Therapeutic potential of oxadiazole or furadiazole containing compounds

As we know that, Oxadiazole or furadi azole ring containing derivatives are an important class of heterocyclic compounds. A heterocyclic five-membered ring that possesses two carbons, one oxygen atom, two nitrogen atoms, and two double bonds is known as oxadiazole. They are derived from furan by the replacement of two methylene groups (= CH) with two nitrogen (-N =) atoms. The aromaticity was reduced with the replacement of these groups in the furan ring to such an extent that it shows conjugated diene character. Four different known isomers of oxadiazole were existed such as 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole & 1,3,4-oxadiazole. Among them, 1,3,4-oxadiazoles & 1,2,4-oxadiazoles are better known and more widely studied by the researchers due to their broad range of chemical and biological properties. 1,3,4-oxadiazoles have become important synthons in the development of new drugs. The derivatives of the oxadiazole nucleus (1,3,4-oxadiazoles) show various biological activities such as antibacterial, anti-mycobacterial, antitumor, anti-viral and antioxidant activity, etc. as reported in the literature. There are different examples of commercially available drugs which consist of 1,3,4-oxadiazole ring such as nitrofuran derivative (Furamizole) which has strong antibacterial activity, Raltegravir as an antiviral drug and Nesapidil drug is used in anti-arrhythmic therapy. This present review summarized some pharmacological activities and various kinds of synthetic routes for 2, 5-disubstituted 1,3,4-oxadiazole, and their derived products.


Background
Health problems were increasing day by day and become the most serious clinical problem. Recently, medicinal chemists have been looking for new drugs to be used safely to treat these serious clinical problems. There are a lot of heterocyclic compounds that are in clinical use to treat infectious disease [1].
The most common heterocyclic are those having five or six-member fused rings and possess nitrogen, oxygen, sulfur groups as heteroatoms. Some time boron, silicon, and phosphorus atoms can be used as hetero atoms [2].
Heterocyclic compounds containing nitrogen atom such as oxadiazole moieties are of interest to researchers in the fields of medicinal and pharmaceutical chemistry [3].
A heterocycles five-member ring that possesses one oxygen, two carbons, two nitrogen atoms, and two double bonds is known as oxadiazole [4]. This type of ring system is also known as azoximes, oxybiazole, biozole, diazoxole, furadiazole, and furoxans. Oxadiazole was first synthesized in 1965 by Ainsworth through the thermolysis of hydrazine. Its molecular formula is C 2 H 2 ON 2 and having a molecular mass of 70.05 g/mol which is soluble in water [2].
Oxadiazoles are thermally stable compounds and their calculated resonance energy is equal to 167.4 kJ/mol. The thermal stability of oxadiazoles is increased with the substitution at the second position [5].
1,3,4-oxadiazole heterocyclic ring is one of the most important heterocyclic moieties due to its versatile biological actions [6]. These are the derivatives of furan in Siwach and Verma BMC Chemistry (2020) 14:70 which two methylene groups were replaced with two nitrogen atoms. Replacement of these two methylene groups by two nitrogen atoms reduces the aromaticity of the ring & the resulting oxadiazole ring exhibits conjugated diene character [7]. Another heteroatom makes a weak base to the oxadiazole due to the inductive effect [6]. Hydrogen atoms were replaced by nucleophiles which are seen in nucleophilic substitution reaction [8].
as reported in the literature [30]. Keeping the view of this, we have discussed different oxadiazole derivatives carrying urea, amide, and sulphonamide groups to investigate their anticancer, antiviral, antimicrobial, antitubercular, and antioxidant activities [31].
So those compounds which inhibit the activity of tyrosine kinases play a substantial role in cancer treatment. Therefore Tyrosine kinases (EGFR family) were selected and explore the binding mode of the novel compounds to EGFR tyrosine kinase active site [32].
There are different examples of commercially available drugs containing 1,3,4-oxadiazole ring (Fig. 2) such as a nitrofuran derivative (Furamizole) which has strong antibacterial activity [35]. Raltegravir as an antiviral drug and Nesapidil drug is used in anti-arrhythmic therapy. The FDA approved anticancer agent Zibotentan is a 1,3,4-oxadiazole nucleus containing the most privileged derivatives available in the market [36]. Tiodazosin is used as an antihypertensive agent [37]. This present review summarized some pharmacological activities and various kinds of synthetic routes for 2,5-disubstituted 1,3,4-Oxadiazole, and their derived products during the last decade (2005-2020).
The mechanism for the formation of 2,5-disubstituted 1,3,4-oxadiazole The probable mechanism for the formation of the 1,3,4-oxadiazole is given in (Fig. 3). The presence of lone pair of electron on the nitrogen atom of acid hydrazide attacks the carbonyl carbon atom of carboxylic acid eliminates a water molecule to form a hydrazide derivative which further reacts with phosphorus oxychloride, undergoes ring closure with the elimination of hydrogen chloride, and form 1,3,4-oxadiazole ring [38].

Structure-activity relationship of 1,3,4-oxadiazole derivatives
The structure-activity relationship of 1,3,4-oxadiazole is given in (Fig. 4). Substitution of phenyl ring with different substituents like p-Cl, p-NO 2 & p-t Bu further increases the activity. The conversion of the methylthio group into the methyl-sulfonyl group also increases the activity. The replacement of the phenyl ring along with the pyridine ring decreases the activity. If the acetyl group is present on the nitrogen atom of the oxadiazole ring did not significantly affect the activity [39]. Thus, based on the aforementioned results, we hypothesized that 2,5-disubstituted 1,3,4-oxadiazole scaffold may lead to novel potent agents with broad biological activity profile and improved pharmacokinetic properties.

Antimicrobial activity
Bhat et al. [48] developed 4-bromo-N-[(5-(substituted phenyl)-1,3,4-oxadiazol-2yl)methyl]aniline (Scheme 1) and these derivatives were screened for antimicrobial activity against S. aureus, E. coli, B. Subtilis, and P. aeruginosa using amoxicillin as a positive control. The antimycotic activity was evaluated for these compounds against A. niger and C. albicans using ketoconazole as a reference standard. Derivatives with different groups like -OH, -NO 2 [1b, 1c, 1d, 1g] shows good antimicrobial activity against fungal strains. Derivatives with groups like p-methoxy, p-chloro, p-methyl [1e, 1f, 1h] show better antimicrobial potential as compared to amoxicillin. The results of the antimicrobial activity of synthesized 1,3,4-oxadiazole derivatives were presented in ( and Gram -ve (K. pneumonia, E. coli, and P. aeruginosa) strains using ofloxacin as a reference standard. The cup plate agar diffusion method was used for the determination of the zone of inhibition. The results of antibacterial activity were summarized in (Table 3, Kumar et al. [43]).
Vinayak et al. [50]  methyl]-substituted-1-amine by using Scheme 7 and evaluated for antiproliferative activity against different cell lines such as HeLa, HepG2, and Caco by MTT assay using 5-Fluorouracil as a reference standard. The derivative 10a and 10d showed excellent activity against HepG2 cell lines. The compound 10f gives better results against the Caco-2 cancer cell line. The results of the anti-proliferative activity of synthesized derivatives were showed in (Table 7a,  phenyl)-1,3,4-oxadiazole by using Scheme 8 and evaluated for antitumor activity against MCF-7 (breast) cancer cell line by MTT assay. Compound 11e shows better cytotoxic activity as compare to 11a, 11b, and 11c. Compounds 11f, 11g, 11h also show the excellent cytotoxic activity as compared to the rest of the derivatives. Compounds 11e and 11h flourished potent cytotoxic activity with minimum percentage viability. Each compound was tested to calculate the percentage viability of cell line  Kavitha et al. [31] developed N-substituted-(3-(5cyclohexyl-1,3,4-oxadiazol-2-yl)phenyl)benzamide, urea, and substituted benzenesulfonamide derivatives by using Scheme 9. The anticancer activity of synthesized derivatives was evaluated against different cancer cell lines like HeLa and MCF-7 using cisplatin as a reference standard. Among the different derivatives, compounds 12a, 12b, 12c, 13c, 13d, and 14b showed significant activity after 48 h exposures . Further derivatives 12a, 13c, 13d, and 14b also showed excellent antitumor activity as compared to the positive control. Compound 12b showed excellent antitumor activity as compared to the rest of other compounds. The results of the antitumor activity of these derivatives were presented in (Table 9, Kavitha et al. [31]).

Conclusion
In this present review article, we have summarized different pharmacological activities of 1,3,4-oxadiazole containing compounds. From this study, we have found that 1,3,4-oxadiazole containing compounds can be synthesized by various kinds of synthetic routes, and these derivatives having a wide range of biological activities such as antitumor, antitubercular, antimicrobial, antiviral and antioxidant, etc. This review article established the fact that 1,3,4-oxadiazole as useful templates for further modification or derivatization to design more potent biologically active compounds.