TY - JOUR
T1 - The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum
AU - Watson, Savannah J.
AU - van der Watt, Mariëtte E.
AU - Theron, Anjo
AU - Reader, Janette
AU - Tshabalala, Sizwe
AU - Erlank, Erica
AU - Koekemoer, Lizette L.
AU - Naude, Mariska
AU - Stampolaki, Marianna
AU - Adewole, Feyisola
AU - Sadowska, Katie
AU - Pérez-Lozano, Pilar
AU - Turcu, Andreea L.
AU - Vázquez, Santiago
AU - Ko, Jihee
AU - Mazurek, Ben
AU - Singh, Davinder
AU - Malwal, Satish R.
AU - Njoroge, Mathew
AU - Chibale, Kelly
AU - Onajole, Oluseye K.
AU - Kolocouris, Antonios
AU - Oldfield, Eric
AU - Birkholtz, Lyn Marié
N1 - We thank Abel Tilahun for his technical contribution in compound synthesis. We gratefully acknowledge the Bill and Melinda Gates Foundation Grand Challenges Africa grant (GCA/DD2/Round10/021/001 to L.M.B.) managed through the Science for Africa Foundation (SFA); the Medicines for Malaria Venture, the South African Medical Research Council (SAMRC to L.M.B. and K.C.) and the South African Research Chairs Initiative (SARChI) of the Department of Science and Innovation (DSI) administered through the South African National Research Foundation (NRF) for their support (L.M.B.\u2500UID 84627 and K.C.); K.C. is the Neville Isdell Chair in African-centric Drug Discovery and Development and thanks Neville Isdell for generously funding the Chair. The Office of Student Research, and Honors Program at Roosevelt University for funding provided to A.T., F.A. & K.S., and a Harriet A. Harlin Professorship and the University of Illinois Foundation to E.O.. We thank Gary L. Turner (Spectral Data Services, Inc.) for providing the qNMR analysis of SQ109 ( 1 ). We also thank Anjo Theron (Council for Scientific and Industrial Research) for biological analyses.
PY - 2024/9/13
Y1 - 2024/9/13
N2 - 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.
AB - 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.
KW - antimalarial
KW - multistage
KW - Plasmodium falciparum
KW - SQ109
KW - transmission-blocking
UR - http://www.scopus.com/inward/record.url?scp=85201828710&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85201828710&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.4c00461
DO - 10.1021/acsinfecdis.4c00461
M3 - Article
C2 - 39143042
AN - SCOPUS:85201828710
SN - 2373-8227
VL - 10
SP - 3358
EP - 3367
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 9
ER -