Dynamics of small molecule-enzyme interactions: Novel benzenesulfonamides as multi-target agents endowed with inhibitory effects against some metabolic enzymes

In contemporary medicinal chemistry, employing a singular small molecule to concurrently multi-target disparate molecular entities is emerging as a potent strategy in the ongoing battle against metabolic disease. In this study, we present the meticulous design, synthesis, and comprehensive biological evaluation of a novel series of 1,2,3-triazolylmethylthio-1,3,4-oxadiazolylbenzenesulfonamide derivatives (8a 8a-m ) as potential multi-target inhibitors against human carbonic anhydrase (EC.4.2.1.1, h CA I/II), alpha-glycosidase (EC.3.2.1.20, alpha-GLY), and alpha-amylase (EC.3.2.1.1, alpha-AMY). Each synthesized sulfonamide underwent rigorous assessment for inhibitory effects against four distinct enzymes, revealing varying degrees of h CA I/II, a-GLY, and a-AMY inhibition across the tested compounds. h CA I was notably susceptible to inhibition by all compounds, demonstrating remarkably low inhibition constants (KI) K I ) ranging from 42.20 f 3.90 nM to 217.90 f 11.81 nM compared to the reference standard AAZ (KI K I of 439.17 f 9.30 nM). The evaluation against h CA II showed that most of the synthesized compounds exhibited potent inhibition effects with K I values spanning the nanomolar range 16.44 f 1.53-70.82 f 4.51 nM, while three specific compounds, namely 8a-b and 8d , showcased lower inhibitory potency than other derivatives that did not exceed that of the reference drug AAZ (with a K I of 98.28 f 1.69 nM). Moreover, across the spectrum of synthesized compounds, potent inhibition profiles were observed against diabetes mellitus- associated alpha-GLY (KI K I values spanning from 0.54 f 0.06 mu M to 5.48 f 0.50 mu M), while significant inhibition effects were noted against alpha-AMY, with IC 50 values ranging between 0.16 f 0.04 mu M and 7.81 f 0.51 mu M) compared to reference standard ACR (KI K I of 23.53 f 2.72 mu M and IC 50 of 48.17 f 2.34 mu M, respectively). Subsequently, these inhibitors were evaluated for their DPPH center dot and ABTS+center dot + center dot radical scavenging activity. Moreover, molecular docking investigations were meticulously conducted within the active sites of h CA I/II, alpha-GLY, and alpha-AMY to provide comprehensive elucidation and rationale for the observed inhibitory outcomes.