Synthesis of 2-,4,-6-, and/or 7-substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents: 3D QSAR-assisted design

Vivek K Vyas; Gulamnizami Qureshi; Drashti Oza; Hardik Patel; Krupali Parmar; Palak Patel; Manjunath D Ghate

doi:10.1016/j.bmcl.2019.01.038

Synthesis of 2-,4,-6-, and/or 7-substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents: 3D QSAR-assisted design

Bioorg Med Chem Lett. 2019 Apr 1;29(7):917-922. doi: 10.1016/j.bmcl.2019.01.038. Epub 2019 Jan 31.

Authors

Vivek K Vyas¹, Gulamnizami Qureshi², Drashti Oza², Hardik Patel³, Krupali Parmar³, Palak Patel³, Manjunath D Ghate²

Affiliations

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

PMID: 30738663
DOI: 10.1016/j.bmcl.2019.01.038

Abstract

Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC₅₀ value of 1.56 µM and 1.22 µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.

Keywords: 3D QSAR; Anticancer agents; Human dihydroorotate dehydrogenase (hDHODH); Substituted quinolines; hDHODH inhibitors.

Publication types

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

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Dihydroorotate Dehydrogenase
Drug Design*
Humans
Models, Molecular
Molecular Structure
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
Quantitative Structure-Activity Relationship
Quinolines / chemistry*
Quinolines / pharmacology*

Substances

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