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

被引：0

作者：

Watson, Savannah J. ^{[1
]}

van der Watt, Mariette E. ^{[2
]}

Theron, Anjo ^{[3
]}

Reader, Janette ^{[1
]}

Tshabalala, Sizwe ^{[1
]}

Erlank, Erica ^{[4
]}

Koekemoer, Lizette L. ^{[4
]}

Naude, Mariska ^{[1
]}

Stampolaki, Marianna ^{[5
]}

Adewole, Feyisola ^{[6
]}

Sadowska, Katie ^{[6
]}

Perez-Lozano, Pilar ^{[7
]}

Turcu, Andreea L. ^{[8
,9
]}

Vazquez, Santiago ^{[8
,9
]}

Ko, Jihee ^{[10
]}

Mazurek, Ben ^{[10
]}

Singh, Davinder ^{[10
]}

Malwal, Satish R. ^{[10
]}

Njoroge, Mathew ^{[11
]}

Chibale, Kelly ^{[11
,12
,13
]}

Onajole, Oluseye K. ^{[6
]}

Kolocouris, Antonios ^{[5
]}

Oldfield, Eric ^{[10
]}

Birkholtz, Lyn-Marie ^{[1
]}

机构：

[1] Univ Pretoria, Inst Sustainable Malaria Control, Dept Biochem Genet & Microbiol, ZA-0002 Pretoria, South Africa

[2] Univ Pretoria, Inst Sustainable Malaria Control, Sch Hlth Syst & Publ Hlth SHSPH, ZA-0002 Pretoria, South Africa

[3] CSIR, Next Generat Hlth, ZA-0001 Pretoria, South Africa

[4] Univ Witwatersrand, Wits Res Inst Malaria, Fac Hlth Sci, Ctr Emerging Zoonot & Parasit Dis,Natl Inst Commun, ZA-2000 Johannesburg, South Africa

[5] Natl & Kapodistrian Univ Athens, Dept Pharm, Sect Pharmaceut Chem, Lab Med Chem, Athens 15771, Greece

[6] Roosevelt Univ, Coll Sci Hlth & Pharm, Dept Biol Phys & Hlth Sci, Chicago, IL 60605 USA

[7] Univ Barcelona, Fac Pharm & Food Sci, Dept Pharm & Pharmaceut Technol & Phys Chem, Barcelona 08028, Spain

[8] Univ Barcelona, Fac Farm & Ciencies Alimentacio, Dept Farmacol Toxicol & Quim Terapeut, Lab Quim Farmaceut,Unitat Assoc,CSIC, E-08028 Barcelona, Spain

[9] Univ Barcelona, Inst Biomed IBUB, E-08028 Barcelona, Spain

[10] Univ Illinois, Dept Chem, Urbana, IL 61801 USA

[11] Univ Cape Town, Drug Discovery & Dev Ctr H3D, ZA-7701 Cape Town, South Africa

[12] Univ Cape Town, Drug Discovery & Dev Ctr, South African Med Res Council, Dept Chem, ZA-7701 Cape Town, South Africa

[13] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Cape Town, South Africa

来源：

ACS INFECTIOUS DISEASES | 2024年 / 10卷 / 09期

基金：

英国医学研究理事会;

关键词：

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

D O I：

10.1021/acsinfecdis.4c00461

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3358 / 3367

页数：10

共 50 条

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