The novel bis-1,2,4-triazine MIPS-0004373 demonstrates rapid and potent activity against all blood stages of the malaria parasite

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Ellis, Katherine M
Lucantoni, Leonardo
Chavchich, Marina
Abraham, Matthew
De Paoli, Amanda
Luth, Madeline R
Zeeman, Anne-Marie
Delves, Michael J
Terán, Fernando Sánchez-Román
Straschil, Ursula
Baum, Jake
Kocken, Clemens Hm
Ralph, Stuart A
Avery, Vicky M
et al.
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Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore, and are proposed to act by a novel, but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine, MIPS-0004373, across the mammalian lifecycle stages of the parasite, and profiled the kinetics of activity against blood and transmission-stage parasites in vitro and in vivo. MIPS-0004373 demonstrated rapid and potent activity against P. falciparum, with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo, suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually-committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model, but no activity against P. cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine, MIPS-0004373, efficiently cleared an established P. berghei infection in vivo, with efficacy similar to artesunate and chloroquine, and a recrudescence profile comparable to chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development towards a novel treatment for acute malaria.

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Antimicrob Agents Chemother
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© 2021 American Society for Microbiology. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
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Medical microbiology
Clinical pharmacology and therapeutics
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Ellis, KM; Lucantoni, L; Chavchich, M; Abraham, M; De Paoli, A; Luth, MR; Zeeman, A-M; Delves, MJ; Terán, FS-R; Straschil, U; Baum, J; Kocken, CH; Ralph, SA; Avery, VM; et al., The novel bis-1,2,4-triazine MIPS-0004373 demonstrates rapid and potent activity against all blood stages of the malaria parasite., Antimicrob Agents Chemother, 2021