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Optimized Synthesis and Antimalarial Activity of 1,2‐Dioxane‐4‐carboxamides
Author(s) -
Lombardo Marco,
Sonawane Dhiraj P.,
Quintavalla Arianna,
Trombini Claudio,
Dhavale Dilip D.,
Taramelli Donatella,
Corbett Yolanda,
Rondinelli Francesca,
Fattorusso Caterina,
Persico Marco,
TaglialatelaScafati Orazio
Publication year - 2014
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201301394
Subject(s) - chemistry , natural product , combinatorial chemistry , plasmodium falciparum , alkyl , chloroquine , stereochemistry , stereocenter , antimalarial agent , in vitro , organic chemistry , malaria , catalysis , enantioselective synthesis , biochemistry , biology , immunology
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.