Premium
Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers
Author(s) -
Lunga Mayibongwe J.,
Chisango Ruramai L.,
Weyers Carli,
Isaacs Michelle,
Taylor Dale,
Edkins Adrienne L.,
Khanye Setshaba D.,
Hoppe Heinrich C.,
Veale Clinton G. L.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800235
Subject(s) - artemisinin , plasmodium falciparum , thio , hela , antimalarial agent , chloroquine , chemistry , malaria , strain (injury) , pharmacology , stereochemistry , combinatorial chemistry , biology , biochemistry , in vitro , immunology , anatomy
Abstract Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1‐(5‐chloro‐1 H ‐indol‐3‐yl)‐2‐[(4‐cyanophenyl)thio]ethanone ( 13 ) and 1‐(5‐chloro‐1 H ‐indol‐3‐yl)‐2‐[(4‐nitrophenyl)thio]ethanone ( 14 ), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non‐haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long‐term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.