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

Savannah J. Watson, Mariëtte E. van der Watt, Anjo Theron, Janette Reader, Sizwe Tshabalala, Erica Erlank, Lizette L. Koekemoer, Mariska Naude, Marianna Stampolaki, Feyisola Adewole, Katie Sadowska, Pilar Pérez-Lozano, Andreea L. Turcu, Santiago Vázquez, Jihee Ko, Ben Mazurek, Davinder Singh, Satish R. Malwal, Mathew Njoroge, Kelly ChibaleOluseye K. Onajole, Antonios Kolocouris, Eric Oldfield, Lyn Marié Birkholtz

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3358-3367
Number of pages10
JournalACS Infectious Diseases
Volume10
Issue number9
DOIs
StatePublished - Sep 13 2024

Keywords

  • antimalarial
  • multistage
  • Plasmodium falciparum
  • SQ109
  • transmission-blocking

ASJC Scopus subject areas

  • Infectious Diseases

Fingerprint

Dive into the research topics of 'The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum'. Together they form a unique fingerprint.

Cite this