Quest for a potent antimalarial drug lead: Synthesis and evaluation of 6,7-dimethoxyquinazoline-2,4-diamines

Yuki Mizukawa; Mayumi Ikegami-Kawai; Masako Horiuchi; Marcel Kaiser; Masayoshi Kojima; Seiki Sakanoue; Seiya Miyagi; Christian Nanga Chick; Hiroyuki Togashi; Masayoshi Tsubuki; Masataka Ihara; Toyonobu Usuki; Isamu Itoh

doi:10.1016/j.bmc.2021.116018

Quest for a potent antimalarial drug lead: Synthesis and evaluation of 6,7-dimethoxyquinazoline-2,4-diamines

Bioorg Med Chem. 2021 Mar 1:33:116018. doi: 10.1016/j.bmc.2021.116018. Epub 2021 Jan 16.

Authors

Affiliations

¹ Synstar Japan Co., Ltd., 2-9-46 Sakaecho, Odawara, Kanagawa 250-0011, Japan.
² Faculty of Pharmaceutical Science, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan. Electronic address: m-kawai@hoshi.ac.jp.
³ Faculty of Pharmaceutical Science, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
⁴ Medical Parasitology & Infection Biology, Swiss Tropical & Public Health Institute, Socinstrasse 57, 4000 Basel CH-4002, Switzerland; University of Basel, Petersplatz 1, 4003 Basel CH-4003, Switzerland.
⁵ Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan.
⁶ Synstar Japan Co., Ltd., 2-9-46 Sakaecho, Odawara, Kanagawa 250-0011, Japan; Faculty of Pharmaceutical Science, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
⁷ Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan. Electronic address: t-usuki@sophia.ac.jp.
⁸ Synstar Japan Co., Ltd., 2-9-46 Sakaecho, Odawara, Kanagawa 250-0011, Japan. Electronic address: isamuito@peach.ocn.ne.jp.

PMID: 33524940
DOI: 10.1016/j.bmc.2021.116018

Abstract

Quinazolines have long been known to exert varied pharmacologic activities that make them suitable for use in treating hypertension, viral infections, tumors, and malaria. Since 2014, we have synthesized approximately 150 different 6,7-dimethoxyquinazoline-2,4-diamines and evaluated their antimalarial activity via structure-activity relationship studies. Here, we summarize the results and report the discovery of 6,7-dimethoxy-N⁴-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine (20, SSJ-717), which exhibits high antimalarial activity as a promising antimalarial drug lead.

Keywords: Antimalarial drug; Derivatization; Quinazoline-2,4-diamines; SAR.

Publication types

Review

MeSH terms

Animals
Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery
Female
Malaria, Falciparum / drug therapy*
Mice
Mice, Inbred ICR
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Structure-Activity Relationship

Substances

Antimalarials