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

Pharmaceutics

卷:14

Catherine Lavazec¹  Florian Dupuy¹  Véronique Sarrasin²  Valérie Soulard³  Loïse Valentin³  Dominique Mazier³  Ludivine Baron³  Pierre Bigeard³  Mallaury Bordessoules³  Maurel Tefit³  Jean-François Franetich³  François-Hugues Porée⁴  Maëlle Carraz⁵  Antoinette Keita⁶  Sandrine Houzé⁶  Romain Duval⁶  Sylvie Michel⁷  Valentine Geay⁷ 

[1] Laboratoire d’Excellence GR-Ex, 75015 Paris, France;

[2] CNR du Paludisme, AP-HP, Hôpital Bichat-Claude-Bernard, 46 Rue Henri-Huchard, 75018 Paris, France;

[3] Centre d’Immunologie et des Maladies Infectieuses, INSERM, CNRS, Sorbonne Université, 75013 Paris, France;

[4] ISCR UMR CNRS 6226, Faculté de Pharmacie, Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35000 Rennes, France;

[5] UMR 152 Pharma-Dev, IRD, UPS, Université de Toulouse, 31400 Toulouse, France;

[6] UMR 261—MERIT, IRD, Université de Paris, 4 Avenue de l’Observatoire, 75006 Paris, France;

[7] UMR 8038—CiTCoM, CNRS, Université de Paris, 4 Avenue de l’Observatoire, 75006 Paris, France;

关键词: malaria;    Plasmodium berghei;    Plasmodium falciparum;    hepatic stages;    blood stages;    prophylaxis;   

DOI  :  10.3390/pharmaceutics14020372

来源: DOAJ

【 摘 要 】

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 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).

【 授权许可】

Unknown