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

Abdul Rehman Sadiq Butt; Muhammad Athar Abbasi; Aziz-Ur-Rehman; Sabahat Zahra Siddiqui; Hussain Raza; Mubashir Hassan; Syed Adnan Ali Shah; Muhammad Shahid; Sung-Yum Seo

doi:10.1016/j.bioorg.2019.01.036

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

Bioorg Chem. 2019 May:86:459-472. doi: 10.1016/j.bioorg.2019.01.036. Epub 2019 Jan 26.

Authors

Abdul Rehman Sadiq Butt¹, Muhammad Athar Abbasi², Aziz-Ur-Rehman¹, Sabahat Zahra Siddiqui¹, Hussain Raza³, Mubashir Hassan³, Syed Adnan Ali Shah⁴, Muhammad Shahid⁵, Sung-Yum Seo⁶

Affiliations

¹ Department of Chemistry, Government College University, Lahore 54000, Pakistan.
² Department of Chemistry, Government College University, Lahore 54000, Pakistan; College of Natural Sciences, Department of Biological Sciences, Kongju National University, Gongju 32588, South Korea. Electronic address: abbasi@gcu.edu.pk.
³ College of Natural Sciences, Department of Biological Sciences, Kongju National University, Gongju 32588, South Korea.
⁴ Faculty of Pharmacy and Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Level 9, FF3, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
⁵ Department of Biochemistry, University of Agriculture, Faisalabad 38040, Pakistan.
⁶ College of Natural Sciences, Department of Biological Sciences, Kongju National University, Gongju 32588, South Korea. Electronic address: dnalove@kongju.ac.kr.

PMID: 30772647
DOI: 10.1016/j.bioorg.2019.01.036

Abstract

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 ¹H NMR, ¹³C 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.

Keywords: Acetamides; Binding energy; Hemolytic; Melanogenesis; Thiazole; Triazole; Tyrosinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / pharmacology*
Agaricales / enzymology
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Kinetics
Molecular Docking Simulation*
Molecular Structure
Monophenol Monooxygenase / antagonists & inhibitors*
Monophenol Monooxygenase / metabolism
Structure-Activity Relationship

Substances

Acetamides
Enzyme Inhibitors
Heterocyclic Compounds
Monophenol Monooxygenase