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

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

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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