Pharmaceutics 2022, 14, 372. https://doi.org/10.3390/pharmaceutics14020372 www.mdpi.com/journal/pharmaceutics Article Potent Antiplasmodial Derivatives of Dextromethorphan Reveal the Ent-Morphinan Pharmacophore of Tazopsine-Type Alkaloids Antoinette Keita 1 , Jean-François Franetich 2,† , Maëlle Carraz 3,† , Loïse Valentin 2,4,† , Mallaury Bordessoules 2 , Ludivine Baron 2 , Pierre Bigeard 2 , Florian Dupuy 5,6 , Valentine Geay 7 , Maurel Tefit 2 , Véronique Sarrasin 8 , Sylvie Michel 7 , Catherine Lavazec 5,6 , Sandrine Houzé 1,8 , Dominique Mazier 2 , Valérie Soulard 2 , François-Hugues Porée 9, * and Romain Duval 1, * 1 UMR 261—MERIT, IRD, Université de Paris, 4 Avenue de l’Observatoire, 75006 Paris, France; antoinettekeita22@yahoo.com (A.K.); sandrine.houze@aphp.fr (S.H.) 2 Centre d’Immunologie et des Maladies Infectieuses, INSERM, CNRS, Sorbonne Université, 75013 Paris, France; jean-francois.franetich@upmc.fr (J.-F.F.); loise.valentin@gmail.com (L.V.); mallaurybordessoulles@gmail.com (M.B.); ludivine.baron.bio@gmail.com (L.B.); pierre.bigeard71@gmail.com (P.B.); maurel.tefit@upmc.fr (M.T.); dominique.mazier@sorbonne-universite.fr (D.M.); valerie.soulard@upmc.fr (V.S.) 3 UMR 152 Pharma-Dev, IRD, UPS, Université de Toulouse, 31400 Toulouse, France; maelle.carraz@ird.fr 4 Biopredic International, Parc d’Affaires de la Bretèche, Bldg A4, 35760 Saint-Grégoire, France 5 Laboratoire d’Excellence GR-Ex, 75015 Paris, France; florian.dupuy@inserm.fr (F.D.); catherine.lavazec@inserm.fr (C.L.) 6 Institut Cochin, Inserm U1016, CNRS UMR 8104, Université de Paris, 75014 Paris, France 7 UMR 8038—CiTCoM, CNRS, Université de Paris, 4 Avenue de l’Observatoire, 75006 Paris, France; valentine.geay@gmail.com (V.G.); sylvie.michel@u-paris.fr (S.M.) 8 CNR du Paludisme, AP-HP, Hôpital Bichat-Claude-Bernard, 46 Rue Henri-Huchard, 75018 Paris, France; veronique.sarrasin-hubert@aphp.fr 9 ISCR UMR CNRS 6226, Faculté de Pharmacie, Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35000 Rennes, France * Correspondence: francois-hugues.poree@univ-rennes1.fr (F.-H.P.); romain.duval@ird.fr (R.D.) † These authors contributed equally. Abstract: 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 har- boring significant antiplasmodial activity in vitro despite suboptimal prophylactic activity in a mu- rine model of malaria, precluding its direct repurposing against the disease. The targeted N-alkyla- tion 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 µM 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 µM and 13.2 µM 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). Keywords: malaria; Plasmodium berghei; Plasmodium falciparum; hepatic stages; blood stages; prophylaxis; tazopsine; dextromethorphan; N-alkylation; hit compound Citation: Keita, A.; Franetich, J.-F.; Carraz, M.; Valentin, L.; Bordessoulles, M.; Baron, L.; Bigeard, P.; Dupuy, F.; Geay, V.; Tefit, M.; et al. Potent Antiplasmodial Derivatives of Dextromethorphan Reveal the Ent-Morphinan Pharmacophore of Tazopsine-Type Alkaloids. Pharmaceutics 2022, 14, 372. https://doi.org/10.3390/pharmaceu- tics14020372 Academic Editor: Giuseppe De Rosa Received: 29 December 2021 Accepted: 3 February 2022 Published: 7 February 2022 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations. Copyright: © 2022 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).