A Review on Oxadiazoles as a Pharmacologically Active Nucleus

The structure of the oxadiazole skeleton is a biologically and biochemically active nucleus that has a multiple number of biological activities. The oxadiazole structure is a five-membered aromatic ring that has been used in numerous studies and molecules synthesised in laboratories. The principle structure of the Oxadiazole ring with a pair of Pyridine-type nitrogen atoms has been confirmed to be valuable for Oxadiazole analogues for having efficacious protein interactions with a large number of enzyme proteins and receptor proteins present in the organ system of the human body through different types of interactions, like Vander Wall interactions, thereby producing a huge variety of biological activities or pharmacological properties. Due to the variety in the pharmacological activity of Oxadiazole and their derivatives and analogues, they have been termed as one of the important pharmacological aspects to study. Multiple numbers of oxadiazole related synthetic compounds possessing high potent action and therapeutic activity are being widely incorporated for treatment and management of multiple diseases and disorders, giving immeasurable progression and establishment value. Oxadiazole derivatives express a multiple number of pharmacological activities like antimicrobial, anti-inflammatory, analgesic, antifungal, antipyretic, antidepressant, anti-tubercular, anticonvulsant, anticholinesterase, antihypertensive, antidiabetic, antitumor/anticancer, anti-HIV, antioxidant, etc. The history of 1,3,4-Oxadiazole is also very interesting. It shows that it attracted many chemists, researchers, and scientists to explore the Oxadiazole nucleus as a biologically active molecule having promising potency. This review article Review Article Singh and Ilango; JPRI, 34(1A): 10-27, 2022; Article no.JPRI.78724 11 mainly focuses on the pharmacological profile of 1,3,4-Oxadiazole with various activities and examples (in the form of figures and structures). Expectations are that this article will be like a path showing torch to help and serve as guidance for new innovations/ideas along the progression of research for the evolution of more active/potent and less poisonous/toxic Oxadiazole-based derivatives.


INTRODUCTION
Compounds having different heterocyclic moieties have earned a special interest in drug discovery.
Among all the heterocyclic compounds, oxadiazoles have influenced remarkable engrossment in medicinal and pharmaceutical chemistry and have exhibited a huge scope of biological and pharmacological properties and actions. 1,3,4-oxadiazole derivatives represent an array of synthetic compounds with significant medicinal importance. Oxadiazole analogues are an intriguing moiety that has been the primary focus of a plethora of recent studies and research. This present article narrates some of the numerous biological and pharmacological activities incorporated into the Oxadiazole structural system.

Fig. 1. Structures of the regioisomeric oxadiazole rings
Oxadiazole is very weakly basic in nature owing to the (+/-) I effect (inductive effect) shown by the additional heteroatom. When a couple of CH moiety from the furan structure are exchanged for a couple of pyridine nitrogen atoms (-N), the aromaticity property of the emerging oxadiazole ring decreases significantly, and the resulting oxadiazole moiety shows/displays the characteristics/properties of conjugated diene. Because of the presence of a comparatively less e-(negative charge) cloud over the available carbon atoms (at different positions for different isomers), the Oxadiazole ring is extremely unfavorable for electrophilic substitutions at the two carbon atoms present, despite the attack of electrophile or electrophilic groups on the pyridine variety of nitrogen atoms when Oxadiazole moiety hydrogens are swapped with EDGs like (-CH3).Nucleophile-based attack is exceptionally impossible in the Oxadiazole moiety due to the presence of two pyridine-type Nitrogen atoms with lone pairs of electrons. However, the Oxadiazole rings with halogen groups as side chains can react in nucleophilic substitution reactions.
The Oxadiazole moiety is very resourceful and has continuously been an area of large scale and vast study in recent years. Compounds possessing an Oxadiazole skeleton in their structures are extensively studied for biological and pharmacological activities such as antiviral, antifungal, antimicrobial, antidiabetic, anticancer, antihypertensive activity, antioxidant, neuroprotective activity, hypolipidemic activities, anticholinesterase activity, inhibition of tyrosinase and anticonvulsant activity. They have also made a valuable contribution as intermediates in the organic manufacturing of various compounds and are largely used as transporting agents for electrons.
In this present review, emphasis is on the diverse pharmacological properties that have been associated with and contributed to by substituted or derivatized oxadiazoles in the past two and a half decades. (1995-2020).

PHARMACOLOGICAL SCAFFOLDS OF OXADIAZOLES
Oxadiazoles have been included in a domain of well-known biologically and pharmacologically active compounds, like, either as a side chain group or in the form of a modification of another heterocyclic ring. There are multiple reports in the literature available describing the oxadiazole derivatives with a multitude of pharmacological and biological effects and a few of them are covered in this review.   Samir Bondock et al. [14] put forward few oxadiazoles related heterocyclic moiety. Five compounds exhibited prominent potency against HepG2, WI 38, MCF-7, & VERO at different MIC concentrations ranging from 10 to 1000µg/ml (17a-17b).
Ajay N. Ambhore et al. [25] synthesised pyridineoxadiazole-thio-ethylidene-hydrazine carbothioamide analogues. A few compounds showed potent growth inhibition and antimycobacterium activity and the others showed moderate activities as compared to the drugs Rifampicin and Isoniazid as standard (28a-28c).
Somnath Gholap et al. [26] synthesized 2,2dimethyl-2,3-dihydrobenzofurane linked oxadiazolo analogues. Few of the proposed derivatives exhibited significant potent activity against non-replicating with comparison to that of to combat replicating broth of Mycobacterium tuberculosis H37Ra ex vivo as well as in vitro at MIC values ranging 2.31 to 23.91µg/ml using the cell lines THP-1, A549 and PANC-1 (29a-29e).
K. Ilango et al. [37] synthesized 2-(4-Acetamido phenoxy methyl) -5-substituted-oxadiazole analogues. One of the synthesized compounds displayed the highest anti-inflammatory activity while few of the derivatives exhibited moderate activities against carrageenan induced paw oedema in rats at the concentration of 50mg/ml using Diclofenac sodium as standard drug (41). Antonio Palumbo Piccionello et al. [42] synthesized two sets of 1,2,4-oxadiazoles, having variant side chains and comprising of a different amount of fluorine atoms. Only one of the proposed compounds was found to exhibit a better activity against S. pyogenes (64mg/L). Linezolid and Ceftriaxone were used as standard drugs [46].

CONCLUSION
This review is focused on the diverse pharmacological properties possessed by and associated with the derivatives of Oxadiazole moiety in the last two and a half decades. Synthetic compounds possessing Oxadiazole ring in their chemical structure have been studied for multiple biological activities such as antifungal, anticancer, anti-HIV, antihypertensive, antibacterial, antimicrobial, anticholinesterase, anticonvulsant, antiviral etc. The studied literature resulted in getting a conclusion that the Oxadiazole ring has been used in multiple number of synthetic studies now-a-days. Oxadiazole moiety has grabbed the attention of many researchers due to its biological versatility.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.