Keita A. auteur aut IRD Franetich J. F. auteur aut IRD Carraz Maëlle auteur aut IRD Valentin L. auteur aut IRD Bordessoules M. auteur aut IRD Baron L. auteur aut IRD Bigeard P. auteur aut IRD Dupuy F. auteur aut IRD Geay V. auteur aut IRD Tefit M. auteur aut IRD Sarrasin V. auteur aut IRD Michel S. auteur aut IRD Lavazec C. auteur aut IRD Houze S. auteur aut IRD Mazier D. auteur aut IRD Soulard V. auteur aut IRD Poree F. H. auteur aut IRD Duval Romain auteur aut IRD text journalArticle eng text/pdf reformatted digital access The alkaloid tazopsine 1 was introduced in the late 2000s as a novel antiplasmodial hit compound active against Plasmodium falciparum hepatic stages, with the potential to develop prophylactic drugs based on this novel chemical scaffold. However, the structural determinants of tazopsine 1 bioactivity, together with the exact definition of the pharmacophore, remained elusive, impeding further development. We found that the antitussive drug dextromethorphan (DXM) 3, although lacking the complex pattern of stereospecific functionalization of the natural hit, was harboring significant antiplasmodial activity in vitro despite suboptimal prophylactic activity in a murine model of malaria, precluding its direct repurposing against the disease. The targeted N-alkylation of nor-DXM 15 produced a small library of analogues with greatly improved activity over DXM 3 against P. falciparum asexual stages. Amongst these, N-2 '-pyrrolylmethyl-nor-DXM 16i showed a 2- to 36-fold superior inhibitory potency compared to tazopsine 1 and DXM 3 against P. falciparum liver and blood stages, with respectively 760 +/- 130 nM and 2.1 +/- 0.4 mu M IC50 values, as well as liver/blood phase selectivity of 2.8. Furthermore, cpd. 16i showed a 5- to 8-fold increase in activity relative to DXM 3 against P. falciparum stages I-II and V gametocytes, with 18.5 mu M and 13.2 mu M IC50 values, respectively. Cpd. 16i can thus be considered a promising novel hit compound against malaria in the ent-morphinan series with putative pan cycle activity, paving the way for further therapeutic development (e.g., investigation of its prophylactic activity in vivo). specialized malaria Plasmodium berghei Plasmodium falciparum hepatic stages blood stages prophylaxis tazopsine dextromethorphan N-alkylation hit compound 050 052 020 14 2 372 [23 ] 2022 https://www.documentation.ird.fr/hor/fdi:010084410 10.3390/pharmaceutics14020372 [F B010084410] https://www.documentation.ird.fr/hor/fdi:010084410 https://horizon.documentation.ird.fr/exl-doc/pleins_textes/2022-04/010084410.pdf IRD - Base Horizon / Pleins textes 2022-04-06 2025-02-24 fdi:010084410 fre