Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies

• Published in: Bioorganic Chemistry
• Main Author: Butt A.R.S.; Abbasi M.A.; Aziz-ur-Rehman; Siddiqui S.Z.; Raza H.; Hassan M.; Shah S.A.A.; Shahid M.; Seo S.-Y.
• Format: Article
• Language: English
• Published: Academic Press Inc. 2019
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85061452076&doi=10.1016%2fj.bioorg.2019.01.036&partnerID=40&md5=6014762675de57ae6db479fe795c8cfe

The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1 H NMR, 13 C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants K i calculated from Dixon plots for this compound was 0.0027 µM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders. © 2019 Elsevier Inc.