Potent Antiplasmodial Derivatives of Dextromethorphan Reveal the Ent -Morphinan Pharmacophore of Tazopsine-Type Alkaloids

• Published in: Pharmaceutics Vol. 14; no. 2; p. 372
• Main Authors: Keita, Antoinette, Franetich, Jean-François, Carraz, Maëlle, Valentin, Loïse, Bordessoules, Mallaury, Baron, Ludivine, Bigeard, Pierre, Dupuy, Florian, Geay, Valentine, Tefit, Maurel, Sarrasin, Véronique, Michel, Sylvie, Lavazec, Catherine, Houzé, Sandrine, Mazier, Dominique, Soulard, Valérie, Porée, François-Hugues, Duval, Romain
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 07.02.2022; MDPI
• Subjects: blood stages; Chemical Sciences; Chromatography; Drugs; hepatic stages; Malaria; Mutation; Parasites; Parasitic diseases; Plasmodium berghei; Plasmodium falciparum; prophylaxis; Reagents; Solvents; Africa; blood stages; Plasmodium falciparum; Plasmodium berghei; hepatic stages; hit compound; malaria; prophylaxis; tazopsine; dextromethorphan; N-alkylation
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics14020372

The alkaloid tazopsine was introduced in the late 2000s as a novel antiplasmodial hit compound active against hepatic stages, with the potential to develop prophylactic drugs based on this novel chemical scaffold. However, the structural determinants of tazopsine bioactivity, together with the exact definition of the pharmacophore, remained elusive, impeding further development. We found that the antitussive drug dextromethorphan (DXM) , 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 -alkylation of -DXM produced a small library of analogues with greatly improved activity over DXM against asexual stages. Amongst these, -2'-pyrrolylmethyl- -DXM showed a 2- to 36-fold superior inhibitory potency compared to tazopsine and DXM against liver and blood stages, with respectively 760 ± 130 nM and 2.1 ± 0.4 μM IC values, as well as liver/blood phase selectivity of 2.8. Furthermore, cpd. showed a 5- to 8-fold increase in activity relative to DXM against stages I-II and V gametocytes, with 18.5 μM and 13.2 μM IC values, respectively. Cpd. can thus be considered a promising novel hit compound against malaria in the -morphinan series with putative pan cycle activity, paving the way for further therapeutic development (e.g., investigation of its prophylactic activity in vivo).