Novel 1,2,4-Oxadiazole Derivatives in Drug Discovery

Abstract

Five-membered 1,2,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bioisosteric properties and an unusually wide spectrum of biological activities. Thus, it is a perfect framework for the novel drug development. After a century since the 1,2,4-oxadiazole have been discovered, the uncommon potential attracted medicinal chemists’ attention, leading to the discovery of a few presently accessible drugs containing 1,2,4-oxadiazole unit. It is worth noting that the interest in a 1,2,4-oxadiazoles’ biological application has been doubled in the last fifteen years. Herein, after a concise historical introduction, we present a comprehensive overview of the recent achievements in the synthesis of 1,2,4-oxadiazole-based compounds and the major advances in their biological applications in the period of the last five years as well as brief remarks on prospects for further development.

Green Synthetic Approach: An Efficient Eco-Friendly Tool for Synthesis of Biologically Active Oxadiazole Derivatives

“…By applying microwave technology, different oxadiazole derivatives can be synthesized and also screened to find out new therapeutic molecules with diverse biological activities such as antibacterial, antifungal, antidepressant, antitubercular and antiinflammatory, etc. [ 71 , 72 , 73 , 74 ]. Hence, oxadiazole is considered a significant heterocyclic core and becomes a major scaffold for the development of new drug candidates because of its potential to be involved in the binding interactions with different targets or receptors with suitable metabolic profile [ 75 , 76 , 77 , 78 ].…”

Groundbreaking Anticancer Activity of Highly Diversified Oxadiazole Scaffolds

“…Among the four isomers, 1,2,4- and 1,3,4-oxadiazoles frequently occur in a large series of drug-like molecules [ 8 ], including antiviral [ 3 , 9 ], antihypertensive [ 10 ], anti-diabetic [ 11 ], anti-inflammatory, and analgesic [ 12 ], as well as anticancer compounds [ 13 , 14 ]. Probably, this is a direct consequence of the orientation of the side chains (-R 1 and -R 2 in Figure 1 ), very similar for 1,2,4- and 1,3,4-oxadiazoles with respect to 1,2,3- and 1,2,5-oxadiazoles.…”

“…Indeed, small bioactive molecules with resembling shapes usually show target-binding similarity that translates into the same biological effects [ 15 ]. Moreover, their bioisosteric correspondence with ester and amide groups makes oxadiazoles an interesting synthetic alternative to avoid intrinsic molecular instability (e.g., due to hydrolysis reactions), guaranteeing different hydrogen-bonding potentials with the receptors [ 8 ].…”

Groundbreaking Anticancer Activity of Highly Diversified Oxadiazole Scaffolds

“…Their aromatic flat surface is effective in the target binding, through π-stacking interactions, or to properly outdistance the substituents according to a specific orientation [7]. Depending on nitrogen atoms position, oxadiazoles exist in four different regioisomeric forms ( Among the four isomers, 1,2,4-and 1,3,4-oxadiazoles frequently occur in a large series of drug-like molecules [8], including anti-viral [3,9], antihypertensive [10], anti-diabetic [11], anti-inflammatory and analgesic [12], as well as anticancer compounds [13,14]. Probably, this is a direct consequence of the orientation of the side chains (-R1 and -R2 in Figure 1), very similar for 1,2,4-and 1,3,4-oxadiazoles with respect to 1,2,3-and 1,2,5-oxadiazoles.…”

“…Moreover, their bioisosteric correspondence with ester and amide groups, makes oxadiazoles an interesting synthetic alternative to avoid intrinsic molecular instability (e.g. due to hydrolysis reaction), guaranteeing different hydrogen-bonding potentials with the receptors [8].…”