Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205 / C.M. Woodley, G.L. Nixon, N. Basilico, S. Parapini, W.D. Hong, S.A. Ward, G.A. Biagini, S.C. Leung, D. Taramelli, K. Onuma, T. Hasebe, P.M. O'Neill. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 12:7(2021), pp. 1077-1085. [10.1021/acsmedchemlett.1c00031]

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205

N. Basilico;S. Parapini;D. Taramelli;
2021

Abstract

Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.
antimalarial; asymmetry; endoperoxide; melting point; Plasmodium falciparum; solubility
Settore MED/04 - Patologia Generale
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/874493
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