Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites

• DOI: 10.1021/acsinfecdis.0c00910
• Publication Date: 2021-03-06T01:11:56Z
• Authors: Meta Leshabane; Godwin Akpeko Dzi...; Dina Coertzen; Janette Reader; Phanankosi Moyo; Mariëtte van der ...; Kelly Chisanga; Consolata Nsanzub...; Richard Ferger; Erica Erlank; Nelius Venter; Lizette Koekemoer; Kelly Chibale; Lyn-Marie Birkholtz
• Keywords: Male; 0301 basic medicine; Life Cycle Stages; 0303 health sciences; Plasmodium falciparum; Gametocytes; Benzimidazole; Pyridobenzimidazole; Malaria; 3. Good health; 03 medical and health sciences; Animals; Humans; Transmission-blocking; Benzimidazoles; Parasites; Malaria, Falciparum

The continued emergence of resistance to front-line antimalarial treatments is of great concern. Therefore, new compounds that potentially have a novel target in various developmental stages of Plasmodium parasites are needed to treat patients and halt the spread of malaria. Here, several benzimidazole derivatives were screened for activity against the symptom-causing intraerythrocytic asexual blood stages and the transmissible gametocyte stages of P. falciparum. Submicromolar activity was obtained for 54 compounds against asexual blood stage parasites with 6 potent at IC50 < 100 nM while not displaying any marked toxicity against mammalian cells. Nanomolar potency was also observed against gametocytes with two compounds active against early stage gametocytes and two compounds active against late-stage gametocytes. The transmission-blocking potential of the latter was confirmed as they could prevent male gamete exflagellation and the lead compound reduced transmission by 72% in an in vivo mosquito feeding model. These compounds therefore have activity against multiple stages of Plasmodium parasites with potential for differential targets.