Design, Synthesis and Biological Evaluation of 2 (((5‐aryl‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazoles: New Antiinflammatory and Antioxidant Agents

Abstract

The oxadiazole linked benzoxazoles derivatives were designed using scaffold hopping approach and their molecular level interactions with both isoforms of cyclooxygenases, Cyclo OXygenase‐1 (COX‐1) and CycloOXygenase‐2 (COX‐2), were carried out using docking protocols. Mini library of oxadiazole linked benzoxazoles derivatives were synthesized and tested for their COX inhibitory activity by in vitro enzyme assay. The results indicated that compound 2‐(((5‐(2,4‐dichlorophenyl)‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazole (5 h), 2‐(((5‐(4‐nitrophenyl)‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazole (5 j) and 2‐(((5‐(4‐(trifluoromethyl)phenyl)‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazole (5 k) selectively inhibited COX‐2 enzyme. The compound 5 j exhibited strong selective COX‐2 inhibition (IC50=4.83 μM) followed by compound 5 h (IC50=5.10 μM) and 5 k (IC50=6.70 μM). The in vivo anti‐inflammatory activity of compound 5 j was found to have better efficiency than the standard drug Ibuprofen at both 3 h and 5 h intervals. The significant molecular level interactions with respect to position of benzoxazole, 1,2,4‐oxadiazole and substituted aryl groups in both COX‐1 and COX‐2 active sites were discussed. Subsequently, 2,2‐diphenyl‐2‐picrylhydrazyl (DPPH) anti‐oxidant activity was also checked for all the compounds and the compound 5 j was found to be good anti‐oxidant among the series with an IC50 of 34.5 μM.

“Azole” as privileged heterocycle for targeting the inducible cyclooxygenase enzyme

“…Notably, the presence of morpholine ring offered highest potency to the test compounds, with IC50 in nanomolar range. The in vitro results corroborated with the in vivo analysis performed for the test compounds on carrageenan induced paw edema model (Yatam, Gundla, et al, 2018; Yatam, Jadav, et al, 2018). Further SAR analysis on benzothiazoles for selectively inhibiting COX‐2 isoenzyme led to the development of compounds 62a–g (Figure 12) containing benzothiazole‐1,2,4‐triazole conjugation connected via NH linker.…”

“…The benzoxazole based compounds 108a–c (Figure 17) provided preferential OX‐2 inhibitory profile with IC50 in the range 4.83–6.70 μM, and displayed significantly high molecular interactions with the residues lining the active site of COX‐2 isoenzyme. The π – π interactions presented by the “N” atom of benzoxazole ring with Tyr355, its hydrogen bonding with Arg120, in addition to the extensive π ‐cation interactions displayed by oxadiazole nucleus with Arg120 resulted in the preferential stabilization of the test molecules in COX‐2 active site loop (Yatam, Gundla, et al, 2018; Yatam, Jadav, et al, 2018). The SAR analysis on various benzoxazole derivatives and hybrid conjugates revealed that the disubstituted ring system participates in interacting with the COX‐2 active site residues, whereas its hybridization with N‐heterocycles shifts the preferential COX‐2 selectivity toward the conjugated ring, in addition to the nature of substituents appended to the anchored ring framework.…”

Therapeutic potential of oxadiazole or furadiazole containing compounds

“…Among the different isomers, 1,3,4-oxadiazole isomer shows a lots of therapeutic activities like antibacterial [9,10], anticonvulsant [11], antitumor [12][13][14][15][16][17][18][19][20][21][22], hypoglycemic, antipyretic [23], anti-tubercular [10,24], anti-viral [25], immunosuppressive, spasmolytic, antioxidant [13,26], anti-inflammatory [23,27,28], insecticidal [20], CNS stimulant, ant amoebic, antiemetic, antidepressant, anthelmintic activities, vasodilator activity, antimycotic activity [29], anti-allergic, anti-Alzheimer activity, ulcerogenic and antihypertensive activities etc.…”

Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on β-Amyloid-Induced PC12 Cells

“…Benzo[d]oxazoles are important scaffolds in heterocyclic compounds, which are extensively found in diverse pharmacologically active substances and natural compounds. For instance, benzo[d]oxazole plays an important role as a key building block in β adrenergic receptor antagonists [ 1 ], and anti-inflammatory [ 2 ], antimicrobial [ 3 ], and anticonvulsant [ 4 ] agents. Studies in recent decades have indicated that the thiadiazole ring is an important framework with broad-spectrum biological activity [ 5 ].…”