We recently proposed 3-methoxy-4-methoxycarbonyl-1,2-dioxanes 3 as promising scaffolds enabling access to potential antimalarial drugs. We present here an optimized two-step synthesis of 3 characterized by high yields, simple work-up procedures and high diastereoselectivity allowing us to readily prepare 3 on multigram scale. The versatility of the 1,2- dioxane scaffold was demonstrated by our generation of a new family of 1,2-dioxane-4-carboxamides 8a–h and the realization of their in vitro activities against chloroquine-sensitive (D10) and chloroquine-resistant (W2) P. falciparum strains. In particular, one of these amides (8e), displayed antimalarial activity on par with the natural product lead plakortin and was 5-fold more active than its methyl ester analogue 3. Structure–activity relationship (SAR) analysis supported by DFT calculations revealed that, for this family of compounds, alkyl substituents at C6 dictate, in large part, the degree of antimalarial activity. This finding contrasts those previously observed for the ester series.

Optimized Synthesis and Antimalarial Activity of 1,2-Dioxane-4-carboxamides

LOMBARDO, MARCO;QUINTAVALLA, ARIANNA;TROMBINI, CLAUDIO;
2014

Abstract

We recently proposed 3-methoxy-4-methoxycarbonyl-1,2-dioxanes 3 as promising scaffolds enabling access to potential antimalarial drugs. We present here an optimized two-step synthesis of 3 characterized by high yields, simple work-up procedures and high diastereoselectivity allowing us to readily prepare 3 on multigram scale. The versatility of the 1,2- dioxane scaffold was demonstrated by our generation of a new family of 1,2-dioxane-4-carboxamides 8a–h and the realization of their in vitro activities against chloroquine-sensitive (D10) and chloroquine-resistant (W2) P. falciparum strains. In particular, one of these amides (8e), displayed antimalarial activity on par with the natural product lead plakortin and was 5-fold more active than its methyl ester analogue 3. Structure–activity relationship (SAR) analysis supported by DFT calculations revealed that, for this family of compounds, alkyl substituents at C6 dictate, in large part, the degree of antimalarial activity. This finding contrasts those previously observed for the ester series.
Marco Lombardo; Dhiraj P. Sonawane; Arianna Quintavalla; Claudio Trombini; Dilip D. Dhavale; Donatella Taramelli; Yolanda Corbett; Francesca Rondinelli; Caterina Fattorusso; Marco Persico; Orazio Taglialatela-Scafati
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/260484
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