The relative rate of kill of the MMV Malaria Box compounds provide links to the mode of antimalarial action and highlight scaffolds of medicinal chemistry interest

Ullah, Imran, Sharma, Raman, Mete, Antonio, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Wetzel, Dawn M. and Horrocks, Paul D. (2020) 'The relative rate of kill of the MMV Malaria Box compounds provide links to the mode of antimalarial action and highlight scaffolds of medicinal chemistry interest'. Journal of Antimicrobial Chemotherapy, Vol 75, Issue 2, pp. 362-370.

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Abstract

Objectives: Rapid rate-of-kill (RoK) is a key parameter in the target candidate profile 1 (TCP1) for the next-generation antimalarial drugs for uncomplicated malaria, termed Single Encounter Radical Cure and Prophylaxis (SERCaP). TCP1 aims to rapidly eliminate the initial parasite burden, ideally as fast as artesunate, but minimally as fast as chloroquine. Here we explore whether the relative RoK of the Medicine for Malaria Venture (MMV) Malaria Box compounds are linked to their mode of action (MoA) and identify scaffolds of medicinal chemistry interest.

Methods: We used a Bioluminescence Relative RoK (BRRoK) assay over 6 and 48h, with exposure to equipotent-IC50 concentrations, to compare the cytocidal effects of Malaria Box compounds to benchmark antimalarials.

Results: BRRoK assay data demonstrate the following relative RoK from fast to slow: inhibitors of 31 PfATP4 > parasite hemoglobin catabolism > DHFR-TS > DHODH > bc1 complex. Core scaffold clustering analyses reveal intrinsic rapid cytocidal action for diamino-glycerols and 2- (aminomethyl)phenol, but slow action for 2-phenylbenzimidazoles, 8-hydroxyquinolines, and triazolopyrimidines.

Conclusions: This study provides proof of principle that a compound’s RoK is related to its MoA and that the target’s intrinsic RoK is also modified by factors affecting a drug’s access to it. Our findings highlight that as we use medicinal chemistry to improve potency, we can also improve the RoK for some scaffolds. Our BRRoK assay provides the necessary throughput for drug discovery and a critical decision-making tool to support development campaigns. Finally, two scaffolds, diamino-glycerols and 2-phenylbenzimidazoles, exhibit fast cytocidal action, inviting medicinal chemistry improvements towards TCP1 candidates.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1093/jac/dkz443
Depositing User:	Cathy Waldron
Date Deposited:	29 Oct 2019 17:47
Last Modified:	30 Oct 2020 02:02
URI:	https://archive.lstmed.ac.uk/id/eprint/12867

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