New Derivatives of the Multi-Stage Active Malaria Box Compound MMV030666 and Their Antiplasmodial Potencies

Theresa Hermann; Robin Wallner; Johanna Dolensky; Werner Seebacher; Eva-Maria Pferschy-Wenzig; Marcel Kaiser; Pascal Mäser; Robert Weis

doi:10.3390/ph15121503

New Derivatives of the Multi-Stage Active Malaria Box Compound MMV030666 and Their Antiplasmodial Potencies

Pharmaceuticals (Basel). 2022 Dec 2;15(12):1503. doi: 10.3390/ph15121503.

Authors

Theresa Hermann¹, Robin Wallner¹, Johanna Dolensky¹, Werner Seebacher¹, Eva-Maria Pferschy-Wenzig², Marcel Kaiser^{3

4}, Pascal Mäser^{3

4}, Robert Weis¹

Affiliations

¹ Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Schubertstraße 1, 8010 Graz, Austria.
² Pharmacognosy, Institute of Pharmaceutical Sciences, University of Graz, Beethovenstraße 8, 8010 Graz, Austria.
³ Swiss Tropical and Public Health Institute, Kreuzstraße 2, Allschwil, CH-4123 Basel, Switzerland.
⁴ Faculty of Philosophy and Natural Sciences, Swiss Tropical and Public Health Institute Petersplatz 1, University of Basel, CH-4003 Basel, Switzerland.

Abstract

MMV's Malaria Box compound MMV030666 shows multi-stage activity against various strains of Plasmodium falciparum and lacks resistance development. To evaluate the importance of its diarylether partial structure, diarylthioethers and diphenylamines with varying substitution patterns were prepared. A number of evident structure-activity relationships were revealed. Physicochemical and pharmacokinetic parameters were determined experimentally (passive permeability) or calculated. Compared to the lead compound a diarylthioether was more active and less cytotoxic resulting in an excellent selectivity index of 850. In addition, pharmacokinetic and physicochemical parameters were improved.

Keywords: MMV; PAMPA; Plasmodium falciparum; cytotoxicity; malaria.

Grants and funding

This research received no external funding.