Abstract:
Diabetes mellitus, particularly type II diabetes mellitus, is a metabolic condition that has a substantial impact on
the health of individuals. The implication of diabetes with increased risk of cardiovascular diseases (CVD) and,
consequently, myocardial infarction is well established. However, developing new antidiabetic drugs with an
established efficacy on cardiovascular health is an underdeveloped area of research. To address this, in the
present study, a new series of chromene-3-carboxylate derivatives (1B1–1B22) as dual inhibitors of Angiotensin
II Type 1 Receptor (AT1R) and Neprilysin (NEP), which are recognized targets in diabetes with CVD, is reported.
The compounds were rationally designed and synthesized, considering the pharmacophoric features of these two
targets. The evaluation was performed via glucose uptake, α-amylase, AT1R, and NEP inhibition assay. The
derivatives were found to increase glucose uptake and inhibit all three targets, of which compound 1B15 was the
most active. The most active compound, 1B15, reduced the oxidative stress and restored the mitochondrial
membrane potential. The biological findings were further corroborated by in silico studies, which included
molecular modelling and dynamics. It was deduced that 1B15 remains unionized in acidic to weak basic pH and
may be passively absorbed. Further, the molecule was found to undergo hydroxylation as a means of Phase I
metabolism and glucuronic conjugation in Phase II. The wet lab experiments on 1B15 further validated the insilico
absorption and metabolism prediction. The compounds, particularly 1B15, could be explored further as a
lead for its utility as an antidiabetic with profound implications on cardiovascular health.