Compounds from the Medicines for Malaria Venture Box Inhibit In Vitro Growth of Babesia divergens, a Blood-Borne Parasite of Veterinary and Zoonotic Importance.

Mohamed Abdo Rizk,Mahmoud S Alkhoudary,Mohamed M Abdel-Daim,Ikuo Igarashi,Khalaf F Alsharif,Shimaa Abd El-Salam El-Sayed

doi:10.3390/molecules26237118

Abstract

Babesiosis is an infectious disease with an empty drug pipeline. A search inside chemical libraries for novel potent antibabesial candidates may help fill such an empty drug pipeline. A total of 400 compounds (200 drug-like and 200 probe-like) from the Malaria Box were evaluated in the current study against the in vitro growth of Babesia divergens (B. divergens), a parasite of veterinary and zoonotic importance. Novel and more effective anti-B. divergens drugs than the traditionally used ones were identified. Seven compounds (four drug-like and three probe-like) revealed a highly inhibitory effect against the in vitro growth of B. divergens, with IC50s ≤ 10 nanomolar. Among these hits, MMV006913 exhibited an IC50 value of 1 nM IC50 and the highest selectivity index of 32,000. The atom pair fingerprint (APfp) analysis revealed that MMV006913 and MMV019124 showed maximum structural similarity (MSS) with atovaquone and diminazene aceturate (DA), and with DA and imidocarb dipropionate (ID), respectively. MMV665807 and MMV665850 showed MMS with each other and with ID. Of note, a high concentration (0.75 IC50) of MMV006913 caused additive inhibition of B. divergens growth when combined with DA at 0.75 or 0.50 IC50. The Medicines for Malaria Venture box is a treasure trove of anti-B. divergens candidates according to the obtained results.

Highlights

Babesiosis is a tick-borne parasitic disease causing serious economic losses in the livestock industry worldwide [1]
The Malaria Box is a valuable source of commercially available compounds, representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against P. falciparum, and was made available to identify novel drugs to combat other apicomplexan parasites [8]
The in vitro inhibitory effects of Malaria Box compounds against 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, and the NCI60 human cancer cell line were published within a large, complete dataset [6]

Summary

Introduction

Babesiosis is a tick-borne parasitic disease causing serious economic losses in the livestock industry worldwide [1]. Babesia divergens (B. divergens) is considered one of the main causes of veterinary and human babesiosis in Europe [3]. The currently available drugs used to control Babesia infection in animals, imidocarb dipropionate (ID) and diminazene aceturate (DA), have proven their limitations regarding toxicity to hosts and parasite resistance [4]. Severe cases of human babesiosis have not responded to treatment with the most commonly used anti-B. divergens drugs, such as clindamycin, azithromycin, quinine, atovaquone, and tetracycline [5]. The discovery and development of more effective and safer antibabesial agents have become an urgent need. The Malaria Box, a collection of 400 compounds, was designed to be the starting point for drug discovery for Plasmodium falciparum (P. falciparum) and other medically important pathogens [6].

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Conclusion