Potent antiplasmodial derivatives of dextromethorphan reveal the ent-morphinan pharmacophore of tazopsine-type alkaloids

Keita, A.; Franetich, J. F.; /Carraz, Maëlle; Valentin, L.; Bordessoules, M.; Baron, L.; Bigeard, P.; Dupuy, F.; Geay, V.; Tefit, M.; Sarrasin, V.; Michel, S.; Lavazec, C.; Houze, S.; Mazier, D.; Soulard, V.; Poree, F. H.; /Duval, Romain

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dc.creator	Keita, A.
dc.creator	Franetich, J. F.
dc.creator	/Carraz, Maëlle
dc.creator	Valentin, L.
dc.creator	Bordessoules, M.
dc.creator	Baron, L.
dc.creator	Bigeard, P.
dc.creator	Dupuy, F.
dc.creator	Geay, V.
dc.creator	Tefit, M.
dc.creator	Sarrasin, V.
dc.creator	Michel, S.
dc.creator	Lavazec, C.
dc.creator	Houze, S.
dc.creator	Mazier, D.
dc.creator	Soulard, V.
dc.creator	Poree, F. H.
dc.creator	/Duval, Romain
dc.date	2022
dc.date.accessioned	2022-04-27T17:37:50Z
dc.date.available	2022-04-27T17:37:50Z
dc.identifier	https://www.documentation.ird.fr/hor/fdi:010084410
dc.identifier	oai:ird.fr:fdi:010084410
dc.identifier	Keita A., Franetich J. F., Carraz Maëlle, Valentin L., Bordessoules M., Baron L., Bigeard P., Dupuy F., Geay V., Tefit M., Sarrasin V., Michel S., Lavazec C., Houze S., Mazier D., Soulard V., Poree F. H., Duval Romain. Potent antiplasmodial derivatives of dextromethorphan reveal the ent-morphinan pharmacophore of tazopsine-type alkaloids. 2022, 14 (2), p. 372 [23 p.]
dc.identifier.uri	http://biblioteca-repositorio.clacso.edu.ar/handle/CLACSO/169116
dc.description	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).
dc.language	EN
dc.subject	malaria
dc.subject	Plasmodium berghei
dc.subject	Plasmodium falciparum
dc.subject	hepatic stages
dc.subject	blood stages
dc.subject	prophylaxis
dc.subject	tazopsine
dc.subject	dextromethorphan
dc.subject	N-alkylation
dc.subject	hit compound
dc.title	Potent antiplasmodial derivatives of dextromethorphan reveal the ent-morphinan pharmacophore of tazopsine-type alkaloids
dc.type	text