Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

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-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-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.

The Plasmodium falciparum eIK1 kinase (PfeIK1) is central for melatonin synchronization in the human malaria parasite. Melatotosil blocks melatonin action on parasite cell cycle

“…In the same line, Lunga et al tested a library of indole compounds as potential antimalarials. 36,45,46 Other indole compound, indolmycin, inhibit the protein translation in P. falciparum apicoplast by inhibiting the tryptophanyl-tRNA synthetase leading to a delayed death of the parasite. 47,48 Since PfeIK1parasites were susceptible to indole derivatives, we also investigated if PfeIK1 knockout would interfere with susceptibility of parasite against classical antimalarials.…”

Role of Melatonin in the Synchronization of Asexual Forms in the Parasite Plasmodium falciparum

“…The authors pointed out that methylation at C2 decreased the activity of the compounds. For the C5 substitutions, hydrophobicity was more important than electron-withdrawing capacity, and substitutions with chloride, fluorine, methyl, methoxy, or nitrile moieties pointed to the existence of an optimal substituent size, with the best result obtained with a chloride radical in C5 [ 111 ]. The most promising compounds were further tested against P. falciparum NF54 and strain K1, which are resistant to chloroquine.…”

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…conducted a focussed optimisation campaign, identifying compounds 75 as a low‐nanomolar inhibitor of P. falciparum , with no observed cytotoxicity in a HeLa cell line assay . A follow‐up study seeking to further elucidate SAR features culminated in compound 76 , as a non‐haemolytic anti‐plasmodial which possessed low‐nanomolar activity against the chloroquine‐sensitive 3D7 strain . Priority compounds from this library were subjected to additional independent anti‐plasmodial analysis.…”

“…Priority compounds from this library were subjected to additional independent anti‐plasmodial analysis. Interestingly, while activity was seemingly reduced against the isogenic NF54 line into the mid‐nanomolar range, the activity displayed against chloroquine‐sensitive NF54 was maintained against a chloroquine‐resistant K1 line, indicating the absence of cross‐resistance …”