Rabbit muscle pyruvate kinase activators: Synthesis, molecular docking and theoretical studies of N-substituted sulfonamide derivatives.

Pyruvate kinase (PK) activators have potential therapeutic applications in diseases such as sickle cell anemia. In this study, N-Substituted sulfonamide derivatives of 1,4-dihydropyridines were synthesized and evaluated as PK activators in vitro and using molecular docking studies. The compounds were synthesized by reacting dicarbonyl compounds with ammonium acetate, 5-nitrobenzaldehyde, and alumina sulfuric acid (ASA), followed by reduction and sulfonylation. The structures of the compounds were analyzed using spectroscopic techniques. DFT calculations provided insights into the electronic properties. Molecular docking of the compounds into the active site of PK showed favorable binding interactions. ADME evaluation indicated suitable solubility, BBB permeation, and lack of CYP450 inhibition. Overall, this study demonstrates the potential of new hybrid 1,4-dihydropyridine substituted sulfonamides as PK activators for further development. According to AC50 values, the compound (DTSF7, 0.97µM) is about 100-fold higher affective than the clinically used sulfonamide compound (AC50 = 90µM) for PK.

Bovine carbonic anhydrase (bCA) inhibitors: Synthesis, molecular docking and theoretical studies of bisoxadiazole-substituted sulfonamide derivatives.

This paper describes the in vitro inhibition potential of bisoxadiazole-substituted sulfonamide derivatives (6a-t) against bovine carbonic anhydrase (bCA) after they were designed through computational analyses and evaluated the predicted interaction via molecular docking. First, in silico ADMET predictions and physicochemical property analysis of the compounds provided insights into solubility and permeability, then density functional theory (DFT) calculations were performed to analyse their ionization energies, nucleophilicity, in vitro electron affinity, dipole moments and molecular interactions under vacuum and dimethyl sulfoxide (DMSO) conditions. After calculating the theoretical inhibition constants, IC50 values determined from enzymatic inhibition were found between 12.93 and 45.77 µM. Molecular docking evaluation revealed favorable hydrogen bonding and π-interactions of the compounds within the bCA active site. The experimentally most active compound, 6p, exhibited the strongest inhibitory activity with a theoretical inhibition constant value of 9.41 nM and H-bonds with Gln91, Thr198, and Trp4 residues and His63 Pi-cation interactions with His63 residues. Overall, the study reveals promising bCA blocking potential for the synthesized derivatives, similar to acetazolamide.

Synthesis, enzyme inhibition, and molecular docking studies of a novel chalcone series bearing benzothiazole scaffold.

This study reports the facile synthesis of a novel series of benzothiazole-chalcones, in addition to their inhibitory profile on important metabolic enzymes including human carbonic anhydrases (hCA-I, hCA-II) and paraoxonase (PON-1). The inhibition parameters, IC50 (concentration for 50% inhibition) and Ki (dissociation constant) values, toward the title enzymes were determined for the studied compounds. As a result, IC50 values of hydratase activity were in the range 4.15-5.47 and 2.56-4.58 µM for hCA-I and hCA-II, respectively. At the same time, IC50 values of esterase activity were in the range 24.91-104.00 and 35.25-97.00 µM, while Ki values were in the range 14.43-59.66 and 26.65-73.34 µM for hCA-I and hCA-II, respectively. In addition, PON-1 enzyme inhibition results showed interesting inhibitory effects, with IC50 values between 13.28 and 16.68 µM. Finally, a comprehensive approach was established for the synthesized compounds based on theoretical calculations, which have been done using B3LYP, PBE0 theories and SVP, TVZP, TVZPP basis sets, followed by docking studies by which the outputs proved the harmonically flows with the experimental results.