Optimized Synthesis and Antimalarial Activity of 1, 2‐Dioxane‐4‐carboxamides. Issue 8 (8th January 2014)

• Record Type: Journal Article
• Authors: Lombardo, Marco; Sonawane, Dhiraj P.; Quintavalla, Arianna; Trombini, Claudio; Dhavale, Dilip D.; Taramelli, Donatella; Corbett, Yolanda; Rondinelli, Francesca; Fattorusso, Caterina; Persico, Marco; Taglialatela‐Scafati, Orazio
• Is Part Of: European journal of organic chemistry. Issue 8(2014)
• Page Start: 1607
• Page End: 1614
• Publication Date: 2014-01-08
• Subjects: Manganese -- Redox chemistry -- Amides -- Cycloaddition -- Radicals -- O–O activation -- Medicinal chemistry -- Anti­malarial activity; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201301394
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract: We recently proposed 3‐methoxy‐4‐methoxycarbonyl‐1, 2‐dioxanes3 as promising scaffolds enabling access to potential antimalarial drugs. We present here an optimized two‐step synthesis of3 characterized by high yields, simple work‐up procedures and high diastereoselectivity allowing us to readily prepare3 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‐carboxamides8a –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 analogue3 . 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. Abstract : An optimized two‐step protocol for the synthesis of 3‐methoxy‐4‐methoxycarbonyl‐1, 2‐dioxanes is reported. This approach is exploited for the synthesis of a new family of 4‐carboxamide derivatives with interesting antimalarial activities.