Carbonic anhydrase inhibitors(University of Wollongong)

Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that play essential roles in physiological processes and are recognized as important therapeutic targets for disorders such as glaucoma, epilepsy, and cancer. In this study, a series of azo-linked chalcone derivatives (1-10) was designed, synthesized, and evaluated for their inhibitory activity against human carbonic anhydrase isoforms I and II (hCA I and hCA II). All compounds demonstrated strong inhibitory activity in the low nanomolar range, with several derivatives surpassing the reference drug acetazolamide in potency. Remarkably, compound 1 exhibited the highest activity, particularly against hCA II, highlighting its potential as a lead candidate. Structure-activity relationship (SAR) analysis indicated that both the azo-linked aromatic moiety and the substitution pattern on the chalcone ring play critical roles in determining activity. Molecular docking studies revealed favorable binding interactions within the active site of the enzyme, which were further validated by molecular dynamics (MD) simulations conducted over 250 ns. In addition, in silico ADMET profiling suggested that the synthesized compounds possess acceptable pharmacokinetic properties, including good oral bioavailability, membrane permeability, and low predicted toxicity, supporting their drug-likeness. Hence, these findings demonstrate that azo-chalcone hybrids constitute a promising scaffold for the development of potent carbonic anhydrase inhibitors, with compound 1 identified as a strong candidate for further optimization and preclinical investigation.

This study aimed to evaluate the inhibitory effects of a series of butenolide derivatives on human carbonic anhydrase isoenzymes I and II (hCA I and hCA II) and to investigate their antioxidant and antimicrobial properties through experimental and computational approaches.

Butenolide derivatives (2a-2j) were evaluated for their inhibitory activity against hCA I and hCA II using in vitro enzyme inhibition assays. Antioxidant activities were assessed using ABTS•⁺ radical scavenging and Fe³⁺ reducing assays, while antimicrobial activities were determined using the disc diffusion method against selected Gram-positive, Gram-negative bacteria and fungal strains. Molecular docking, Prime/MM-GBSA binding free energy calculations, and molecular dynamics simulations were performed to investigate ligand - enzyme interactions and binding stability.

Among the tested compounds, derivative 2c showed the most potent inhibition against hCA I and hCA II with K_i values of 0.212 ± 0.018 μM and 0.051 ± 0.015 μM, respectively, exceeding the activity of the reference inhibitor acetazolamide. Antioxidant assays indicated that compound 2h exhibited the strongest radical scavenging and reducing activity. Several derivatives demonstrated moderate antibacterial activity, whereas limited antifungal activity was observed. Computational studies supported the experimental findings and revealed stable ligand - enzyme interactions.

The results suggest that butenolide derivatives represent promising multifunctional scaffolds for the development of new carbonic anhydrase inhibitors with additional antioxidant and antimicrobial potential.