonic anhydrase inhibition

All the newly synthesized compounds were evaluated for their ability to inhibit the physiologically relevant cytosolic hCA isoforms, hCA I and II as well as the transmembrane tumor-associated isoforms hCA IX and XII using acetazolamide (AAZ) as a standard reference employing the stopped flow CO2 hydrase assay method and the CA inhibition data were presented in Table 3.

Table 3 Inhibition data of human CA isoforms hCA I, II, IX and XII with 3-alkenyl-oxindole derivatives 4a-d, 5, 7, 91a–c, 111a–c, 131a–c, 151a–c and the standard inhibitor Acetazolamide (AAZ) by stopped flow CO2 hydrase assay
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Regarding the inhibition of the cytosolic isoform hCA I, it was observed that the tested compounds revealed Ki values ranged between 8.4 and > 10,000 nM. Compound 4d was the most potent inhibitor in the series with Ki of 8.4 nM, whereas compounds 9a, 11a, 13a, and 15a displayed moderate activities with Ki values of 332.3, 320.8, 483.0, and 844.5 nM, respectively, compared to the used reference standard AAZ (Ki = 250 nM). Compounds 4c, 5, 7, and 11b showed weak inhibitory activity with Ki values of 6323, 6345, 6236, and 9108 nM, respectively. Whereas the rest of the compounds showed no hCA I inhibitory activity with Ki values higher than 10,000 nM. The results showed that the compounds containing N1 unsubstituted benzenesulfonamide moiety have higher inhibitory activity than that of the substituted or cyclic analogues. Furthermore, the carboxylic acid bioisostere e.g., compound 4c showed lower activity than the benzenesulfonamide derivatives. Additionally, direct attachment of the sulfamate and sulfamide moieties to the 3-alkenyl-indolin-2-one scaffold led to a significant decrease in the inhibitory effect, as can be noticed in compounds 5 and 7. The spacer diversity (amido, methyl amino, enaminone, and ureido) have no obvious effect on the inhibitory activity.

As can be seen in Table 2, the tested compounds showed nearly the same inhibitory activities, activity pattern, and SAR towards hCA II isoform as that are shown towards hCA I with Ki values ranging between 3.9 and > 10,000 nM.

Concerning the tumor-associated hCA IX inhibition results, it was found that the tested compounds exhibit Ki values ranging between 68.8 and > 10,000 nM. Compound 9a with primary sulfonamide and amido spacer showed the most potent hCA IX inhibition with Ki value of 68.8 nM and selectivity ratio of 4.83 and 4.55 over hCA I and hCA II, respectively, with the used standard (AAZ) showing Ki of 25.80 nM and selectivity ratio of 9.69 and 0.47 over hCA I and hCA II, respectively. Moreover, compound 13a showed a potent hCA IX inhibition with Ki value of 91.3 nM and selectivity ratio of 5.29 and 3.36 over hCA I and hCA II, respectively. On the other hand, despite its potent hCA IX inhibition with Ki of 84.2 nM, compound 4d showed higher selectivity towards hCA I and hCA II over hCA IX with selectivity ratios of 0.10 and 0.046, respectively. Compounds 5 and 7, with ZBGs directly attached to the 3-methylene oxindole scaffold, showed moderate inhibitory activity towards hCA IX with Ki values of 208.2 and 940.7 nM, respectively, which is lower than that of hCA I and hCA II giving selectivity ratios of 30.48 and 4.39, respectively, for compound 5, and 6.63 and 5.93, respectively, for compound 7. As for compounds 11a, 11b, and 15a (hCA IX Ki values of 217.4, 7856, and 863.3 nM, respectively), they showed the same level of activity towards physiological hCA I and/or hCA II and tumor-associated hCA IX with no sign of selectivity towards neither of them. Whereas the rest of the compounds showed no hCA IX inhibitory activity with Ki values higher than 10,000 nM.

Against the tumor-associated hCA XII, the tested compounds showed inhibition constant Ki range between 8.7 and > 10,000 nM. Compounds 5, 9a, and 11a exerted a potent inhibition towards hCA XII with Ki value of 42.4, 59.4, and 78.6 nM, respectively, showing reasonable selectivity ratios of 149.65, 5.59, and 4.08, respectively, over hCA I and of 21.54, 5.27 and 9.50, respectively, over hCA II compared to the reference compound acetazolamide with Ki of 5.7 nM and selectivity ratios of 43.86 and 2.12 over hCA I and II, respectively. As noted, the presence of the amido and (CH2–NH) linkers along with the primary sulfonamide group in compounds 9a and 11a resulted in a promising tumor-associated hCA XII inhibition profile. Compounds 7, 13a and 15a showed moderate activities with Ki values of 133, 182.7 and 175 nM, respectively, showing reasonable selectivity ratios of 46.89, 2.64, and 4.83, respectively, over hCA I and of 41.97, 1.68 and 4.36, respectively, over hCA II. Despite its potent inhibitory activity (Ki = 8.7 nM), compound 4d was less selective towards hCA XII in comparison to hCA I and II (selectivity ratios = 0.966 and 0.448, respectively). On the other hand, compound 11b showed both low potency (Ki = 8574 nM) and selectivity ratios towards hCA XII over hCA I and II (1.06 and 0.31, respectively). Whereas the rest of the compounds showed no hCA XII inhibitory activity with Ki values higher than 10,000 nM.

It could be concluded from these findings that CA inhibition activity showed less selectivity towards hCA IX which could mean that the antiproliferative action of the synthesized compounds is independent from the CA activity.

In vitro tyrosine kinase activity

Despite its weak CA inhibitory activity, compound 15c showed a remarkable antiproliferative activity against a wide range of cell lines. These results indicate that compound 15c exerts its cytotoxic activity through another mechanism of action.

The activation of multiple signaling pathways in the tumor microenvironment associated with the dysfunction of protein kinase activity specially receptor tyrosine kinases (RTKs) such as RET, Kit, VEGFR-1, VEGFR-2, FGFR1, PDGFR, BRAF, and c-Met [3, 66, 67]. These TKs play an important role in the development and progression of multiple cancers. Moreover, some of these TKs such as vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) play crucial roles in the biology of normal and tumor vasculature as well as neo-angiogenesis (angiokinases) which is vital for the survival and proliferation of tumor cells [68]. Furthermore, VEGFR is involved in many downstream pathways, such as PI3K, p38 MAPK, FAK, Src, and Akt that are sometimes overexpressed in several tumors including ovarian, renal, melanoma playing a vital role in neoplasm metastasis [69]. Therefore, inhibition of cancer angiogenesis and the blockage of multiple growth factors could be of great interest to increase the efficacy of cancer therapy.

The promising activity of compound 15c could be attributed to its kinase inhibition activity. Interestingly, this compound comprises the main pharmacophoric features reported for the multi-kinase inhibition profile as in the clinically approved multi-kinase inhibitor, sorafenib [70] (Fig. 7). Thus, the kinase inhibitory activity for compound 15c was evaluated against different protein kinases (RET, Kit, c-Met, VEGFR-1, VEGFR-2, FGFR1, PDGFR and BRAF) to validate this hypothesis.

Fig. 7
figure 7

Structural insights of compound 15c, showing the main pharmacophoric features reported for the multi-kinase inhibition activity of sorafenib and oxindole-based inhibitors

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Initial screening at a single dose of 10 μM concentration.

To test the potential kinase inhibitory activity of compound 15c, initial single dose testing was performed at 10 μM on a panel of kinases and their inhibition % were determined. The assays were performed at Thermo Fischer Scientific, USA (www.thermofischer.com/selectscreen) against RET, Kit, c-Met, VEGFR-1, VEGFR-2, FGFR1, PDGFR and BRAF using staurosporine as a reference compound (Additional file 1; S3: In vitro biological activity).

Interestingly, compound 15c showed promising activity against most of the tested kinases with a percent inhibition range of 31–74% and with a higher potency towards the tumor-associated VEGFR-2 over VEGFR-1 [71] (Table 4).

Table 4 Percent inhibition at 10 uM against RET, Kit, c-Met, VEGFR-1, VEGFR-2, FGFR1, PDGFR and BRAF achieved by compound 15c.
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Measurement of potential enzyme inhibitory activity (IC50)

The promising candidate 15c demonstrated an inhibition percentage above 70% against FGFR1, RET and VEGFR-2 kinases at 10 μM concentration that prompted us to further examine its dose-related enzymatic inhibition at five different concentrations (10 nM–100 nM–1 μM–10 μM–100 μM) to determine its IC50 values against these kinases. The 3-methylene oxindole derivative 15c displayed a potent multi-kinase inhibitory activity against FGFR1, VEGFR-2 and RET kinases with IC50 values of 1.287, 0.117 and 1.185 μM, respectively. These significant activities could be related to the combination of certain privilege scaffolds such as ureido and thiazole moieties (Table 5; Additional file 1; S3: In vitro biological activity).

Table 5 IC50 values against FGFR1, VEGFR-2 and RET achieved by the most active candidate 15c
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Molecular modeling study

Molecular docking in carbonic anhydrase isozymes (CA II, CA IX and CA XII)

The most potent compounds (4d, 5, and 7) were docked into the active site of hCA II, hCA IX and hCA XII isoforms to investigate their binding pattern. To this end, the protein structure of hCA II (PDB ID: 3HS4) [72], hCA IX (PDB ID: 5FL4) [73], and hCA XII (PDB ID: 1JD0) [74] isozymes were retrieved from the protein data bank. The Molecular docking protocol was initially validated by self-docking of the complexed inhibitor in proximity of the active site of each isozyme. The validation step showed the aptness of the used docking protocol for the intended molecular docking study as evidenced by the small RMSD values (1.460 Å, 1.095 Å, and 1.558 Å in CA II, CA IX and CA XII, respectively) and by the capability of the complexed inhibitors docking poses to regenerate all the important interactions achieved by the complexed inhibitors with the key residues in CA II, CA IX, and CA XII active sites (Zn2+, Thr199 and/or Thr200) (For further details, see Additional file 1; S2: Molecular docking study). Then, the binding pattern of compounds (4d, 5, and 7) in the active sites of the target carbonic anhydrase isozymes was investigated using the validated molecular docking protocol.

The molecular docking study indicated that the binding pattern of the tested compounds with the three CA isoforms involves the sulfamoyl moiety fitting in the active site via the coordination with the Zn2+ cation and H-bond with the main residues Thr199 and/or Thr200. Moreover, the thiadizole ring in compound 4d and the indolinone ring in compounds 5 and 7 are engaged in hydrophobic interactions with the hydrophobic side chains of the residues Val121 in the three isozymes, Leu198 in CA II and CA XII, and Leu199, and Pro203 in CA IX (Fig. 8 and for further details see Additional file 1; S2: Molecular docking study). In compound 4d, the distal indolinone ring interacting further through hydrophobic interactions with the side chains of the residues Ile91 and Phe131, Val130 and Val134, and Ala131in CA II, CA IX, and CA XII, respectively, (Fig. 8) what rationalizing its superior inhibitory activity as indicating by its experimental results (Table 2) and docking scores in comparison to the used reference standard AAZ (Table 6). As can be noticed in Fig. 8 and Additional file 1, the NH−–Zn2+ distances are in the range of 2.23–2.41 Å which is slightly higher than that of the crystal structures (1.94–2.07 Å) which could be attributed to the nature of the performed rigid-protein docking which tries to fit the whole molecule in the rigid active site on the expense of the pivotal Zn2+ coordinate bond geometry which is the most relevant to the CA enzyme inhibition.

Fig. 8
figure 8

2D interaction diagrams and 3D representations showing compound 4d docking pose interactions with the key amino acids in the CA II (A), CA IX (B), and CA XII (C) active sites. (Distances in Å)

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Table 6 Docking energy scores (S) in kcal/mol for compounds 4d, 5, and 7 and the reference AAZ in CA II, CA IX and CA XII active sites
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Molecular docking in the protein kinases (VEGFR-2, FGFR1 and RET)

Molecular docking simulations were also carried out to study the binding mode of compound 15c in the active site of the kinases VEGFR-2, FGFR1, and RET and to rationalize its inhibitory activity.

The diaryl urea structure of compound 15c proposes its probable type II-like PTK inhibitory binding mode which involves the occupation of the hinge region, the gate area, and the extension further than the gatekeeper into the allosteric back pocket at the kinase domain. So, in the present simulations, the used VEGFR-2 (PDB ID: 4ASD [75]) and FGFR-1 (PDB ID:4V01 [76]) protein structures are in complex with a type II PTK inhibitor, sorafenib and ponatinib, respectively, adapting a DFG-out conformation with the three key binding regions open and set for binding. As for RET kinase, a DFG-out conformation bound to a type II kinase inhibitor (sorafenib) was constructed using PDB ID: 6NEC [77] (vide infra in the experimental).

Initially, docking protocol was validated by performing self-docking of the complexed kinase inhibitors in the proximity of the VEGFR-2, RET, and FGFR-1 kinase domain. The self-docking validation step regenerated the interaction pattern of the complexed inhibitors accurately indicating that the adopted docking setup is appropriate for the proposed docking study. This is shown by the low RMSD between the complexed inhibitors and their docking poses (0.470 Å, 0.398 Å, and 0.331 Å in PDB IDs 4ASD, 4V01, and 6NEC, respectively). Moreover, by the capability of the resulted poses to regenerate all the main interactions achieved by the complexed inhibitors with the key residues at the kinase domain; Glu885, Cys919 and Asp1046 (in VEGFR-2), Glu531, Ala564 and Asp641 (in FGFR1), and Glu775, Ala807 and Asp892 (in RET) kinases (Table 7) and (Additional file 1; S2: Molecular docking study; Figures S1–S3).

Table 7 Docking energy scores (S) in kcal/mol for compound 15c and the co-crystalized ligands in VEGFR-2, FGFR1 and RET active sites
Full size table

Compound 15c showed a comparable binding mode in the three target kinases that agrees with that of type II kinase inhibitors (Fig. 9). In the central gate area, the phenyl uriedo moiety interacts through cation-π and hydrophobic interactions by their phenyl moiety with the side chains of the gate area amino acids Val848, Val916, Cys1045 and Lys868 in VEGFR-2, Ile545, Val561, Ala640 and Lys514 in FGFR-1, and Ile788, Val804, Leu881, and Lys758 in RET and through hydrogen bonding by their urea moiety with Asp1046, Asp641, and Asp892 of the conserved DFG motif in VEGFR-2, FGFR-1, and RET, respectively, and with the side chain carboxylate of Glu885, Glu531, and Glu775 of the αC helix in VEGFR-2, FGFR-1, and RET, respectively. This binding mode directs from one side the indolinone moiety towards the front pocket (hinge region) interacting through hydrogen bonding with Cys919, Ala564, and Ala807 in VEGFR-2, FGFR-1, and RET, respectively, and through hydrophobic interaction with the hydrophobic side chains of the amino acids Leu840, Phe918, Cys919, Leu1035 and Phe1047 in VEGFR-2, Leu484, Val492, Ala564, Leu630 and Phe642 in FGFR-1, and Leu730, Val738, Ala756, and Ala807 in RET. On the other side, it directs the thiazole moiety towards the allosteric back pocket interacting through hydrophobic interaction with the hydrophobic side chains of its lining residues Ile888, Leu889, Ile892, Val898, Val899, Leu1019 and Ile1044 in VEGFR-2, Met534, Met535, Ile538, Ile544, Leu614, Cys619 and Ile639 in FGFR-1, and Val778, Leu779, Val782, Ile890, and Phe893 in RET kinases (Fig. 9).

Fig. 9
figure 9

2D interaction diagrams and 3D representations showing compound 15c docking pose interactions with the key amino acids in the VEGFR-2 (A), FGFR1 (B), and RET (C) active sites. (Distances in Å)

Full size image

Conclusion

To target carbonic anhydrase as antiproliferative therapy, diverse molecular structure modifications on 3-alkenyl indolin-2-one scaffold were designed with consideration of keeping the essential pharmacophoric features for carbonic anhydrase inhibition. Optimization strategies such as bio-isosteric replacement (4b-d, 5 and 7), ring fusion (4a) and extension (91a–c, 111a–c, 131a–c and 151a–c) were adopted.

The newly designed series 3-alkenyl indolin-2-one were synthesized and evaluated for their in vitro carbonic anhydrase inhibitory activity on hCA isoforms I, II, IX and XII as well as anti-proliferative activity against NCI sixty cell lines panel.

Compound 15c showed no carbonic anhydrase inhibitory activity, however, it showed distinct potent and broad antiproliferative activity with mean growth inhibition 61.83% and with IC50 values of 4.39, 1.06, and 0.34 nM, respectively against MCT-7, DU 145, and HCT-116 cell lines. The activity was then explained through other suggested mechanisms from literature and from getting more insight into the pharmacophoric features affecting its antiproliferative activity.

Compound 15c was evaluated against eight tyrosine kinases (RET, Kit, c-Met, VEGFR-1, VEGFR-2, FGFR, PDGFR and BRAF) to explore its potential multi-kinase targeting efficacy towards the whole cascade of tumorigenesis. The newly synthesized 3-alkenyl indolin-2-one derivative bearing aryl and thiazole urea tail via an NH linker showed the most active inhibition activity against FGFR, VEGFR-2 and RET kinases showing IC50 values of 1.28, 0.117 and 1.18 μM, respectively. These results were studied further using molecular docking studies, which demonstrated the capability of compound 15c to achieve the essential interactions, known to be crucial for the inhibition of FGFR, VEGFR-2 and RET kinases with additional H bond and hydrophobic interactions.

In conclusion, compound 15c could be a promising multi-kinase inhibitory agent and this clearly justifies its potent efficacy towards different cancer cell lines.

Experimental

Chemistry

General remarks

Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification. All the reactions were monitored by thin layer chromatography silica gel F 254, Aluminum sheets 20 × 20 cm (Sigma-Aldrich) were used. Dichloromethane: methanol (1: 0.1) was the adopted elution system. Compounds 2 [54], 3a [78, 79], 3d [80], 5, 6 [81], 8(1a–c), 10(1a–c), 12(1a–c) and 14(1a–c) [56,57,58,59,60,61,62,63,64] were synthesized according to reported procedures. Further general remarks related to the chemistry experimental are reported in the Additional file 1; S1: spectral data.

General procedure for preparation of target compounds (4a–d)

The appropriate amine (3a-–) (2.67 mmol) was added to a solution of (2) (2.67 mmol, 0.5 g) in acetic acid (5 mL) and the reaction mixture was heated under reflux for 12 h, the acetic acid was evaporated under vacuum and the residue was washed with diethyl ether, recrystallized from EtOAc and hexane.

3-{[(1,1-Dioxidobenzo[d]isothiazol-3-yl)amino]methylene}indolin-2-one (4a)

Yield 90%, mp 195–199 °C. IR (KBr, ύ cm−1): 3150–3383 (2NH), 3083 (CH aromatic), 1691 (CO), 1606 (NH bending), 1550 (C=C aromatic), 1159, 1361 (SO2); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.92 (d, 1H, oxindole-H7, J = 7.6 Hz), 6.99 (t, 1H, oxindole-H5, J = 8.4 Hz), 7.19 (t, 1H, oxindole-H6, J = 7.6 Hz), 7.82 (d, 1H, –C=CH–, J = 7.2 Hz), 7.9–7.97 (m, 3H, saccharine-H5,H6,H7), 8.15 (d, 1H, saccharine-H4, J = 7.2 Hz), 8.52 (brs, 1H, oxindole-H4), 11.07 (s, 1H, oxindole–NH, D2O exchangeable), 12.2 (s, 1H, –C=CH–NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 110.6, 112.8, 121.5, 122.2, 122.6, 123.6, 128.4, 131.1, 133.5, 134.00, 134.4, 140.3, 141.9, 142.7, 161.3, 170.7; MS: (Mwt.: 325.34): m/z (% rel. Int.), 325.40 (M+, 5.95%), 326.22 (M+ + 1, 4.93%), 144.23 (100%); Anal. Calcd. for C16H11N3O3S: C, 59.07; H, 3.41; N, 12.92; S, 9.85; Found: C, 59.24; H, 3.67; N, 13.09; S, 9.97.

4-{[(2-Oxoindolin-3-ylidene)methyl]amino}-N-(pyrimidin-2-yl)benzenesulfonamide (4b)

Yield 83%, m.p 238–240 °C. IR (KBr, ύ cm−1): 3151–3366 (3NH), 3055 (CH aromatic), 1671 (CO), 1618 (NH bending), 1521–1575 (C=C aromatic), 1177, 1371 (SO2); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.83 (d, 1H, oxindole-H7, J = 8 Hz), 6.9 (t, 1H, oxindole-H5, J = 8 Hz), 6.98–7.09 (m, 2H, oxindole-H6, pyrimidine-H5), 7.5 (d, 2H, Ar–H, J = 8.4 Hz), 7.57 (d, 1H, –C=CH–, J = 8.4 Hz), 7.91 (d, 2H, Ar–H, J = 8.8 Hz), 8.45 (dd, 2H, pyrimidine-H2, H4, J = 8.8 Hz), 8.56 (d, 1H, oxindole-H4, J = 12 Hz), 10.55 (s, 1H, oxindole-NH, D2O exchangeable), 10.8 (d, 1H, –C=CH–NH, D2O exchangeable, J = 12 Hz), 11.5 (sbr, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 102.4, 109.80, 115.7, 118.0, 121.0, 124.1, 125.3, 129.9, 130.0, 130.2, 133.9, 136.9, 144.20, 153.4, 157.5, 158.7, 170.2; MS: (Mwt.: 393.42): m/z (% rel. Int.), 393.55 (M+, 3.48%), 394.75 (M+ + 1, 3.44%), 45.26 (100%); Anal. Calcd. for C19H15N5O3S: C, 58.01; H, 3.84; N, 17.80; S, 8.15; Found: C, 58.21; H, 4.06; N, 17.98; S, 8.27.

4-{[(2-Oxoindolin-3-ylidene)methyl]amino}benzoic acid (4c)

Yield 92%, m.p > 300 °C, IR (KBr, ύ cm−1): 2500–3300 broad band (COOH, 2NH), 1569, 1667 (2CO); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.86 (d, 1H, oxindole-H7, J = 8 Hz), 6.93 (t, 1H, oxindole-H5, J = 8 Hz), 7.03 (t, 1H, oxindole-H6, J = 8 Hz), 7.46 (d, 2H, Ar–H, J = 8 Hz), 7.62 (d, 1H, –C=CH–, J = 8 Hz), 7.93 (d, 2H, Ar–H, J = 8 Hz), 8.63 (d, 1H, oxindole-H4, J = 12 Hz), 10.58 (s, 1H, oxindole-NH, D2O exchangeable), 10.85 (d, 1H, –C=CH–NH, D2O exchangeable, J = 12 Hz), 12.53 (s, 1H, –COOH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 102.0, 109.8, 115.7, 116.4, 118.0, 121.0, 124.3, 125.2, 131.5, 137.1, 137.9, 144.2, 167.3, 170.3; MS: (Mwt.: 280.28): m/z (% rel. Int.), 280.34 (M+, 20.34%), 381.35 (M+ + 1, 3.81%), 144.25 (100%); Anal. Calcd. for C16H12N2O3: C, 68.56; H, 4.32; N, 9.99; Found: C, 68.34; H, 4.50; N, 10.21.

5-{[(2-Oxoindolin-3-ylidene)methyl]amino}-1,3,4-thiadiazole-2-sulfonamide (4d)

Yield 66%, mp 210–216 °C, Z/E mixture 3:1. IR (KBr, ύ cm−1): 3144, 3270, 3381 (2NH, NH2), 3050 (CH aromatic), 1680 (CO), 1615 (NH bending), 1529 (C=C aromatic), 1170, 1336 (SO2); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.85–6.89, 7.59–7.61 (m, 1H, oxindole-H7), 6.93–6.98, 7.63–7.65 (m, 1H, oxindole-H5, J = 7.2 Hz), 7.1–7.18, 7.71–7.74 (m, 1H, oxindole-H6), 8.06–8.1, 8.23 (m, 1H, –C=CH–), 8.34–8.43 (m, 2H, SO2NH2, D2O exchangeable), 8.66 (brs, 1H, oxindole-H4), 10.44 (s, 1H, NH, D2O exchangeable), 10.68 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 106.8, 108.0, 109.7, 119.1, 121.2, 127.1, 132.9, 139.4, 166.6, 169.2, 172.1; MS: (Mwt.: 323.35): m/z (% rel. Int.), 323.85 (M+, 3.47%), 144.27 (100%); Anal. Calcd. for C11H9N5O3S2: C, 40.86; H, 2.81; N, 21.66; S, 19.83; Found: C, 40.08; H, 2.94; N, 21.88; S, 19.75.

3-(sulfamidmethylene)indoline-2-one (5)

A mixture of (2) (4.15 mmol, 0.78 g) and sulfamide (26 mmol, 2.4 g) in 1,4-dioxane was heated to reflux for 4 h. Then, the reaction was cooled and diluted with water, extracted with chloroform, dried over MgSO4 and evaporated under vacuo, the residue was recrystallized from n-butanol to give compound (5).

Yield 40%, m.p: 158–160 °C, Z/E mixture 1:1. IR (KBr, ύ cm−1): 3116–3250 broad band (NH, NH2), 3051 (CH aromatic), 1684 (CO), 1677 (NH bending), 1514 (C=C aromatic), 1178, 1374 (SO2)); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.87–6.97 (m, 2H, oxindole-H7, H5), 7.08–7.16 (m, 1H, oxindole-H6), 7.39–7.46 (m, 2H, –NHSO2NH2, D2O exchangeable), 7.61, 7.69 (2d, 1H, –C=CH–, J = 8.4 Hz), 7.77, 8.04 (2s, 1H, NH2SO2NH-, D2O exchangeable), 8.19, 8.46 (brs, s, 1H, oxindole-H4), 10.4, 10.56 (2s, 1H, oxindole-NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 112.6, 114.30, 118.6, 129.3, 130.9, 132.5, 143.4, 158.7, 169.4; MS: (Mwt.: 239.25): m/z (% rel. Int.), 239.58 (M+, 8.02%), 144.28 (100%); Anal. Calcd. for C9H9N3O3S: C, 45.18; H, 3.79; N, 17.56; S, 13.40; Found: C, 45.43; H, 3.88; N, 17.82; S, 13.51.

(2-Oxoindolin-3-ylidene)methyl sulfamate (7)

Mixture of (0.1 mol, 16.1 mg) of (6) and (0.25 mol, 24 mg) of sulfamide in 1,4-dioxane was heated with stirring in an oil bath at 130 °C for 1 h, then excess of (0.25 mol, 24 mg) sulfamide was added, heating was continued at 130 °C for 0.5 h, and then the temperature was raised slowly to 180 °C. After heating for additional 3 h with stirring, the mixture was allowed to cool and was stirred with a mixture of 150 ml of water and 150 ml of methylene chloride. The organic layer was separated, and the solvent was removed, the residue was recrystallized from methanol giving compound 7.

Yield 60%, m.p: 165–170 °C, Z/E mixture 2:1. IR (KBr, ύ cm−1): 3133–3333 broad band (NH, NH2), 3063 (CH aromatic), 1669 (CO), 1615 (NH bending), 1517 (C=C aromatic), 1192, 1328 (SO2 of sulfamate); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.17, 6.40 (2s, 1H, –C=CH–), 6.87–6.94 (m, 2H, oxindole-H7,H5), 7.06–7.32 (m, 3H, oxindole-H6, NH2, D2O exchangeable), 8.59, 9.07 (2s, 1H, oxindole-H4), 10.15–10.73 (s, 1H, oxindole-NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 112.6, 115.7, 118.3, 123.2, 125.1, 138.3, 146.2, 159.8, 170.2; MS: (Mwt.: 393.42): m/z (% rel. Int.), 240.23 (M+, 16.51%), 105.29 (100%); Anal. Calcd. for C9H8N2O4S: C, 45.00; H, 3.36; N, 11.66; S, 13.35; Found: C, 45.28; H, 3.47; N, 11.92; S, 13.29.

General procedure for preparation of target compounds (91a–c, 111a–c, 131a–c and 151a–c)

The appropriate amine (81a–c, 121a–c, 141a–c and 161a–c) (0.39 mmol) was added to a solution of (2) (2.65 mmol, 0.5 g) in acetic acid (3 mL) and the reaction mixture was heated under reflux for 4 h., then the acetic acid was evaporated under vacuum, the residue was washed three times 3 × 10 ml with diethyl ether to furnish compounds (91a–c and 151a–c). compounds (111a–c) recrystallized from ethanol/1,4-dioxane. Compounds (131a–c) purified by thin layer plate chromatography using (CH2Cl2: methanol 9:1) as eluent to afford the pure desired compounds.

4-{[(2-Oxoindolin-3-ylidene)methyl]amino}-N-(4-sulfamoylphenyl)benzamide (9a)

Yield 89%, mp > 300 °C. IR (KBr, ύ cm−1): 3266, 3359 (NH, NH2), 3083 (CH aromatic), 1686, (CO), 1591 (NH bending), 1516 (C=C aromatic), 1182, 1396 (SO2); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.86 (d, 1H, oxindole-H7, J = 11.2 Hz), 6.95 (t, 1H, oxindole-H5, J = 8.4 Hz), 7.04 (t, 1H, oxindole-H6, J = 8.4 Hz), 7.28 (s, 2H, SO2NH2, D2O exchangeable), 7.55 (d, 2H, benzenesulfonamide-H3, H5, J = 8.8 Hz), 7.64 (d, 1H, –C=CH–, J = 3.6 Hz), 7.8 (d, 2H, benzenesulfonamide-H2, H6, J = 8.8 Hz), 7.96 (d, 2H, Ar–H, J = 9.6 Hz), 8.03 (d, 2H, Ar–H, J = 9.6 Hz), 8.67 (d, 1H, oxindole-H4, J = 10.4 Hz), 10.45 (s, 1H, oxindole-NH, D2O exchangeable), 10.57 (s, 1H, NH, D2O exchangeable), 10.86 (d, 1H, –C=CH–NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 101.8, 109.8, 115.6, 120.2, 121.0, 124.3, 125.4, 126.9, 128.5, 130.1, 133.5, 137.3, 137.9, 139.0, 142.7, 143.9, 165.3, 170.3; Anal. Calcd. for C22H18N4O4S: C, 60.82; H, 4.18; N, 12.90; S, 7.38; Found: C, 60.71; H, 4.34; N, 13.09; S, 7.45.

4-{[(2-Oxoindolin-3-ylidene)methyl]amino}-N-{4-[N-(pyrimidin-2-yl)sulfamoyl]phenyl}benzamide (9b)

Yield 81%, m.p > 300 °C. IR (KBr, ύ cm−1): 3263–3382 broad band (4NH), 3081 (CH aromatic), 1704, 1760 (2CO), 1514–1578 (C=C aromatic), 1187, 1379 (SO2); 1H. NMR (DMSO-d6, 400 MHz) δ ppm: 6.86 (d, 1H, oxindole-H7, J = 8 Hz), 6.94 (t, 1H, oxindole-H5, J = 8 Hz), 7.04 (m, 2H, oxindole-H6, pyrimidine-H5), 7.54 (d, 2H, benzenesulfonamide-H3,5, J = 8 Hz), 7.63 (d, 1H, –C=CH–, J = 8 Hz), 7.98–8.01 (m, 4H, Ar–H), 8.02 (d, 2H, benzenesulfonamide-H2,6, J = 7.6 Hz), 8.51 (d, 2H, pyrimidine-H4,6, J = 4 Hz), 8.64 (d, 1H, oxindole-H4, J = 16 Hz), 10.47 (s, 1H, NH, D2O exchangeable), 10.57 (s, 1H, oxindole-NH, D2O exchangeable), 10.84 (d, 1H, C=CH–NH, D2Oexchangeable), 11.8 (s, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 101.9, 109.8, 115.6, 116.2, 118.0, 120.00, 121.0, 124.3, 125.1, 128.4, 129.1, 130.20, 134.7, 137.2, 137.90, 143.6, 157.4, 158.8, 165.6, 170.3, 172.5; MS: (Mwt.: 512.54): m/z (% rel. Int.), 512.27 (M+, 1.85%), 513.39 (M+ + 1, 7.12%), 514.30 (M+ + 2, 4.93%), 144.30 (100%); Anal. Calcd. for C26H120N6O4S: C, 60.93; H, 3.93; N, 16.40; S, 6.26; Found: C, 60.75; H, 4.09; N, 16.67; S, 6.40.

4-{[(2-Oxoindolin-3-ylidene)methyl]amino}-N-(thiazol-2-yl)benzamide (9c)

Yield 85%, mp > 300 °C. IR: (KBr, ύ cm−1): 3166–3359 (3NH), 1656 (CO), 1527 (C=C aromatic); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.86 (d, 1H, oxindole-H7 of, J = 8 Hz), 6.97 (t, 1H, oxindole-H5, J = 8 Hz), 7.04 (t, 1H, oxindole-H6, J = 8 Hz), 7.26 (d, 1H, thiazole-H5), 7.35 (m, 3H, Ar–H, thiazole-H4), 7.63 (d, 1H, –C=CH–, J = 8 Hz), 8.14 (d, 2H, Ar–H, J = 8 Hz),), 8.67 (d, 1H, oxindole-H4, J = 12 Hz), 10.58 (s, 1H, oxindole-NH, D2O exchangeable), 10.84 (d, 1H, –C=CH–NH, D2O exchangeable), 12.49 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 102.1, 107.8, 109.7, 114.1, 115.7, 118.0, 121.0, 124.3, 125.2, 126.2, 130.4, 137.1, 137.9, 144.10, 164.4, 166.4, 170.3; MS: (Mwt.: 362.41): m/z (% rel. Int.), 362.49 (M+, 19.50%), 102.24 (100%); Anal. Calcd. for C19H114N4O2S: C, 62.97; H, 3.89; N, 15.46; S, 8.85; Found C, 61.15; H, 4.05; N, 15.70; S, 8.91.

4-{[4-({[2-Oxoindolin-3-ylidene]methyl}amino)benzyl] amino}benzenesulfonamide (11a)

Yield 65%, mp: 195–200 °C. IR: (KBr, ύ cm−1): 3116–3400 broad band (3NH, NH2), 3063 (CH aromatic), 1668 (CO), 1593 (NH bending), 1518 (C=C aromatic); 1H NMR (DMSO-d6, 400 MHz)) δ ppm: 3.9 (brs, 2H, –CH2), 6.86 (d, 1H, oxindole-H7, J = 8 Hz), 6.95 (t, 1H oxindole-H5, J = 8 Hz), 7.04 (t, 1H, oxindole-H6, J = 8 Hz), 7.27–7.35 (m, 6H, Ar–H, SO2NH2, D2O exchangeable), 7.56 (d, 2H, Ar–H, J = 8 Hz), 7.62 (d, 1H, –C=CH–, J = 8 Hz), 7.75–7.81 (m, 2H, Ar–H), 8.56 (brs, 1H, oxindole-H4), 10.3 (s, 1H, oxindole-NH, D2O exchangeable), 10.51 (s, 1H, NH, D2O exchangeable), 10.61 (s, 1H, NH, D2O exchangeable)); MS: (Mwt.: 420.49): m/z (% rel. Int.), 420.14 (M+, 16.51%), 261.43 (100%); Anal. Calcd. for C22H120N4O3S: C, 62.84; H, 4.79; N, 13.32; S, 7.62; Found C, 63.09; H, 4.86; N, 13.58; S, 7.74.

4-{[4-({[2-Oxoindolin-3-ylidene]methyl}amino)benzyl]amino}-N-(pyrimidin-2-yl)benzenesulfonamide (11b)

Yield 60%, mp: 168–171 °C. IR: (KBr, ύ cm−1): 3154–3333 broad band (4NH), 1588 (NH bending), 1667 (CO), 1518 (C=C aromatic), 1186, 1369 (SO2); 1H NMR (DMSO-d6, 400 MHz)) δ ppm: 3.93 (m, 2H, –CH2), 6.86 (d, 1 H, oxindole-H7, J = 8 Hz), 6.9–7.03 (m, 3H, oxindole-H5,H6, pyrimidine-H5), 7.23–7.4 (m, 4H, Ar–H), 7.53–7.64 (m, 3H, Ar–H, –C=CH–), 7.9 (d, 2H, Ar–H, J = 10 Hz), 8.53–8.69 (m, 3H, oxindole-H4, pyrimidine-H3,H5), 10.14 (s, 1H, NH, D2O exchangeable), 10.46 (s, 1H, oxindole-NH, D2O exchangeable), 10.58 (d, 1H, –C=CH–NH, D2O exchangeable). 10.87 (s, 1H, SO2NH, D2O exchangeable); %); Anal. Calcd. for C26H122N6O3S: C, 62.64; H, 4.45; N, 16.86; S, 6.43; Found: C, 62.85; H, 4.61; N, 17.09; S, 6.03.

3-{[(4-((Thiazol-2-ylamino)methyl)phenyl)amino]methylene}indolin-2-one (11c)

Yield 77%, mp: 150–153 °C. IR: (KBr, ύ cm−1): 3119–3232 broad band (3NH), 3082 (CH aromatic), 1671 (CO), 1592 (NH bending), 1521 (C=C aromatic); 1H NMR (DMSO-d6, 400 MHz)) δ ppm: 4.1 (s, 2H, –CH2), 6.86–7.09 (m, 3H, oxindole-H5, H6, H7), 7.35–7.39 (m, 2H, thiazole-H5, H4), 7.57 (d, 2H, Ar–H, J = 8 Hz), 7.63 (d, 1H, –C=CH–, J = 6.8 Hz), 7.89 (d, 2H, Ar–H, J = 10.8 Hz), 8.66 (d, 1H, oxindole-H4, J = 12 Hz), 10.4 ((s, 1H, oxindole-NH, D2O exchangeable), 10.58 (s, 1H, NH, D2O exchangeable), 10.9 (d, 1H, –C=CH–NH, D2O exchangeable, J = 10.8 Hz), MS: (Mwt.: 348.42): m/z (% rel. Int.), 348.34 (M+, 9.91%), 64.37 (100%); Anal. Calcd. for C19H116N4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20; Found: C, 65.28; H, 4.74; N, 18.31; S, 9.03.

4-{[-3-Oxo-3-(4-{[(-2-oxoindolin-3-ylidene)methyl]amino}phenyl)prop-1-en-1-yl]amino}benzenesulfonamide (13a)

Yield 73%, mp: 275–278 °C, Z/E mixture 1:1. IR (KBr, ύ cm−1): 3216–3363 broad band (3NH, NH2), 3083 (CH aromatic), 1643, 1677 (2CO), 1589 (NH bending), 1183, 1370 (SO2); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.27, 6.58 (2d, 1 H, –CH=CH–NH, J = 8, 12 Hz), 6.87 (d, 1H, oxindole-H7, J = 8 Hz), 6.95 (t, 1H, oxindole-H5, J = 8 Hz), 7.05 (t, 1H, oxindole-H6, J = 8 Hz), 7.27–7.33 (m, 3H, Ar–H, SO2NH2, D2O exchangeable), 7.51 (d, 2H, Ar–H, J = 8 Hz), 7.64 (d, 1H, –C=CH–, J = 8 Hz), 7.76–7.78, 8.16 (m, 3 H, Ar–H, –CH=CH–NH), 7.92–7.99 (m, 2H, Ar–H), 8.03 (d, 1H, Ar–H, J = 8 Hz), 8.69 (brs, 1H, oxindole-H4), 10.36, 12.07 (2d, 1 H, –CO–CH=CH–NH, D2O exchangeable, J = 12 Hz), 10.61 (s, 1H, NH, D2O exchangeable), 10.89 (s, 1H, –C=CH–NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 95.2, 99.8 (–CO–CH=CH), 102.0, 109.8, 115.3, 116.2, 118.0, 121.0, 124.3, 127.1, 127.9, 129.8, 137.1, 137.8, 138.4, 143.20, 143.4, 143.7, 144.4, 170.3 (CO of oxindole), 186.5, 189.0 (–CO–CH=CH); MS: (Mwt.: 460.51): m/z (% rel. Int.), 460.86 (M+, 10.18%), 235.27 (100%); Anal. Calcd. for C24H120N4O4S: C, 62.60; H, 4.38; N, 12.17; S, 6.96; Found: C, 62.47; H, 4.54; N, 12.49; S, 6.85.

4-{[3-Oxo-3-(4-{[(2-oxoindolin-3-ylidene)methyl]amino}phenyl)prop-1-en-1-yl]amino}-N-(pyrimidin-2-yl)benzenesulfonamide (13b)

Yield 70%, mp: 290–294 °C, Z/E mixture 1:1. IR (KBr, ύ cm−1): 3000–3375 broad band (4NH), 2313 (N–CH), 1600, 1668 (2CO), 1573 (NH bending), 1157, 1340 (SO2); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.27, 6.58 (2d, 1 H, –CH=CH–NH, J = 8, 12 Hz), 6.87 (d, 1H, oxindole-H7, J = 8 Hz), 6.95 (t, 1H, oxindole-H5, J = 8 Hz), 7.04 (t, 2H, oxindole-H6, pyrimidin-H5), 7.29 (d, 1H, Ar–H, J = 8 Hz), 7.51 (d, 2H, Ar–H, J = 8 Hz), 7.64 (d, 1H, –C=CH–, J = 8 Hz), 7.78–7.95, 8.12 (m, t, 5 H, Ar–H, –CH=CH–NH, J = 12 Hz), 8.03 (d, 1H, Ar–H, J = 8 Hz), 8.52 (d, 2H, pyrimidine-H2,4, J = 8 Hz), 8.68 (d, 1H, oxindole-H4, J = 12 Hz), 10.39, 12.05 (2d, 1 H, –CO–CH=CH–NH, D2O exchangeable, J = 12 Hz), 10.61 (s, 1H, oxindole-NH, D2O exchangeable), 10.87–10.91 (m, 1H, –C=CH–NH, D2O exchangeable), 11.75 (s, 1H, SO2NH, D2O exchangeable; 13C NMR (DMSO-d6) δ: 95.65, 100.42 (–CO–CH=CH, cis and trans conformers), 101.9, 109.80, 115.1, 115.8, 118.0, 121.0, 124.3, 129.8, 130.0, 130.2, 133.7, 137.2, 137.9, 142.8, 143.80, 144.3, 145.5, 148.4, 157.4, 158.8, 170.3, (CO of oxindole), 186.5, 189.2 (–CO–CH=CH, cis and trans conformers); MS: (Mwt.: 538.58): m/z (% rel. Int.), 538.53 (M+, 6.47%), 185.30 (100%); Anal. Calcd. for C28H122N6O4S: C, 62.44; H, 4.12; N, 15.60; S, 5.95; Found: C, 62.31; H, 4.29; N, 15.87; S, 6.03.

3-{[(4-{3-[Thiazol-2-ylamino]acryloyl}phenyl)amino]methylene}indolin-2-one (13c)

Yield 73%, mp: 260–262 °C, Z/E mixture 1:1 1H NMR (DMSO-d6, 400 MHz) δ ppm: 5.68, 6.3, 6.55, 6.69 (4d, 1 H, –CO–CH=CH–NH, J = 4 Hz), 6.88 (d, 1H, oxindole-H7, J = 8 Hz), 6.94–7.01 (m, 1H, oxindole-H5), 7.03–7.07 (m, 1H, oxindole-H6), 7.4 (brs, 1H, thiazole-H5), 7.51 (d, 1H, thiazole-H4, J = 8 Hz), 7.61–7.66 (m, 2H, Ar–H), 7.69 (d, 1H, –C=CH–, J = 8 Hz), 7.79–7.88, 8.38 (m, brs, 2H, –CO–CH=CH–NH, Ar–H), 7.97 (d, 1H, Ar–H, J = 8 Hz), 8.64 (d, 1H, oxindole-H4, J = 12 Hz), 10.55, 10.69 (2s, 1H, oxindole-NH, D2O exchangeable), 10.63, 11.00 (s, d, 1H, –CO–CH=CH–NH, D2O exchangeable, J = 12 Hz), 10.81–10.9 (m, 1H, –C=CH–NH, D2O exchangeable); MS: (Mwt.: 388.45): m/z (% rel. Int.), 388.31 (M+, 12.46%), 317.94 (100%); Anal. Calcd. for C21H16N4O2S: C, 64.93; H, 4.15; N, 14.42; S, 8.25; Found: C, 65.19; H, 4.28; N, 14.7; S, 8.33.

4-{3-[4-({[2-Oxoindolin-3-ylidene]methyl}amino)phenyl]ureido}benzenesulfonamide (15a)

Yield 73%, m.p: 270–275 °C, IR (KBr, ύ cm−1): 1162, 1369 (SO2), 1604, 1653 (2CO), 3249–3373 broad band (5NH); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.84 (d, 1H, oxindole-H7), 6.9–7.0 (m, 2H, oxindole-H5, H6), 7.21 (s, 2H, SO2NH2, D2O exchangeable), 7.34 (d, 2H, Ar–H), 7.48 (d, 2H, Ar–H), 7.57 (d, 1H, –C=CH–), 7.61 (d, 2H, Ar–H), 7.72 (d, 2H, Ar–H,), 8.52 (m, 1H, oxindole-H4), 8.78 (s, 1H, NHCONH, D2O exchangeable), 9.06 (s, 1H, NHCONH, D2O exchangeable), 10.46 (s, 1H, oxindole-NH, D2O exchangeable), 10.71 (d, 1H, –C=CH–NH, D2O exchangeable, J = 11.2 Hz); 13C NMR (DMSO-d6) δ: 99.38, 109.57, 116.98, 117.27, 117.92, 120.34, 120.76, 124.09, 124.80, 124.84, 127.30, 135.40, 137.22, 137.47, 138.69, 143.37, 152.77, 170.34; MS: (Mwt.: 527.56): m/z (% rel. Int.), 527.40 (M+, 25.17%), 144.23 (100%); Anal. Calcd. for C22H119N5O4S: C, 58.79; H, 4.26; N, 15.58; S, 7.13; Found: C, 59.06; H, 4.38; N, 15.84; S, 7.21.

4-{3-[4-({[2-Oxoindolin-3-ylidene]methyl}amino)phenyl]ureido}-N-(pyrimidin-2-yl)benzenesulfonamide (15b)

Yield 68%, mp > 300 °C; IR (KBr, ύ cm−1): 1182, 1331 (SO2), 1671, 1708 (2CO), 3074 (CH aromatic), 3192, 3251, 3294, 3378, 3404 (5NH); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.84 (d, 1H, oxindole-H7, J = 8 Hz), 6.90 (t, 1H, oxindole H-5), 6.98 (t, 1H, oxindole-H6), 7.03 (t, 1H, pyrimidin-H5), 7.34 (d, 2H, Ar–H), 7.45 (d, 2H, Ar–H), 7.55 (d, 1H, –C=CH–), 7.62 (d, 2H, Ar–H), 7.9 (d, 2H, Ar–H), 8.5–8.55 (m, 3H, oxindole-H4, pyrimidin-H2,H4), 8.8 (s, 1H, NHCONH,, D2O exchangeable), 9.12 (s, 1H, NHCONH, D2O exchangeable), 10.46 (s, 1H, oxindole-NH, D2O exchangeable), 10.71 (d, 1H, –C=CH–NH, D2O exchangeable, J = 9.6 Hz), 11.68 (s, 1H, SO2NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 99.3, 109.5, 116.2, 116.9, 117.2, 117.6, 120.3, 120.7, 124.2, 124.8, 129.4, 132.8, 135.3, 137.2, 138.8, 144.4, 152.6, 157.50, 158.8, 170.3, 172.5; MS: (Mwt.: 527.40): m/z (% rel. Int.), 527.43 (M+, 25.17%), 108.34 (100%); Anal. Calcd. for C26H21N7O4S; Anal. Calcd. for C26H121N7O4S: C, 59.19; H, 4.01; N, 18.59; S, 6.08; Found: C, 59.45; H, 4.18; N, 18.73; S, 5.97.

1-{4-[((2-Oxoindolin-3-ylidene)methyl)amino]phenyl}-3-(thiazol-2-yl)urea (15c)

Yield 84%, m.p > 300. IR: (KBr, ύ cm−1): 1604, 1667 (2CO), 3166–3375 (4NH), 3083 (CH aromatic); 1H NMR (DMSO-d6, 400 MHz) δ ppm: 6.87–6.94 (m, 2H, oxindole-H7, H5), 6.98–7.02 (m, 1H, oxindole-H6), 7.31 (d, 1H, thiazole-H5), 7.44 (d, 1H, thiazole-H4), 7.53 (d, 1H, –C=CH–, J = 8 Hz), 7.58 (d, 2H, Ar–H, J = 12 Hz), 7.72 (d, 2H, Ar–H, J = 12 Hz),), 8.48 (d, 1H, oxindole-H4), 8.95 (s, 1H, NHCONH,, D2O exchangeable), 9.33 (s, 1H, NHCONH, D2O exchangeable), 10.47 (s, 1H, oxindole-NH, D2O exchangeable), 10.75 (brs, 1H, –C=CH–NH, D2O exchangeable); 13C NMR (DMSO-d6) δ: 99.80, 109.5, 116.90, 117.6, 120.4, 120.7, 121.5, 124.27, 124.8, 132.2, 136.2, 137.3, 138.4, 138.6, 163.8, 164.9, 170.3; MS: (Mwt.: 377.42): m/z (% rel. Int.), 377.74 (M+, 26.37%), 372.47 (100%); Anal. Calcd. for C19H115N5O2S: C, 60.47; H, 4.01; N, 18.56; S, 8.49; Found C, 60.59; H, 4.20; N, 18.82; S, 8.70.

In vitro biological evaluation

In-vitro anti-proliferative activity assay against NCI 60-cell line panel

From the newly synthesized compounds, eleven compounds were selected by the National Cancer Institute (NCI) Developmental Therapeutics Program (DTP), Bethesda, Maryland, USA for the in vitro anti-proliferative activity evaluation (For further details see supplementary materials).

In vitro five-dose assay on selected cell lines (MCT-7, HCT-116, and DU 145)

Five dose assay was performed using cancer cell cultures obtained from Nawah Scientific Inc., (Mokatam, Cairo, Egypt), Cell viability was assessed by SRB assay. The output from the dose–response is reported as a mean graph (Additional file 1; S3: In vitro biological activity).

Carbonic anhydrase inhibition

An Applied Photophysics stopped-flow instrument has been used for assaying the CA catalyzed CO2 hydration activity [82]. The inhibition constants were obtained by non-linear least-squares methods using PRISM 3 and the Cheng-Prusoff equation [83] to represent the mean from at least three different determinations. The four tested CA isoforms were recombinant ones obtained in-house as reported earlier [84].

Enzyme inhibitory assay

The FGFR, VEGFR-2 and RET tyrosine kinase assays were carried out at Thermo Fischer Scientific, USA (www.thermofischer.com/selectscreen). (For further details see Additional file 1; S3: In vitro biological activity).

Molecular docking

Molecular docking was carried out using Molecular Operating Environment software (MOE, 2020.0901). The detailed molecular docking setup used as well as its validation are provided in the Additional file 1; S2: Molecular docking study.

Availability of data and materials

Spectral data, molecular modeling and biological evaluation data generated or analysed during this study are included in this published article and its Additional file 1.

References

  1. Viegas-Junior C, Danuello A, da Silva Bolzani V, Barreiro EJ, Fraga CAM. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem. 2007;14:1829–52.

    Article  CAS  PubMed  Google Scholar 

  2. Ivasiv V, Albertini C, Goncalves AE, Rossi M, Bolognesi ML. Molecular hybridization as a tool for designing multitarget drug candidates for complex diseases. Curr Top Med Chem. 2019;19:1694–711.

    Article  CAS  PubMed  Google Scholar 

  3. Eldehna WM, El Kerdawy AM, Al-Ansary GH, Al-Rashood ST, Ali MM, Mahmoud AE. Type IIA–Type IIB protein tyrosine kinase inhibitors hybridization as an efficient approach for potent multikinase inhibitor development: design, synthesis, anti-proliferative activity, multikinase inhibitory activity and molecular modeling of novel indolinone-based ureides and amides. Eur J Med Chem. 2019;163:37–53.

    Article  CAS  PubMed  Google Scholar 

  4. Al-Warhi T, El Kerdawy AM, Aljaeed N, Ismael OE, Ayyad RR, Eldehna WM, Abdel-Aziz HA, Al-Ansary GH. Synthesis, biological evaluation and in silico studies of certain oxindole-indole conjugates as anticancer CDK inhibitors. Molecules 2020, 25.

  5. Abdel-Mohsen HT, El Kerdawy AM, Omar MA, Berrino E, Abdelsamie AS, El Diwani HI, Supuran CT. New thiopyrimidine-benzenesulfonamide conjugates as selective carbonic anhydrase II inhibitors: synthesis, in vitro biological evaluation, and molecular docking studies. Bioorg Med Chem. 2020;28: 115329.

    Article  CAS  PubMed  Google Scholar 

  6. Eldehna WM, Al-Rashood ST, Al-Warhi T, Eskandrani RO, Alharbi A, El Kerdawy AM. Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3beta inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies. J Enzyme Inhib Med Chem. 2021;36:270–85.

    Article  CAS  PubMed  Google Scholar 

  7. Abdel-Mohsen HT, El Kerdawy AM, Omar MA, Petreni A, Allam RM, El Diwani HI, Supuran CT. Application of the dual-tail approach for the design and synthesis of novel Thiopyrimidine–Benzenesulfonamide hybrids as selective carbonic anhydrase inhibitors. Eur J Med Chem. 2022;228: 114004.

    Article  CAS  PubMed  Google Scholar 

  8. Fortin S, Bérubé G. Advances in the development of hybrid anticancer drugs. Expert Opin Drug Discov. 2013;8:1029–47.

    Article  CAS  PubMed  Google Scholar 

  9. Ozensoy Guler O, Capasso C, Supuran CT. A magnificent enzyme superfamily: carbonic anhydrases, their purification and characterization. J Enzyme Inhib Med Chem. 2016;31:689–94.

    Article  CAS  PubMed  Google Scholar 

  10. Supuran CT. Carbonic anhydrases and metabolism. Metabolites. 2018;8(2):25.

  11. Chafe SC, Vizeacoumar FS, Venkateswaran G, Nemirovsky O, Awrey S, Brown WS, McDonald PC, Carta F, Metcalfe A, Karasinska JM, Huang L. Genome-wide synthetic lethal screen unveils novel CAIX-NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors. Sci Adv. 2021;7(35):eabj0364.

  12. Benej M, Pastorekova S, Pastorek J. Carbonic anhydrase IX: regulation and role in cancer. Subcell Biochem. 2014;75:199–219.

    Article  CAS  PubMed  Google Scholar 

  13. Kopecka J, Campia I, Jacobs A, Frei AP, Ghigo D, Wollscheid B, Riganti C. Carbonic anhydrase XII is a new therapeutic target to overcome chemoresistance in cancer cells. Oncotarget. 2015;6:6776–93.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pastorekova S, Parkkila S, Pastorek J, Supuran C. Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J Enzyme Inhib Med Chem. 2004;19:199–229.

    Article  CAS  PubMed  Google Scholar 

  15. Supuran CT. How many carbonic anhydrase inhibition mechanisms exist? J Enzyme Inhib Med Chem. 2016;31:345–60.

    Article  CAS  PubMed  Google Scholar 

  16. Maresca A, Supuran CT. Coumarins incorporating hydroxy-and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II. Bioorg Med Chem Lett. 2010;20:4511–4.

    Article  CAS  PubMed  Google Scholar 

  17. Lomelino CL, Supuran CT, McKenna R. Non-classical inhibition of carbonic anhydrase. Int J Mol Sci. 2016;17:1150.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Supuran CT. Carbon-versus sulphur-based zinc binding groups for carbonic anhydrase inhibitors? J Enzyme Inhib Med Chem. 2018;33:485–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Scozzafava A, Owa T, Mastrolorenzo A, Supuran CT. Anticancer and antiviral sulfonamides. Curr Med Chem. 2003;10:925–53.

    Article  CAS  PubMed  Google Scholar 

  20. Alterio V, Di Fiore A, D’Ambrosio K, Supuran CT, De Simone G. Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chem Rev. 2012;112:4421–68.

    Article  CAS  PubMed  Google Scholar 

  21. Awadallah FM, Bua S, Mahmoud WR, Nada HH, Nocentini A, Supuran CT. Inhibition studies on a panel of human carbonic anhydrases with N 1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails. J Enzyme Inhib Med Chem. 2018;33:629–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bonardi A, Nocentini A, Bua S, Combs J, Lomelino C, Andring J, Lucarini L, Sgambellone S, Masini E, McKenna R. Sulfonamide inhibitors of human carbonic anhydrases designed through a three-tails approach: improving ligand/isoform matching and selectivity of action. J Med Chem. 2020;63:7422–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Di Fiore A, Maresca A, Alterio V, Supuran CT, De Simone G. Carbonic anhydrase inhibitors: X-ray crystallographic studies for the binding of N-substituted benzenesulfonamides to human isoform II. Chem Commun. 2011;47:11636–8.

    Article  Google Scholar 

  24. Mahon BP, Hendon AM, Driscoll JM, Rankin GM, Poulsen S-A, Supuran CT, McKenna R. Saccharin: a lead compound for structure-based drug design of carbonic anhydrase IX inhibitors. Bioorg Med Chem. 2015;23:849–54.

    Article  CAS  PubMed  Google Scholar 

  25. Carradori S, Secci D, De Monte C, Mollica A, Ceruso M, Akdemir A, Sobolev AP, Codispoti R, De Cosmi F, Guglielmi P. A novel library of saccharin and acesulfame derivatives as potent and selective inhibitors of carbonic anhydrase IX and XII isoforms. Bioorg Med Chem. 2016;24:1095–105.

    Article  CAS  PubMed  Google Scholar 

  26. Nocentini A, Vullo D, Bartolucci G, Supuran CT. N-Nitrosulfonamides: a new chemotype for carbonic anhydrase inhibition. Bioorg Med Chem. 2016;24:3612–7.

    Article  CAS  PubMed  Google Scholar 

  27. Chinchilli KK, Royyala VN, Thacker PS, Angeli A, Danaboina S, Singh P, Nanduri S, Supuran CT, Arifuddin M. Design, synthesis, SAR, and biological evaluation of saccharin‐based hybrids as carbonic anhydrase inhibitors. Archiv der Pharmazie. 2022;355(8):2200019.

  28. Frija LM, Pombeiro AJ, Kopylovich MN. Coordination chemistry of thiazoles, isothiazoles and thiadiazoles. Coord Chem Rev. 2016;308:32–55.

    Article  CAS  Google Scholar 

  29. Raper ES. Copper complexes of heterocyclic thioamides and related ligands. Coord Chem Rev. 1994;129:91–156.

    Article  CAS  Google Scholar 

  30. Raper ES. Complexes of heterocyclic thionates. Part 1. Complexes of monodentate and chelating ligands. Coord Chem Rev. 1996;153:199-255.

  31. Raper ES. Complexes of heterocyclic thionates Part 2: complexes of bridging ligands. Coord Chem Rev. 1997;165:475–567.

    Article  CAS  Google Scholar 

  32. Tugrak M, Gul HI, Sakagami H, Gulcin I. Synthesis, cytotoxic, and carbonic anhydrase inhibitory effects of new 2-(3-(4-methoxyphenyl)-5-(aryl)-4, 5-dihydro-1 H-pyrazol-1-yl) benzo [d] thiazole derivatives. J Heterocycl Chem. 2020;57:2762–8.

    Article  CAS  Google Scholar 

  33. Ayati A, Emami S, Moghimi S, Foroumadi A. Thiazole in the targeted anticancer drug discovery. Future Med Chem. 2019;11:1929–52.

    Article  CAS  PubMed  Google Scholar 

  34. Petrou A, Geronikaki A, Terzi E, Guler OO, Tuccinardi T, Supuran CT. Inhibition of carbonic anhydrase isoforms I, II, IX and XII with secondary sulfonamides incorporating benzothiazole scaffolds. J Enzyme Inhib Med Chem. 2016;31:1306–11.

    Article  CAS  PubMed  Google Scholar 

  35. Kidwai M, Jahan A, Mishra N. Isatins: a diversity orientated biological profile. Med Chem. 2014;4:451–68.

    Article  Google Scholar 

  36. Havrylyuk D, Kovach N, Zimenkovsky B, Vasylenko O, Lesyk R. Synthesis and anticancer activity of isatin-based pyrazolines and thiazolidines conjugates. Arch Pharm. 2011;344:514–22.

    Article  CAS  Google Scholar 

  37. Abdel-Hamid MK, Abdel-Hafez AA, El-Koussi NA, Mahfouz NM, Innocenti A, Supuran CT. Design, synthesis, and docking studies of new 1,3,4-thiadiazole-2-thione derivatives with carbonic anhydrase inhibitory activity. Bioorg Med Chem. 2007;15:6975–84.

    Article  CAS  PubMed  Google Scholar 

  38. Ma J, Li S, Reed K, Guo P, Gallo JM. Pharmacodynamic-mediated effects of the angiogenesis inhibitor SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral glioma xenograft models. J Pharmacol Exp Ther. 2003;305:833–9.

    Article  CAS  PubMed  Google Scholar 

  39. Lane ME, Yu B, Rice A, Lipson KE, Liang C, Sun L, Tang C, McMahon G, Pestell RG, Wadler S. A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells. Can Res. 2001;61:6170–7.

    CAS  Google Scholar 

  40. Güzel-Akdemir Ö, Akdemir A, Karalı N, Supuran CT. Discovery of novel isatin-based sulfonamides with potent and selective inhibition of the tumor-associated carbonic anhydrase isoforms IX and XII. Org Biomol Chem. 2015;13:6493–9.

    Article  PubMed  Google Scholar 

  41. Eldehna WM, Al-Ansary GH, Bua S, Nocentini A, Gratteri P, Altoukhy A, Ghabbour H, Ahmed HY, Supuran CT. Novel indolin-2-one-based sulfonamides as carbonic anhydrase inhibitors: synthesis, in vitro biological evaluation against carbonic anhydrases isoforms I, II, IV and VII and molecular docking studies. Eur J Med Chem. 2017;127:521–30.

    Article  CAS  PubMed  Google Scholar 

  42. Abo-Ashour MF, Eldehna WM, Nocentini A, Ibrahim HS, Bua S, Abou-Seri SM, Supuran CT. Novel hydrazido benzenesulfonamides-isatin conjugates: synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies. Eur J Med Chem. 2018;157:28–36.

    Article  CAS  PubMed  Google Scholar 

  43. Eldehna WM, Fares M, Ceruso M, Ghabbour HA, Abou-Seri SM, Abdel-Aziz HA, Abou El Ella DA, Supuran CT. Amido/ureidosubstituted benzenesulfonamides-isatin conjugates as low nanomolar/subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform XII. Eur J Med Chem. 2016;110:259–66.

  44. Hilberg F, Roth G, Krssak M. Nintedanib_CanRes2008. Cancer Res. 2008;68:4774–83.

    Article  CAS  PubMed  Google Scholar 

  45. Ray-Coquard I, Cibula D, Mirza MR, Reuss A, Ricci C, Colombo N, Koch H, Goffin F, González-Martin A, Ottevanger PB. Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer. Int J Cancer. 2020;146:439–48.

    Article  CAS  PubMed  Google Scholar 

  46. Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006;145:660–4.

    Article  PubMed  Google Scholar 

  47. Rini BI. Sunitinib. Expert Opin Pharmacother. 2007;8:2359–69.

    Article  CAS  PubMed  Google Scholar 

  48. Sabatier R, Eymard J, Walz J, Deville J, Narbonne H, Boher J, Salem N, Marcy M, Brunelle S, Viens P. Could thyroid dysfunction influence outcome in sunitinib-treated metastatic renal cell carcinoma? Ann Oncol. 2012;23:714–21.

    Article  CAS  PubMed  Google Scholar 

  49. Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, Fukuda JY, Chu J-Y, Nematalla A, Wang X. Discovery of 5-[5-fluoro-2-oxo-1, 2-dihydroindol-(3 Z)-ylidenemethyl]-2, 4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem. 2003;46:1116–9.

    Article  CAS  PubMed  Google Scholar 

  50. Goel G. Evolution of regorafenib from bench to bedside in colorectal cancer: is it an attractive option or merely a “me too” drug? Cancer Manag Res. 2018;10:425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Overton LC, Heinrich MC. Regorafenib for treatment of advanced gastrointestinal stromal tumors. Expert Opin Pharmacother. 2014;15:549–58.

    Article  CAS  PubMed  Google Scholar 

  52. Heo Y-A, Syed YY. Regorafenib: a review in hepatocellular carcinoma. Drugs. 2018;78:951–8.

    Article  CAS  PubMed  Google Scholar 

  53. Khetmalis YM, Shivani M, Murugesan S, Sekhar KVGC. Oxindole and its derivatives: A review on recent progress in biological activities. Biomed Pharmacother. 2021;141: 111842.

    Article  CAS  PubMed  Google Scholar 

  54. Kumar SP, Gut J, Guedes RC, Rosenthal PJ, Santos MM, Moreira R. Design, synthesis and evaluation of 3-methylene-substituted indolinones as antimalarials. Eur J Med Chem. 2011;46:927–33.

    Article  Google Scholar 

  55. Parker M, Reitz A, Maryanoff B. Novel benzo-fused heteroaryl sulfamide derivatives useful as anticonvulsant agents. Google Patents, 2006.

  56. Wright JB. The synthesis of 2,1,3-benzothiadiazine 2,2-dioxides and 1,2,3-benzoxathiazine 2,2-dioxides. J Org Chem. 1965;30:3960–2.

    Article  CAS  Google Scholar 

  57. Schmelkes FC, Rubin M. Substituted p-aminobenzoic acids. J Am Chem Soc. 1944;66:1631–2.

    Article  CAS  Google Scholar 

  58. Lin S-J, Tsai W-J, Chiou W-F, Yang T-H, Yang L-M. Selective COX-2 inhibitors. Part 2: Synthesis and biological evaluation of 4-benzylideneamino-and 4-phenyliminomethyl-benzenesulfonamides. Bioorg Med Chem 2008;16:2697–06.

  59. Sakamoto M, Miyazawa K, Tomimatsu Y. Addition reactions of heterocumulenes. II. 1, 4-cycloaddition reactions of diphenylketene with azadienes. Chem Pharm Bull 1976;24:2532–40.

  60. Abu-Raddad LJ, Chemaitelly H, Ayoub HH, Al Kanaani Z, Al Khal A, Al Kuwari E, Butt AA, Coyle P, Jeremijenko A, Kaleeckal AH. Characterizing the Qatar advanced-phase SARS-CoV-2 epidemic. Sci Rep. 2021;11:1–15.

    Article  Google Scholar 

  61. Eldehna WM, Abo-Ashour MF, Berrino E, Vullo D, Ghabbour HA, Al-Rashood ST, Hassan GS, Alkahtani HM, Almehizia AA, Alharbi A. SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX. Bioorg Chem. 2019;83:549–58.

    Article  CAS  PubMed  Google Scholar 

  62. Mikkelsen GK, Langgård M, Schrøder TJ, Kreilgaard M, Jørgensen EB, Brandt G, Griffon Y, Boffey R, Bang-Andersen B. Synthesis and SAR studies of analogues of 4-(3, 3-dimethyl-butyrylamino)-3, 5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063) as adenosine A2A receptor ligands with improved aqueous solubility. Bioorg Med Chem Lett. 2015;25:1212–6.

    Article  CAS  PubMed  Google Scholar 

  63. Hirauchi K, Amano T. Studies on the phosphorimetric determination of amines with halonitrocompounds. I. Phosphorimetric determination of 4-homosulfanilamide with 4-fluoronitrobenzene. Chem Pharm Bull. 1977;25(6):1326–9.

  64. McClellan WJ, Dai Y, Abad-Zapatero C, Albert DH, Bouska JJ, Glaser KB, Magoc TJ, Marcotte PA, Osterling DJ, Stewart KD. Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases. Bioorg Med Chem Lett. 2011;21:5620–4.

    Article  CAS  PubMed  Google Scholar 

  65. Teicher BA. Anticancer drug development guide: preclinical screening, clinical trials, and approval. Springer; 2013.

  66. Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, Wu Y, Li X, Li X, Li G. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018;17:1–14.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249–57.

  68. Musumeci F, Radi M, Brullo C, Schenone S. Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors. J Med Chem. 2012;55:10797–822.

    Article  CAS  PubMed  Google Scholar 

  69. Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2003;163:1801–15.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Dhokne P, Sakla AP, Shankaraiah N. Structural insights of oxindole based kinase inhibitors as anticancer agents: Recent advances. Eur J Med Chem. 2021;216: 113334.

    Article  CAS  PubMed  Google Scholar 

  71. Huang Y, Chen X, Dikov MM, Novitskiy SV, Mosse CA, Yang L, Carbone DP. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood J Am Soc Hematol. 2007;110:624–31.

    CAS  Google Scholar 

  72. Sippel KH, Robbins AH, Domsic J, Genis C, Agbandje-McKenna M, McKenna R. High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design. Acta Crystallogr Sect F: Struct Biol Cryst Commun. 2009;65:992–5.

    Article  CAS  PubMed  Google Scholar 

  73. Leitans J, Kazaks A, Balode A, Ivanova J, Zalubovskis R, Supuran CT, Tars K. Efficient expression and crystallization system of cancer-associated carbonic anhydrase isoform IX. J Med Chem. 2015;58:9004–9.

    Article  CAS  PubMed  Google Scholar 

  74. Whittington DA, Waheed A, Ulmasov B, Shah GN, Grubb JH, Sly WS, Christianson DW. Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells. Proc Natl Acad Sci. 2001;98:9545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. McTigue M, Murray BW, Chen JH, Deng Y-L, Solowiej J, Kania RS. Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Natl Acad Sci. 2012;109:18281–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure. 2014;22:1764–74.

    Article  CAS  PubMed  Google Scholar 

  77. Terzyan SS, Shen T, Liu X, Huang Q, Teng P, Zhou M, Hilberg F, Cai J, Mooers BH, Wu J. Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib. J Biol Chem. 2019;294:10428–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rode H, Sprang T, Besch A, Loose J, Otto H-H. Pseudosaccharin amine derivatives: synthesis and elastase inhibitory activity. Die Pharmazie-An Int J Pharm Sci. 2005;60:723–31.

    CAS  Google Scholar 

  79. Brigas AF, Fonseca CS, Johnstone RA. Preparation of 3-chloro-1, 2-benzisothiazole 1, 1-dioxide (pseudo-saccharyl chloride). J Chem Res. 2002;2002:299–300.

    Article  Google Scholar 

  80. Joshi S, Manish K, Badiger A. Synthesis and evaluation of antibacterial and antitubercular activities of some novel imidazo [2, 1-b][1, 3, 4] thiadiazole derivatives. Med Chem Res. 2013;22:869–78.

    Article  CAS  Google Scholar 

  81. Wolfbeis OS, Junek H. β,β-Diacyl-enamines and-enoles, III formylation of CH2-acidic compounds via the anilinomethylene derivatives. Zeitschrift für Naturforschung B. 1979;34:283–9.

    Article  Google Scholar 

  82. Ibrahim HS, Allam HA, Mahmoud WR, Bonardi A, Nocentini A, Gratteri P, Ibrahim ES, Abdel-Aziz HA, Supuran CT. Dual-tail arylsulfone-based benzenesulfonamides differently match the hydrophobic and hydrophilic halves of human carbonic anhydrases active sites: Selective inhibitors for the tumor-associated hCA IX isoform. Eur J Med Chem. 2018;152:1–9.

    Article  CAS  PubMed  Google Scholar 

  83. Nocentini A, Moi D, Balboni G, Salvadori S, Onnis V, Supuran CT. Synthesis and biological evaluation of novel pyrazoline-based aromatic sulfamates with potent carbonic anhydrase isoforms II, IV and IX inhibitory efficacy. Bioorg Chem. 2018;77:633–9.

    Article  CAS  PubMed  Google Scholar 

  84. Nakai M, Pan J, Lin K-S, Thompson JR, Nocentini A, Supuran CT, Nakabayashi Y, Storr T. Evaluation of 99mTc-sulfonamide and sulfocoumarin derivatives for imaging carbonic anhydrase IX expression. J Inorg Biochem. 2018;185:63–70.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors express their thanks to NCI, Maryland USA, for cooperation in carrying out the in vitro cytotoxicity study.

Funding

Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). Open access funding provided by The Egyptian Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt

    Rania S. M. Ismail & Dalia H. Soliman

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt

    Ahmed M. El Kerdawy, Hanan H. Georgey & Nagwa M. Abdel Gawad

  3. Department of Pharmaceutical Chemistry, School of Pharmacy, Newgiza University (NGU), Newgiza, km 22 Cairo–Alexandria Desert Road, Cairo, Egypt

    Ahmed M. El Kerdawy

  4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, P.O. Box 11471, Cairo, Egypt

    Dalia H. Soliman

  5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt

    Hanan H. Georgey

  6. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy

    Andrea Angeli & Claudiu T. Supuran

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  1. Rania S. M. Ismail
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Contributions

RSMI: Methodology, Investigation, Writing, and Original Draft, AMElK: Conceptualization, Methodology, Writing, Review, and Editing, DHS: Conceptualization, Methodology, Review, and Editing, HHG: Conceptualization, Review, Editing, and Supervision, NMAG: Conceptualization, Review, and Supervision, AA: Methodology, and CTS: Methodology, Review, and Editing.

Corresponding authors

Correspondence to Rania S. M. Ismail, Nagwa M. Abdel Gawad or Claudiu T. Supuran.

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Supplementary Information

Additional file 1.

S1. Spectral data. S2. Molecular docking study. S3. In Vitro biological activity.

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Ismail, R.S.M., El Kerdawy, A.M., Soliman, D.H. et al. Discovery of a new potent oxindole multi-kinase inhibitor among a series of designed 3-alkenyl-oxindoles with ancillary carbonic anhydrase inhibitory activity as antiproliferative agents. BMC Chemistry 17, 81 (2023). https://doi.org/10.1186/s13065-023-00994-3

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Keywords

BMC Chemistry

ISSN: 2661-801X

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