Design, synthesis and pharmacological evaluation of novel substituted quinoline-2-carboxamide derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents

Vivek K Vyas; Bhavesh Variya; Manjunath D Ghate

doi:10.1016/j.ejmech.2014.05.064

Design, synthesis and pharmacological evaluation of novel substituted quinoline-2-carboxamide derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents

Eur J Med Chem. 2014 Jul 23:82:385-93. doi: 10.1016/j.ejmech.2014.05.064. Epub 2014 May 27.

Authors

Vivek K Vyas¹, Bhavesh Variya², Manjunath D Ghate³

Affiliations

¹ Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
² Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
³ Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India. Electronic address: manjunath.ghate@nirmauni.ac.in.

PMID: 24929289
DOI: 10.1016/j.ejmech.2014.05.064

Abstract

In continuation of our research for novel human dihydroorotate dehydrogenase (hDHODH) inhibitors, herein we reported design, synthesis and pharmacological evaluation of novel substituted quinoline-2-carboxamide derivatives. Human DHODH enzyme inhibition assay was used to screen the synthesized compounds as hDHODH inhibitors. The synthesized compounds were also evaluated for their antiproliferative effects on the cancer cell lines (HEP-3B and A-375) to establish a proof as anticancer agents. The chemical structures of compounds were confirmed by (1)H, (13)C NMR, IR, MS and elemental analysis. The purity of compounds was also checked by HPLC analysis. Compounds with bulky groups (-OCH3, -OCF3 and -CF3) at C6-position of quinoline ring showed good activity.

Keywords: Anticancer agents; Dihydroorotate dehydrogenase (DHODH); Pyrimidine biosynthesis; Quinolines; hDHODH inhibitors.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dihydroorotate Dehydrogenase
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
Oxidoreductases Acting on CH-CH Group Donors / metabolism
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Dihydroorotate Dehydrogenase
Enzyme Inhibitors
Quinolines
Oxidoreductases Acting on CH-CH Group Donors