Synthesis, characterization and anti-inflammatory activity evaluation of 1,2,4-triazole and its derivatives as a potential scaffold for the synthesis of drugs against prostaglandin-endoperoxide synthase

Abstract

Substituted 1,2,4-triazole nucleus is common in several drugs used in a variety of clinical conditions including infections, hypoglycemia, hypertension and cancer. In this study, we synthesized 1,2,4-triazole and its 16 hydrazone derivatives (B1–B16), characterized them by IR, NMR and Mass spectroscopy, and evaluated their radical scavenging and anti-inflammatory activities in vitro and in vivo. Out of 16 derivatives, five (B1, B5, B6, B9, and B13) demonstrated a significant radical scavenging and anti-inflammatory activity in vitro. B6, which possessed two electron-donating hydroxyl groups, was most active among all. Molecular docking and MD simulation of the complex of B6 with prostaglandin-endoperoxide synthase (PTGS) or cyclooxygenase (COX) showed that B6 occupied celecoxib binding site in COX with high affinity (the binding free energy of the complex with COX-1 was –10.5, and –11.2 kcal/mol with COX-2). Maximum anti-inflammatory activity was also shown by the B6 derivative in vivo, in the rat model of carrageenan-induced inflammation. B6, along with four other derivatives (B1, B5, B9 and B13) exhibited 80–90% free radical scavenging activity. The IC₅₀ values of these compounds were ≥40 µM. Griess nitrite and dichloro-dihydro-fluorescein-diacetate assays suggested a significant inhibition of nitric oxide and reactive oxygen species, especially by B6 and B9. Taken together, out of 16 derivatives, B6 is reported to have highest anti-inflammatory and antioxidant activity at a low dose level, which may be attributed to its two electron-donating hydroxyls. B6 is proposed to be an important scaffold for the synthesis of new drugs against PTGS for use in a myriad of inflammatory and infectious diseases.

Communicated by Ramaswamy H. Sarma

Keywords:

• 1,2,4-Triazole
• molecular docking
• MD simulation
• inflammation
• cyclooxygenases

Acknowledgements

BK acknowledges UGC for Maulana Azad National Fellowship. BK expresses her gratitude to Professor Faizan Ahmad, for his unconditional support, advice and guidance. AN acknowledges the Indian Council of Medical Research (ICMR) for Senior Research Fellowship. SA acknowledges the DBT Bioinformatics infrastructure facility, BIF, Jamia Hamdard under BTISNet.

Disclosure statement

The authors declare no conflict of interest.