2. Academic Validation
  3. The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum

  • ACS Infect Dis. 2024 Sep 13;10(9):3358-3367. doi: 10.1021/acsinfecdis.4c00461.
Savannah J Watson,  Mariëtte E van der Watt,  Anjo Theron 1,  Janette Reader,  Sizwe Tshabalala,  Erica Erlank 2,  Lizette L Koekemoer 2,  Mariska Naude,  Marianna Stampolaki 3,  Feyisola Adewole 4,  Katie Sadowska 4,  Pilar Pérez-Lozano 5,  Andreea L Turcu 6,  Santiago Vázquez 6,  Jihee Ko 7,  Ben Mazurek 7,  Davinder Singh 7,  Satish R Malwal 7,  Mathew Njoroge 8,  Kelly Chibale 8 9,  Oluseye K Onajole 4,  Antonios Kolocouris 3,  Eric Oldfield 7,  Lyn-Marié Birkholtz
Affiliations

Affiliations

  • 1 Next Generation Health, Council for Scientific and Industrial Research, Pretoria 0001, South Africa.
  • 2 Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Services, Wits Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Johannesburg 2000, South Africa.
  • 3 Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, 15771 Athens, Greece.
  • 4 Department of Biological, Physical and Health Sciences, College of Science, Health & Pharmacy, Roosevelt University, 425 South Wabash Avenue, Chicago, Illinois 60605, United States.
  • 5 Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona 08028, Spain.
  • 6 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Barcelona E-08028, Spain.
  • 7 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
  • 8 Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Capetown 7701, South Africa.
  • 9 South African Medical Research Council Drug Discovery and Development Centre, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, Capetown 7701, South Africa.
PMID: 39143042 DOI: 10.1021/acsinfecdis.4c00461
Abstract

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria Parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

Keywords

Plasmodium falciparum; SQ109; antimalarial; multistage; transmission-blocking.

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