ABSTRACT
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-m) as potential multi-target inhibitors against human carbonic anhydrase (EC.4.2.1.1, hCA I/II), α-glycosidase (EC.3.2.1.20, α-GLY), and α-amylase (EC.3.2.1.1, α-AMY). Each synthesized sulfonamide underwent rigorous assessment for inhibitory effects against four distinct enzymes, revealing varying degrees of hCA I/II, a-GLY, and a-AMY inhibition across the tested compounds. hCA I was notably susceptible to inhibition by all compounds, demonstrating remarkably low inhibition constants (KI) ranging from 42.20 ± 3.90 nM to 217.90 ± 11.81 nM compared to the reference standard AAZ (KI of 439.17 ± 9.30 nM). The evaluation against hCA II showed that most of the synthesized compounds exhibited potent inhibition effects with KI values spanning the nanomolar range 16.44 ± 1.53-70.82 ± 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 KI of 98.28 ± 1.69 nM). Moreover, across the spectrum of synthesized compounds, potent inhibition profiles were observed against diabetes mellitus-associated α-GLY (KI values spanning from 0.54 ± 0.06 µM to 5.48 ± 0.50 µM), while significant inhibition effects were noted against α-AMY, with IC50 values ranging between 0.16 ± 0.04 µM and 7.81 ± 0.51 µM) compared to reference standard ACR (KI of 23.53 ± 2.72 µM and IC50 of 48.17 ± 2.34 µM, respectively). Subsequently, these inhibitors were evaluated for their DPPH· and ABTS+· radical scavenging activity. Moreover, molecular docking investigations were meticulously conducted within the active sites of hCA I/II, α-GLY, and α-AMY to provide comprehensive elucidation and rationale for the observed inhibitory outcomes.
ABSTRACT
Propolis, a natural product collected by honeybees from various plant sources, has gained significant attention due to its diverse bioactive compounds and potential therapeutic properties. To further explore its contents and biological activities, this study aimed to analyze the phenolic compounds in Siirt propolis extracts obtained using different solvents, namely ethanol, water, and ethanol-water mixtures. The primary objective of this research was to investigate the phenolic profile, as well as the antidiabetic and antioxidant activities of the propolis extracts. Chemical profiling of extracts was performed using LC-MS/MS. The antioxidant potential of the propolis extracts was evaluated through free radical scavenging methods, including DPPH and ABTS assays. As a result of these analyses, propolis extracts showed moderate radical scavenging potential with 13.86%-35.72% for DPPH and 33.62%-62.50% for ABTS at a concentration of 30 µg mL-1, respectively. This radical scavenging potential of the extracts sheds light on its ability to combat oxidative stress, which is implicated in the development of diabetes, and its potential effects on cellular health. Additionally, the study assessed the antidiabetic properties of the propolis extracts by examining their inhibition effects on α-amylase and α-glycosidase enzymes. Extracts with high phenolic content showed a high inhibitory effect against α-glucosidase with an IC50 of 5.72 ± 0.83 µg mL-1. This research provided significant findings regarding the potential use of propolis in the treatment of diabetes and related metabolic disorders.