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Experimental and computational studies of an antiplasmodial derivative of allantoin; antimycobacterial essential oil from Cordia batesii WERNHAM (Boraginaceae)

Abstract

Background

Chemical and pharmacological investigations were performed on the stems of Cordia batesii (Boraginaeae); chemical studies included quantum calculations applied on a newly described compound.

Results

A new derivative of allantoin (1) named batesiin (2) was characterized. Thirteen other known compounds involving allantoin (1) were either isolated or identified. GC–MS enabled the identification of six compounds from a fraction containing essential oil. MeOH extract and some isolated compounds were tested in vitro against Pf7G8 CQS and Pf Dd2 CQR strains of Plasmodium falciparum; extract disclosed a moderate antiplasmodial activity (IC50 = 50 μg mL−1). Meantime, the CH2Cl2 extract and essential oil fraction were tested on a resistant mycobacterial strain of Mycobacterium tuberculosis; a potent antimycobacterial activity with a MIC = 9.52 μg mL−1 was deduced from essential oil. Density functional theory (DFT) calculations were carried on batesiin (2). Calculated chemical shifts at B3LYP/6-31G(d,p) and MPW1PW91/6-31G+(d,p) showed much better correlations with the experimental data. Time dependent DFT at B3LYP/6-31G+(d,p) displayed a major absorption band 3.01 nm higher than the experimental value.

Conclusion

Cordia batesii can be considered as promising in search of compounds with antimalarial and antitubercular properties. DFT studies are very helpful when trying to learn more about the spectroscopic insights of a derivative of allantoin (1).

Peer Review reports

Introduction

One of the main goals of World Health Organization (WHO) is to end the epidemics of neglected tropical diseases, tuberculosis (TB) and malaria (which remains the major public health and mortality problem in the tropics) by 2030 [1, 2]. In 2018, TB infected about 10.0 million people, mainly in WHO regions of South-East Asia (44%), Africa (24%) and the Western Pacific (18%); in parallel, about 213 million cases of malaria were found in the WHO African region. In the same year, half a million newly rifampicin-resistant TB cases were estimated. In general, 3.4% of new TB cases and 18% of formerly cured patients displayed either multidrug resistant TB or rifampicin-resistant TB (MDR/RR-TB) [3,4,5]. Trying to overcome the high cost or the shortage of drugs for treatment of malaria remains a challenge for chemists, and some authors proposed the synthesis of compounds disclosing an imidazole unit with efficient activities against malaria [6]. Recently, Al-Otaibi et al. [7] reported quantum calculations achieved on such derivatives; in their work, the authors evaluated the structural and electronic traits of those derivatives. 1H- and 13C-NMR spectroscopy is a central tool in the structure elucidation of organic compounds. A review by Lodewyk et al. [8] emphasized on computational predictions of NMR data on synthetic organic compounds and natural products. Natural products can be isolated from plants, which are considered to be an important source of major compounds in drug development because of their successful use in treating various human ailments since millenniums. In this context, searching for new natural products from medicinal plants could provide new ways for antimalarial and antitubercular drugs. Among these plants, some species of the genus Cordia (Boraginaceae) are reported to be useful in the treatment of tuberculosis, bronchitis and malaria [9].

The genus Cordia (Boraginaceae) is composed of trees or shrubs and is widespread in Central and South America, India, Asia and Africa [10]. Previous phytochemical investigations of plants from this genus reported the isolation and characterization of different classes of secondary metabolites including naphthoquinones, hydroquinones [11] or polyphenols [12]. Concurrently and based on some pharmacological surveys, essential oils from C. curassivica and C. gilletii appeared as active against some microbial strains [13, 14]. Biological activities and in silico investigations of C. dichotoma were recently reported [15]; the plant is also known to contain, apart from allantoin (1) [16, 17] which has been the subject of many quantum calculations [18, 19], fatty acids (FA) [20]. FA have been recognized as energy sources for M. tuberculosis inside host tissues and are supposed to induce dormancy in Mycobacterium bacilli [21, 22]. A few Mycobacterium bacilli were inhibited by C. sebestena extracts as results of biological analyses [23]. Sebestenoid D is a component of the latter species and was a matter of density functional theory (DFT) studies, with its optimized molecular geometry and HOMO–LUMO plot as outcomes [24, 25]. Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were also calculated during a survey aiming to check the coherence between experimental and theoretical NMR and IR data; this investigation was done on a compound with an imidazole unit [26] like allantoin (1). Other simulations completed on a particular range of complex natural products involved IR as well as electronic transitions for UV analyses through time dependent DFT (TD-DFT); findings were afterwards compared to experimental results [27].

Despite the intensive work performed on some Cordia species, no or less investigation has been done on Cordia batesii species, maybe because of its limited geographic location. In our continuing search of secondary metabolites with powerful antiplasmodial and antitubercular activities, chemical investigations were carried on the stems of Cordia batesii, a forest shrub growing in the central and western regions of Cameroon. This paper describes the isolation of a new derivative of 1 named batesiin (2) along with other compounds. In vitro activities regarding extracts of stems and some isolated compounds against two CQR strains of Plasmodium falciparum were examined, when essential oil from the plant was tested against a resistant mycobacterial strain of Mycobacterium tuberculosis. The detailed characterization of 2 was investigated based on experimental NMR and UV–visible spectroscopic analyses; DFT at B3LYP/6-31G(d,p) [28, 29] and MPW1PW91/6-31G+(d,p) [30, 31] and TD-DFT simulations at B3LYP/6-31G+(d,p) were then undertaken on the alleged structure. These quantum calculations were applied on 2 for two main reasons: the compound is described for the first time, its NMR data are closed to chemical shifts of 1 but the UV–visible spectra of both seem different. DFT calculations at B3LYP/6-311G++(d,p) were also performed to check some electronic and thermodynamic properties of 2.

Results

Experimental results

Compounds 1, 314 were identified based on comparison of their physical and spectral data with authentic samples or those already reported (Fig. 1). Their assignments were consistent with structures of: allantoin (1) [32], pyrimidine 2,4-(1H,3H)-dione (3) [33], cordialin A (4) and cordialin B (5) [34], quercetin (6) [35], myricetin (7) [36], genistein 4′-O-glucuronide (8) [37], methyl palmitate (9) [38], palmitic acid (10) [39], methyl (9E,12E)-octadeca-9,12-dienoate (11) [40], methyl oleate (12) [41], methyl tridecanoate (13) [42] and (Z)-octadec-11-enoic acid (14) [43].

Fig. 1
figure1figure1

Structures of the isolated/identified compounds (1–14) from the stems of C. batesii

Characterization of compound 2

Compound 2 was isolated as a white solid from CH2Cl2/MeOH mixture. Its molecular formula was deduced as C7H8N6O5 from the ESI-MS signal at m/z 257.4 [M+H]+ and from the HR-LC/MS signal at m/z 279.1603 [M+Na]+, in accordance with seven degrees of unsaturations. Additional data from the ESI-MS spectrum displayed other peaks at m/z 159.4 [M1+H]+ and 181.6 [M1 + Na]+ which are characteristics of allantoin (1) [44]. These preliminary data suggested a close relationship between allantoin (1) and compound 2. The 1H-NMR spectrum of 2 exhibited a very prominent peak at δH 5.30 (2H, d, 3 J(H,H) = 2.0 Hz, H–C(5)) ppm. Moreover, we observed from the same spectrum some signals attributable to protons attached to heteroatoms (especially to nitrogen) with chemical shifts at δH 8.04 [2H, s, H–N(1)], 10.51 [2H, s, H–N(3)], 6.86 [2H, d, 3 J(H,H) = 2.0 Hz, H–N(6)] ppm (Table 1).

Table 1 1H- and 13C-NMR 1D and 2D spectroscopic data of 1 and 2 (500 and 125 MHz in DMSO-d6) in ppm

The 13C-NMR spectrum of 2 showed four remarkable signals at 157.4 [C(2), 2C], 173.6 [C(4), 2C], 62.4 [C(5), 2C] and 156.8 [C(7), 1C] ppm; when considering that 2 contains seven carbon atoms, the number of aforementioned signals presume the occurrence of a symmetry. The DEPT 135 NMR spectrum of 2 revealed one signal at δC 62.4 [C(5)] ppm indicating one methine group. These observations were confirmed by its HSQC spectrum which indicates a correlation between the proton at δH 5.30 ppm [H–C(5)] and the said carbon. Two remaining signals from the 13C NMR spectrum are observable at δC 48.6 and 54.9 ppm and are suggestive of signals of MeOH and CH2Cl2 respectively; this assertion is strengthened by correlations between signals at δC 48.6 and δH 3.17 ppm in one side, and signals at δC 54.9 and δH 5.74 ppm from the same HSQC spectrum [45].

The HMBC spectrum exhibited noticeable correlations between protons at δH 5.30 ppm [H–C(5)] and the carbon atoms at δC 173.6 ppm [C(4)] and 156.8 ppm [C(7)], between protons at δH 6.88 ppm [H–N(6)] and carbon atoms at δC 173.6 [C(4)], 62.4 [C(5)] and 156.8 [C(7)]. Other correlations were found between nitrogenous protons at δH 8.04 [H–N(1)] ppm and carbon atoms at δC 157.3 ppm [C(2)], δC 173.6 ppm [C(4)] and 62.4 ppm [C(5)]. The UV spectrum of 2 (Fig. 2) exhibited one major maximum at λmax = 296 nm, different from values of 1 [19].

Fig. 2
figure2

UV–visible spectrum of batesiin (2)

Lakshmanan et al. [44] confirmed through an X-ray analysis that the occurring enantiomer of 1 is its (S) one. A thorough analysis of all the spectra and comparison with data from the literature revealed that compound 2 is described for the first time as a new derivative of allantoin (1); it was identified as (S,S)-1,3-bis(2,5-dioxoimidazolidin-4-yl)urea, trivially named batesiin (2). Table 1 shows some NMR data of allantoin (1) and batesiin (2); it strengthens the agreement of a close relationship between those two compounds in terms of NMR spectroscopic data.

Biological properties

The antimalarial efficiency of screening against P. falciparum Dd2 and 7G8 (CQR) strains of the MeOH extract of stems of C. batesii and compounds 2, 3, 5 and 6 was performed according to the Sybr Green I fluorescence-based assays [46]. The results are presented in Fig. 3; they indicate the IC50 of extract of stems of C. batesii and the percentage of growth inhibition against Dd2 and 7G8 P. falciparum strains respectively.

Fig. 3
figure3

Result of twofold dose response analysis of the extract of C. batesii against Dd2 P. falciparum strain (a). Inhibition percentage of stems of C. batesii and isolated compounds against P. falciparum Dd2 strain (b). Inhibition percentage of stems of C. batesii and isolated compounds against P. falciparum 7G8 strain (c)

Figure 3a mentioned that the MeOH extract of stems discloses an IC50 = 50 μg mL−1 against Dd2 P. falciparum strain which can be considered as a moderate activity. It appears from Fig. 3b that, apart from artemisinin (95.75% of inhibition) used as reference, the MeOH extract has the highest antiplasmodial activity with 88.24% percentage inhibition followed by 2 with approximately 78% of growth inhibition against Dd2 strain. Compounds 3 and 5 showed high activity (> 65%) of inhibition, exhibiting a growth inhibition of Dd2 strain P. falciparum with percentages corresponding to 66.43% and 72.99% respectively.

When tested against 7G8 P. falciparum strain, MeOH extract and compounds 2, 3 and 5 displayed the percentages of growth inhibition of 18.82%, 34.26%, 10.04% and 2.84% at 10 μg mL−1 respectively. The same extract and isolated compounds at 100 μg mL−1 unveiled 25.03%, 63.86%, 98.07% and − 18.44% of percentages of growth inhibition. These results are summarized in Fig. 3c and admit that 2 and 3 present the highest inhibition percentage (> 60%) on 7G8 P. falciparum strains.

From the antimycobacterial tests results (Table 2), it should be noticed that the mixture of FA (A1) exhibited a good antitubercular activity with a Minimal Inhibitory Concentration (MIC) value at 9.52 μg mL−1. According to Cantrell et al. [47], isolated compounds that exhibit a MIC ≤ 64 μg mL−1 are considered promising. For crude extracts, the MIC should be ≤ 125 μg mL−1 [48]. The extract made known poor inhibitory activity against Mycobacterium tuberculosis, exhibiting a MIC and a Minimal Bactericidal Concentration (MBC) of 1250 and 2500 μg mL−1 respectively.

Table 2 MIC and MBC values of the methanol extract and the mixture of fatty acids (A1) against Mycobacterium tuberculosis (AC 45)

Computational results of compound 2

The structure of compound 2 was assigned based on spectroscopic analyses including, UV, IR, 1H- and 13C-NMR, 1D and 2D techniques. To get supplementary detailed awareness into the structure, DFT calculations were completed. The structure of the compound with the right stereochemistry was firstly optimized at B3LYP method using 6-31G(d) basis set and the optimized structure was submitted to a relaxed scan around one H–C(5)–N(6)–H dihedral angle. Secondly, an additional relaxed scan around the other H–C(5)–N(6)–H dihedral angle (with no change in basis set) was applied on a conformer with low energy got from the preceding step. The desired conformer still with low energy was thereafter subjected to two relaxed scans around the C(5)–N(6)–C(7)–N(6) dihedral angles. All these scans led to an optimized geometry for 2, based on the cis-relationship between H–C(5)–N(6)–H (3 J(H,H) = 2.0 Hz). It is shown in Fig. 4 and takes in account previous reports on 1 [44, 49]. The five membered ring is almost planar as observed in the case of allantoin (1) [19].

Fig. 4
figure4

a ORTEP diagram of allantoin (1) [44]; optimized geometry of batesiin (2) at b B3LYP/6-31G(d) and c B3LYP/6-31++G(d,p)

The HOMO and LUMO of compound 2 (Fig. 5) as other descriptors were analyzed at B3LYP/6-31G(d) and 6-311G++(d,p) and compared with those of allantoin (1). The calculated HOMO–LUMO gap was 6.209 eV; results are summarized in Table 3.

Fig. 5
figure5

HOMO (a) and LUMO (b) of 2, calculated at B3LYP/6-311G++(d,p). The orbitals are plotted at isodensity of 0.02. The green color indicates the positive values of the phase while the negative values are characterized by the red color

Table 3 Some electronic and thermodynamic results of batesiin (2) compared to data of allantoin (1) at B3LYP

The 1H- and 13C-NMR spectra of compound 2 were experimentally measured in DMSO-d6 on 500 and 125 MHz spectrometers respectively. The theoretical NMR were calculated at B3LYP/6-31G(d,p) and MPW1PW91/6-31+G(d,p) in DMSO. The chemical shifts were also simulated at B3LYP/6-31G(d), B3LYP/6-31+G(d,p), MPW1PW91/6-31G(d) and MPW1PW91/6-31G(d,p); however, the correlation with the experiment was relatively weak. GIAO (Gauge Invariant Atomic Orbital) formalism was used during these calculations, and the solvent effect was introduced through polarizable continuum model (PCM) by applying integral equation formalism (IEF). A comparison of the theoretical 13C-NMR values at B3LYP/6-31G(d,p) and MPW1PW91/6-31+G(d,p) with the experimental ones is given in Table 4. A better correlation with the experiment can be achieved if a scaling factor is applied to the 13C-NMR theoretical values.

Table 4 Experimental and calculated [at B3LYP/6-31G(d,p) and MPW1PW91/6-31+G(d,p)] 13C-NMR data of 1

UV–visible spectrum of 1 displayed three maxima at λmax 183, 195 nm (representing the absorption bands of amide and imide functions) [19] and 265 nm [44]. Despite on the fact that batesiin (2) is characterized by the same chromophore groups, its UV–visible spectrum (Fig. 2) exhibits one major absorption band at λmax = 296 nm and minor absorptions as shoulder sections (letters A and B) with λmax around 287 and 304 nm respectively. Simulated UV–visible spectra of 2 were achieved at B3LYP/6-31+G(d,p) with chloroform (non-polar aprotic solvent) and ethanol (polar protic solvent) (Fig. 6), based on its tautomeric and ionic forms (Fig. 7): all λmax results (experimental and theoretical) are summarized in Table 5. Excitation energy (in nm) determined in CHCl3 at 283.89 is closed to experimental value at 287 nm while simulation in EtOH exhibits an energy (in nm) at 315.59 which is comparable to the experimental λmax at 304 nm. It must also be precised that results of IR calculations were almost similar to previous ones regarding allantoin (1) [19], since 1 and 2 share the same functional groups; hence, there was no need to report them.

Fig. 6
figure6

UV–visible spectra of 2 in chloroform (a) and in ethanol (b), calculated at B3LYP/6-31G+(d,p)

Fig. 7
figure7

Tautomeric and ionic forms of 2; based on UV–visible results, it seems most likely that the (C) form should be the major one

Table 5 Main experimental and vertical excitation energies of batesiin (2) along with oscillator strengths and transitions

Discussion

NMR data summarized in Table 3 strengthen the close relationship between allantoin (1) and batesiin (2), their 13C chemical shifts being almost analogous (Table 1). The main difference relies on 1H NMR spectra of both compounds: in 1, a value at δH 5.23 (1H, H–C(5)) ppm [50] is equivalent to chemical shift in 2 at δH 5.30 (2H, d, 3 J(H,H) = 2.0 Hz, H–C(5)) ppm. This 0.7 ppm variation between the aforesaid chemical shifts could be explained by the conformation of 2 (Fig. 4b, c) which seems to induce deshielding of the hydrogen atoms located on carbons C(5).

Results from bioassays against 7G8 P. falciparum strain reveal that an increase in concentration (10 to 100 μg mL−1) marks an increase in percentages of inhibition for MeOH extract, 2 and 3, but a decrease (with a negative percentage) for 5, which should indicate that the latter is totally inactive at high concentrations. The moderate activity of the MeOH extract suggests insufficient synergistic or additive effects of potential antiplasmodial secondary metabolites from C. batesii. In contrast to the mixture of FA, the weak antimycobacterial properties of the crude extract suggest the occurrence within C. batesii of components with very poor antimycobacterial effects (Table 2). Moreover, a report from literature indicates that mycobacteria have a lipid-rich hydrophobic cell wall and are often susceptible to less polar compounds [51]. According to Peterson and Shanholtzer [52], bacteriostatic activity has been defined as a ratio of MBC to MIC of > 4. Hence, essential oil exhibited bacteriostatic activity.

The high value of the HOMO–LUMO band gap is indicative of a relative stability of the molecule towards oxidation–reduction reactions. However, it is less than the HOMO–LUMO band gap of allantoin (1) (see Table 3) at the same method, maybe as an expression of additional stability of 2 and difference in biological behavior between both chemical entities. Plots of frontier orbitals show that HOMOs and LUMOs are globally focused over the entire molecule. Meanwhile, in the case of HOMOs, the ureidyl moiety is less concerned by the orbital overlap whereas it is recognized as the area covering the positive phase in LUMOs (Fig. 5). The theoretical 13C-NMR values are, on the average, higher than the experimental ones when using MPW1PW91/6-31+G(d,p); by contrast, it is not the same observation with results provided by the B3LYP/6-31G(d,p) process. Regardless of the difference in the absolute values, the theoretical values match nicely with the experimental data. Based on the simulated UV–visible spectrum, batesiin (2) should most likely appear as an intermediate between various iminols and iminolates groups, precisely due to additional stability as already hypothesized (Fig. 8). Two free protons are supposed to be located somewhere between, in each case, a nitrogen and an anionic oxygen of the same iminolate group, at a site however nearer to oxygen (distance < 1.4 Ǻ) than to nitrogen (distance > 2.3 Ǻ) (Fig. 8). Hence, a virtual loss of symmetry becomes noticeable within 2, inducing a change in MOs with an impact on electronic transitions (Fig. 9). LUMO and LUMO + 1 are localized on one imidazole fragment (especially in the region covering a free proton and the anionic oxygen located in its neighborhood) when the other one looks totally unoccupied. Moving from HOMO-1 to HOMO-3 causes an increase in orbital overlap within the entire chemical entity. Table 5 expresses the nature of electronic transitions which are in agreement with the corresponding λmax, depending on the nature of the solvent.

Fig. 8
figure8

One case of simulated "iminol"/"iminolate" form of 2 with distances between protons and nitrogen or oxygen atoms at B3LYP/6-31G+(d,p); this form seems to induce the electronic transitions (in nm)

Fig. 9
figure9

Various MOs of 2 involved in electronic transitions, at B3LYP/6-31G+(d,p). The green color represents the positive values of the phase while the red color is indicative of its negative values

Conclusion

Batesiin (2) has been characterized for the first time by means of 1H-, 13C-NMR and UV spectroscopies; its structure was confirmed by DFT and TD-DFT calculations at B3LYP/6-31G(d,p), 6-31G+(d,p), 6-311G++(d,p) and MPW1PW91/6-31G+(d,p) from this study. The MeOH crude extract of the stems showed a moderate activity against Dd2 P. falciparum strain with IC50 = 50 μg mL−1. The antiplasmodial properties of 2 and some other compounds are deduced from high percentages of growth inhibition against the 7G8 P. falciparum strain; in parallel, antimycobacterial activities against M. tuberculosis arise from the essential oil equivalent to the mixture of FA (914) with a MIC = 9.52 μg mL−1. Additional data corresponding to HOMO, LUMO, enthalpy, entropy or some reactivity descriptors like IP or EA were also simulated, this time at B3LYP/6-31G(d) and 6-311G++(d,p) and compared with data from literature of allantoin (1) [19]; moreover, no comparison with the experiment in this case could be made. This work supports a good agreement between experimental data and DFT calculations in case of structure elucidation. These preliminary results also support the hypothesis of further development of new antimalarial and antitubercular drugs from the genus Cordia.

Methods

General

Melting points were uncorrected and were measured on a Mettler Toledo instrument. IR spectra were recorded on an Alpha II FT-IR spectrometer from Bruker in the region of 4000–600 cm–1, using KBr pellet technique with 1.0 cm–1 resolution at room temperature. 1D and 2D NMR spectra were obtained on a Bruker DRX 500 (500 MHz for 1H and 125 MHz for 13C spectra) spectrometer (Bruker, Rheinstetten, Germany) with chemical shifts reported as δ (ppm), using TMS as an internal standard. The ESI-MS were obtained on LTQ-FT instrument (Thermo Scientific). LC–MS were measured with Shimadzu LC–MS system using a L-column 2 ODS (I.D. 2.1 × 100 mm, Chemical Evaluation and Research Institute, Japan), at a flow rate of 0.2 mL min−1 with a detection wavelength of 300 nm and FMW (HCOOH/MeCN/H2O = 1:12:87) as eluent, ESI+ 4.5 kV, ESI− 3.5 kV, 250 °C. Optical rotations were measured on a Perkin-Elmer 341 polarimeter. Silica gel 60 (230–400 mesh E. Merck, Darmstadt, Germany) and Sephadex® LH-20 were employed for CC, the solvent mixing systems for elution were mainly CH2Cl2/MeOH for the phytochemical study with increasing polarity and pure MeOH, while precoated aluminum sheets silica gel 60 F254 were used for TLC [53].

Plant material

The plant material was collected on March 2014 at Koumoul in center region of Cameroon. The identity of plant material was confirmed by the taxonomist Victor Nana. A voucher sample (14,106 SRF) is deposited at the National Herbarium of Cameroon, Yaounde.

Extraction and isolation

The stems were dried in shade and cut into small pieces and then submitted for further studies. 80% of air dried pieces of stems of C. batesii (500 g) were extracted with MeOH (5 × 500 mL, 30 min each) using an Elma® sonic S 100 at r. t. The extract was filtered; the filtrate was evaporated to dryness in a Rotavapor. The residue obtained from the MeOH extract (about 53 g) was dissolved into hexane–water 80:20 (100 mL) during 1 day; the resulting hexane–water gum (42 g) was dissolved in a mixture of CHCl3–H2O 80:20 (100 mL) once again in a period of 24 h; the resulting CHCl3–H2O extract (36 g) was dissolved in CH3COOH–H2O 70:30 (100 mL) during 24 h. The final extract (26 g) was submitted to further CC analyses. The crude MeOH extract (26 g) was subjected to CC of LH-20 (2.5 cm, 50 cm, eluent MeOH). Four main fractions were obtained: A (10.36 g), B (4.6 g), C (3.0 g) and D (7.0 g). Fraction A (10.36 g) was subjected to a silica gel CC (1.8 cm, 3 × 50 cm, eluent CH2Cl2–MeOH 100–1:1) and provided three sub-fraction (A1, A2, and A3). Sub-fraction A2 (5.20 g) was fractionated by silica gel CC (1.8 cm, 3 × 50 cm, eluent CH2Cl2–MeOH 50:1–30:1) to produce two compounds, 4 (4.6 mg) and 5 (11 mg). Fraction B (4.6 g) was chromatographed as described above to give five sub-fractions (B1, B2, B3, B4 and B5). Sub-fraction B1 (0.20 g) was purified by silica gel CC (1.8 cm, 3 × 50 cm, eluent CH2Cl2–MeOH 30:1–20:1) to yield compound 1 (9 mg). Compound 2 (7.5 mg) was isolated from sub-fraction B3 (0.31 g) using a silica gel CC (1.8 cm, 3 × 50 cm, eluent CH2Cl2–MeOH 40:1–20:1). Sub-fraction B4 (0.60 g) was fractionated and purified using a silica gel CC (1.8 cm, 3 × 50 cm, eluent CH2Cl2–MeOH 40:1–15:1) to provide 3 (4 mg). The essential oil (sub-fraction A1, 0.60 g) resulting from the crude extract was analyzed by LC–MS, exhibiting compounds 6, 7 and 8. A1 was soluble in pure hexane and crystallized from pure CH2Cl2. 487 mg were analyzed by GC–MS which revealed the compounds 9, 10, 11, 12, 13 and 14.

Characteristics of compound 2

Batesiin (2), white solid: mp 231–233 °C. TLC (CH2Cl2:MeOH, 20:1 v/v) Rf = 0.6; \({[\mathrm{\alpha }]}_{\mathrm{D}}^{20}\) = − 98.3° (0.04 M in acetone). 1H NMR (500 MHz, DMSO-d6) δ 10.51 (2H, s, NH), 8.04 (2H, s, NH), 6.88 (2H, d, J = 2 Hz, NH), 5.23 (2H, d, J = 2 Hz); 13C NMR (125 MHz, DMSO-d6) δ 62.4, 156.8, 157.4, 173.6; IR (KBr) cm–1 3425, 3340 (O–H), 3125, 3060 (N–H), 1810, 1740, 1680, 1560 (C=O); UV/Vis: λmax (MeOH) nm: 296. HR-LC/MS (m/z): [M+Na]+ calcd for C7H8N6O5Na+; 279.1608; found 279.1603; analysis (calcd., found for C7H8N6O5Na): C (30.12, 30.09); H (2.89, 2.85); N (30.10, 30.10); O (28.66, 28.65).

Biological assays

In vitro cultivation of P. falciparum strains

PfDd2 and Pf7G8 strains of P. falciparum were used in vitro in blood stage culture to test the antimalarial efficacy of MeOH extract of stems of C. batesii and isolated compounds 2, 3 and 5. The culture was maintained at the Laboratory of parasitology, Centre Pasteur du Cameroon. P. falciparum culture was maintained according to the method described by Trager and Jensen [54] with slight modifications. P. falciparum Dd2 and 7G8 cultures were maintained in fresh O+ve human erythrocytes suspended at 4% haematocrit in RPMI 1640 (Sigma Aldrich—France) containing 0.2% sodium bicarbonate, 0.5% Albumax, 45 μg L−1 hypoxanthine and 50 μg L−1 gentamicin, and incubated at 37 °C under a gas mixture 5% O2, 5% CO2, and 90% N2. Every day, infected erythrocytes were transferred into fresh complete medium to propagate the culture.

Drug dilutions

Artemisinin (Sigma Aldrich—France) and isolated compounds were prepared in DMSO. All stocks were then diluted with culture medium to achieve the required concentrations. The final solution of all plant extracts, isolated compounds and artemisinin contained 0.4% DMSO, which was found to be non-toxic to the parasites. Drugs and test compounds were then placed in 96-well flat bottom tissue culture grade plates.

Assay for antiplasmodial activity

The stems of C. batesii were evaluated for their antimalarial activity against P. falciparum strains Dd2 and 7G8. For drug screening, SYBR green I-based fluorescence assay was setup as described by Smilkstein et al. [46]. Sorbitol synchronized parasites were incubated under normal culture conditions at 2% haematocrit and 1% parasitemia in the absence or presence of increasing concentrations of MeOH extracts of C. batesii. Artemisinin was used as positive control, while 0.4% DMSO was used as the negative control. After 48 h of incubation, 100 μL of SYBR Green I solution [0.2 μL mL−1 of 10,000× SYBR Green I (Sigma Aldrich—France)] in lysis buffer [Tris (20 mM; pH 7.5), EDTA (5 mM), saponin (0.008%; w/v) and Triton X-100 (0.08%; v/v)] was added to each well. The microtiter plate was mixed twice gently with multi-channel pipette and incubated in dark at 37 °C for 1 h. Fluorescence was measured with a fluorescence multi-well plate reader (Perkin Elmer) with excitation and emission wavelength bands centred at 485 and 530 nm, respectively. The fluorescence counts were plotted against the drug concentration and the inhibitory percentage of each plant extract and compound was calculated using the following equation:

$${\text{I}}\left( \% \right) = \frac{{{\text{Abs}}_{{{\text{control}}}} - {\text{Abs}}_{{{\text{extracts}}/{\text{isolated compounds}}}} { }}}{{{\text{Abs}}_{{{\text{control}}}} }} \times 100$$

where Abscontrol is the absorbance of untreated well and Absextracts/isolated compounds is the absorbance of extracts or compounds well.

Antimycobacterial tests

For the present study, the mycobacterium (M. tuberculosis) used was a clinical isolated strain resistant to isoniazid codified as AC 45 (this strain was obtained from Sangmelima district’s Hospital in south region of Cameroon). The genetical profile of the resistance has been carried out at Laboratory for Tuberculosis Research (Biotechnology Centre, University of Yaoundé I) through Line probe Assay method. The mycobacteria strains have been cultured at 37 °C for 2 weeks in Middlebrook 7H9 (Himedia, India) supplemented with 0.05% (v/v), 2% glycerol and 10% OADC (oleic acid-albumin-dextrose-catalase of Liofilchem s.r.l, Italia). The optical density of 0.45 to 0.55 was measured using spectrophotometer at 550 nm to obtain a suspension of 1.5 × 108 UFC mL−1. The activity of all phytochemicals (extract and pure compounds) against the aforementioned M. tuberculosis strains was tested using the microplate Alamar Blue assay as described previously by Collins and Franzblau [55]. In a 96 well microplates, all wells received 100 μL of supplemented Middlebrook 7H9 broth, then working metabolites solutions (100 μL) were poured into the first well of each row, from which twofold dilution series were made through the microplate column. The test inoculum (100 μL) was added to all testing wells, as well as to the drug-free control wells. The final concentration of DMSO in wells was 7% v/v. The final concentrations tested ranged from 250 to 0.244 μg mL−1 for pure compounds and 5000 to 4.882 μg mL−1 for extracts. Rifampicin was used as standard drug. Each concentration was assayed in triplicate. Each microplate was sealed with parafilm paper and incubated for 14 days at 37 °C. After that, 40 μL of Alamar blue solution was added to two columns of each triplicate in order to show mycobacterial growth and the plates were re-incubated at 37 °C for 24 h. After 1 day of incubation, the MIC was defined as the lowest concentration of phytochemicals that inhibited the bacterial growth (prevents a color change from blue to pink) after incubation time [56]. For the MBC determination, 50 μL of each well which concentration was ≥ MIC was sub-cultured in 150 μL of Mbk 7H9 medium and incubated at 37 °C for 10 days, then mycobacterial growth was carried out by addition of 40 μL of alamar blue. MBC was defined as the lowest concentration of extract at which no visible growth of the germ was observed.

Computational details

All calculations were performed with Gaussian 09 suite of programs [57] and UV–visible curves were generated by GaussSum [58]. Geometries were optimized at hybrid B3LYP method using 6-31G(d) basis set. The B3LYP mode provides a good balance between cost and precision [59, 60]. A preliminary predict of the geometry of compound 2 is based on the stereochemistry ascribed through 1D and 2D NMR characterizations. Compound 2 has conformational flexibility around the symmetric dihedral angles H–C(5)–N(6)–H and C(5)–N(6)–C(7)–N(6). The dihedral angles around the C(5)–N(6) axes were scanned at 15 degrees step and a minimum at 22.9° around the C(5)–N(6) axes was retained because of its conformation closed to the structure of allantoin (1). Afterwards, dihedral angles around the N(6)–C(7) axes were scanned at 10 degrees step, to find the lowest energy conformer. It was then submitted to geometry optimization at B3LYP/6-31G(d) and B3LYP/6-311++G(d,p) levels of theory to provide the optimized geometries of 2 (Fig. 4). The optimized structure was in each case confirmed by frequency analysis at the same levels as a true minimum (no imaginary frequency). Six methods were evaluated for the simulation of 1H- and 13C-NMR spectra; B3LYP/6-31G(d), B3LYP/6-31G(d,p), B3LYP/6-31G+(d,p), MPW1PW91/6-31G(d), MPW1PW91/6-31G(d,p) and MPW1PW91/6-31G+(d,p). The electronic properties at isodensity 0.02 such as Ionization Potential (IP), Electron Affinity (EA), HOMO, LUMO and band gaps were calculated at B3LYP/6-31G(d) and B3LYP/6-311G++(d,p). The band gap was taken as the difference in energies of HOMO and LUMO. Meantime, thermodynamic properties like enthalpy, entropy or molar capacity at constant volume along with reactivity descriptors like chemical potential, electronegativity, hardness, softness were also calculated by means of the same methods. TD-DFT studies were evaluated at B3LYP/6-31G+(d,p) in CHCl3 and in EtOH after a geometry optimization at the same level of theory of the iminolate in Fig. 8. Six steps were applied to get excitation energies.

Availability of data and materials

All data generated or analyzed during this study are included in this published article (and its Additional file 1).

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Acknowledgements

We thank Mr. Victor Nana for the collection and identification of the plant material. We are indebted to Mr. Felix Fehr (Department of Chemistry, University of Fribourg) and to Koert’s group (Philipps-Universitat Marburg) for spectral analyses; we also thank the German cooperation through the DAAD/YaBiNaPa program for running the LC–MS analyses.

Funding

The authors acknowledge financial support from the Ministry of Higher Education, Cameroon and from the University of Yaounde I grant committee.

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ERT, NMN and PHBD performed the experiments, DSNB, IMN and AAAZ analyzed the data, conceived and designed the experiments and wrote the article. LA, BLN, JNM and DEP, contributed samples/reagents/materials/analysis tools and analyzed the data. All authors read and approved the final manuscript.

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Correspondence to Auguste Abouem A Zintchem.

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Supplementary Information

Additional file 1.

NMR spectra of compound 2, some HMBC correlations, GC–MS analyses of compounds 9, 10, 11, 12, 13 and 14, LC–MS and GC–MS chromatograms of the extract of C. batesii, the ESI-MS spectrum of compound 2, the genotype profile of M. tuberculosis codified AC 45, the shielding tensors of the nuclei of 2, the electronic (HOMO, LUMO) properties, the cartesian coordinates of the optimized geometry of compound 2 and TD-DFT are available as additional file.

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Tiam, E.R., Bikobo, D.S.N., Ndassa, I.M. et al. Experimental and computational studies of an antiplasmodial derivative of allantoin; antimycobacterial essential oil from Cordia batesii WERNHAM (Boraginaceae). BMC Chemistry 15, 15 (2021). https://doi.org/10.1186/s13065-021-00742-5

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Keywords

  • Cordia batesii
  • Allantoin
  • Batesiin
  • Spectroscopy
  • Essential oil
  • DFT
  • Molecular orbitals
  • Plasmodium falciparum
  • Mycobacterium tuberculosis