Synthesis and molecular modeling studies of naphthazarin derivatives as novel selective inhibitors of ?-glucosidase and ?-amylase

Abstract

Diabetes mellitus is known as one of the most life-threatening diseases and has attracted the attention of medicinal chemists. The design and synthesis of novel potential candidates for the inhibition of alpha-amylase and alpha-glucosidase enzymes which are responsible for the digestion of dietary carbohydrates are an important approach for the treatment of diabetes. In this current work, a range of novel mono and naphthazarin derivatives were successfully synthesized by the esterification reaction of naphthazarin with different benzoyl chlorides and heterocyclic acyl chlorides. The synthesized compounds were subjected to in vitro antidiabetic activities through alpha-glucosidase and alpha-amylase inhibition properties. Despite the limited inhibition potential against alpha-amylase enzymes, naphthazarin derivatives would be promising targets for antidiabetic study due to the specificity for alpha-glucosidase enzyme. The compound 18 revealed a dual inhibition behavior, however all the other active compounds were detected as specific for alpha-glucosidase inhibition and quite potent compared to the standard acarbose which is promising for eliminating the side effects associated with the non-selectivity of acarbose. The compound 19 was the best candidate for inhibition with IC50 value of 7.4 mu M and resulted 150-fold better activity compared to the standard. Free energy calculations support the experimental binding affinity of compound 19 found as the most promising drug candidate for alpha-glucosidase among the synthesized compounds. The plausible binding mode and the interaction of compound 19 complexed with a-glucosidase has been revealed by MD simulations. (c) 2023 Elsevier B.V. All rights reserved.