Discovery and Structure-Activity Relationships of Quinazolinone-2-carboxamide Derivatives as Novel Orally Efficacious Antimalarials

  • J Med Chem. 2021 Sep 9;64(17):12582-12602. doi: 10.1021/acs.jmedchem.1c00441.
Benoît Laleu  1 ,  Yuichiro Akao  2 ,  Atsuko Ochida  2 ,  Sandra Duffy  3 ,  Leonardo Lucantoni  3 ,  David M Shackleford  4 ,  Gong Chen  4 ,  Kasiram Katneni  4 ,  Francis C K Chiu  4 ,  Karen L White  4 ,  Xue Chen  5 ,  Angelika Sturm  6 ,  Koen J Dechering  6 ,  Benigno Crespo  7 ,  Laura M Sanz  7 ,  Binglin Wang  5 ,  Sergio Wittlin  8  9 ,  Susan A Charman  4 ,  Vicky M Avery  3 ,  Nobuo Cho  2 ,  Masahiro Kamaura  2
Affiliations
  • 1. Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
  • 2. Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 3. Discovery Biology, Griffith University, Brisbane Innovation Park, Don Young Road, Nathan 4111, Queensland, Australia.
  • 4. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • 5. WuXi AppTec (Wuhan) Company Ltd., 666 Gaoxin Avenue, Donghu New Technology Development Area, Wuhan 430075, China.
  • 6. TropIQ Health Sciences, Transistorweg 5-C02, 6534 AT Nijmegen, The Netherlands.
  • 7. Global Health, GlaxoSmithKline R&D, Tres Cantos, 28760, Madrid, Spain.
  • 8. Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
  • 9. University of Basel, 4002 Basel, Switzerland.
PMID: 34437804 DOI: 10.1021/acs.jmedchem.1c00441
Abstract

A phenotypic high-throughput screen allowed discovery of quinazolinone-2-carboxamide derivatives as a novel antimalarial scaffold. Structure-activity relationship studies led to identification of a potent inhibitor 19f, 95-fold more potent than the original hit compound, active against laboratory-resistant strains of malaria. Profiling of 19f suggested a fast in vitro killing profile. In vivo activity in a murine model of human malaria in a dose-dependent manner constitutes a concomitant benefit.

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