Metal catalyst-free β-amination of branched rac-C8N-type such as C7N carbasugars via intramolecular aza-michael addition: Biological evolution, DFT studies and ADME properties

Abstract

In this study, a new stereospecific strategy for the preparation of C8N aminocyclohexenols such as C7N, validamine analogs were developed from starting compound 4 via intramolecular aza-michael β-amination reaction between α, β-unsaturated ketones and ammonia in methanol. The strategy was to produce C8N derivatives such as validamine C7N via Kornblum-DeLaMare rearrangement, which involves stereocontrolled amination of a double bond, esterification, carbonyl group reduction, benzofuran ring opening, ammonolysis of acetate groups. The mechanism of target molecules is discussed. Pseudosugars with different configurations containing an amino group at the anomeric position were tested against α-glucosidase, β-glucosidase, and α-amylase. Among these compounds, compound 12 against α-glucosidase, compound 14 against β-glucosidase, and compound 21 against α-amylase exhibited the best activity compared to acarbose. Moreover, enzyme kinetic studies to understand the enzyme inhibition mechanism and DFT studies to investigate binding interactions with enzyme active sites were performed on these compounds (12, 14, and 21). Additionally, the pharmacokinetic parameters (ADME) were examined using the QikProp module to determine their potential as drug candidates.