Design, synthesis, biological evaluation and docking analysis of pyrrolidine-benzenesulfonamides as carbonic anhydrase or acetylcholinesterase inhibitors and antimicrobial agents.

The synthesis and biological assessment of novel multi-functionalized pyrrolidine-containing benzenesulfonamides were reported along with their antimicrobial, antifungal, CAs inhibition, and AChE inhibition as well as DNA-binding effects. The chemical structure of the compounds was elucidated by using FTIR, NMR, and HRMS. Compound 3b, which had Ki values of 17.61 ± 3.58 nM (hCA I) and 5.14 ± 0.61 nM (hCA II), was found the be the most potent CAs inhibitor. Compounds 6a and 6b showed remarkable AChE inhibition effects with Ki values 22.34 ± 4.53 nM and 27.21 ± 3.96 nM in comparison to tacrine. Compounds 6a-6c had moderate antituberculosis effect on M. tuberculosis with a MIC value of 15.62 µg/ml. Compounds had weaker antifungal and antibacterial activity in the range of MIC 500-62.5 µg/ml against standard bacterial and fungal strains. Besides these above, molecular docking studies were performed to examine and evaluate the interaction of the remarkable compounds (3b, 6a and 6b) against the current enzymes (CAs and AChE). Novel compounds gained interest in terms of enzyme inhibitory potencies. Therefore, the most potent enzyme inhibitors may be considered lead compounds to be modified for further research.Communicated by Ramaswamy H. Sarma.

Recent insights about pyrrolidine core skeletons in pharmacology.

To overcome numerous health disorders, heterocyclic structures of synthetic or natural origin are utilized, and notably, the emergence of various side effects of existing drugs used for treatment or the resistance of disease-causing microorganisms renders drugs ineffective. Therefore, the discovery of potential therapeutic agents that utilize different modes of action is of utmost significance to circumvent these constraints. Pyrrolidines, pyrrolidine-alkaloids, and pyrrolidine-based hybrid molecules are present in many natural products and pharmacologically important agents. Their key roles in pharmacotherapy make them a versatile scaffold for designing and developing novel biologically active compounds and drug candidates. This review aims to provide an overview of recent advancements (especially during 2015-2023) in the exploration of pyrrolidine derivatives, emphasizing their significance as fundamental components of the skeletal structure. In contrast to previous reviews that have predominantly focused on a singular biological activity associated with these molecules, this review consolidates findings from various investigations encompassing a wide range of important activities (antimicrobial, antiviral, anticancer, anti-inflammatory, anticonvulsant, cholinesterase inhibition, and carbonic anhydrase inhibition) exhibited by pyrrolidine derivatives. This study is also anticipated to serve as a valuable resource for drug research and development endeavors, offering significant insights and guidance.

The impact of extracellular and intracellular Ca2+ on ethanol-induced smooth muscle contraction.

AIM: To evaluate the impact of extracellular and intracellular Ca2+ on contractions induced by ethanol in smooth muscle. METHODS: Longitudinal smooth muscle strips were prepared from the gastric fundi of mice. The contractions of smooth muscle strips were recorded with an isometric force displacement transducer. RESULTS: Ethanol (164 mmol/L) produced reproducible contractions in isolated gastric fundal strips of mice. Although lidocaine (50 and 100 micromol/L), a local anesthetic agent, and hexamethonium (100 and 500 micromol/L), a ganglionic blocking agent, failed to affect these contractions, verapamil (1-50 micromol/L) and nifedipine (1-50 micromol/L), selective blockers of L-type Ca2+ channels, significantly inhibited the contractile responses of ethanol. Using a Ca(2+)-free medium nearly eliminated these contractions in the same tissue. Ryanodine (1-50 micromol/L) and ruthenium red (10-100 micromol/L), selective blockers of intracellular Ca2+ channels/ryanodine receptors; cyclopiazonic acid (CPA; 1-10 mumol/L), a selective inhibitor of sarcoplasmic reticulum (SR) Ca(2+)-ATPase; and caffeine (0.5-5 mmol/L), a depleting agent of intracellular Ca2+ stores, significantly inhibited the contractile responses induced by ethanol. In addition, the combination of caffeine (5 mmol/L) plus CPA (10 micromol/L), and ryanodine (10 micromol/L) plus CPA (10 micromol/L), caused further inhibition of contractions in response to ethanol. This inhibition was significantly different from those associated with caffeine, ryanodine or CPA. Furthermore the combination of caffeine (5 mmol/L), ryanodine (10 micromol/L) and CPA(10 micromol/L) eliminated the contractions induced by ethanol in isolated gastric fundal strips of mice. CONCLUSION: Both extracellular and intracellular Ca2+ may have important roles in regulating contractions induced by ethanol in the mouse gastric fundus.

The location of photodegradable nitric oxide store in the mouse stomach fundus.

The aim of this study was to investigate the location of photodegradable nitric oxide (NO) store using a pharmacological approach in mouse gastric fundus. The ultraviolet light irradiation (UV; 360 nm, 60 s), electrical field stimulation (EFS; 4 Hz, 25 V, 1 ms, 15s-train), exogenous nitric oxide (NO; 10 microM), nitroglycerin (100 microM) and isoproterenol (5 nM) induced relaxation in mouse gastric fundus preparations in the absence or presence of an intact mucosa. The NO scavenger, haemoglobin (20 microM), significantly inhibited the relaxation of intact and denuded mucosa stomach fundus to UV light irradiation, EFS and NO, but not to nitroglycerin and isoproterenol. The superoxide anion generator, pyrogallol (50 microM), inhibited relaxation of intact and denuded mucosa stomach fundus induced by UV light irradiation, EFS, NO, but not to nitroglycerin and isoproterenol. The inhibition observed with pyrogallol was prevented by exogenous Cu/Zn superoxide dismutase (SOD; 100 U/ml), a membrane impermeable antioxidant. The Cu/Zn SOD inhibitor, diethyldithiocarbamic acid (DETCA; 8 mM), inhibited the relaxation of intact and denuded mucosa stomach fundus to UV light irradiation, EFS, NO and nitroglycerin but not those to isoproterenol. Exogenous SOD (100 U/ml) partially prevented the inhibitory effect of DETCA on relaxation to UV light irradiation, EFS, NO but not to nitroglycerin. DETCA-induced inhibition of the nitroglycerin-induced relaxation was partially prevented by the cell-permeable polyethylene-glycol-superoxide dismutase (100 U/ml). These results indicate that photodegradable NO store is, at least in part, unlikely to be within smooth muscle cells, and furthermore, that UV light-induced relaxation is not dependent on gastric mucosal layer.

Ethanol-induced relaxation of mouse esophagus: subcellular mechanisms.

Ethanol (164 mm) produced reproducible relaxations in isolated mouse esophageal strips. Hexamethonium (10-500 microm), a ganglionic blocking agent, and lidocaine (10-100 microm), a local anesthetic agent, failed to affect the relaxations induced by ethanol in the mouse esophagus. Although verapamil (10-500 microm), a selective blocker of L-type Ca(2+) channels, failed to affect the relaxations to ethanol, ruthenium red (10-100 microm), a selective blocker of ryanodine receptors (intracellular Ca(2+) channels), and cyclopiazonic acid (1-10 microm), a selective blocker of sarcoplasmic reticulum Ca(2+) ATPase (SERCA), significantly inhibited these relaxations. In addition, tetraethylammonium (10-100 microm), a potassium-selective ion channel blocker and N(omega)-nitro-l-arginine (l-NOARG; 10-500 microm), a specific inhibitor of nitric oxide synthase (NOS), neomycin (10-500 microm), a phospholipase C inhibitor and indomethacine (1-10 microm), a non-selective COX inhibitor, significantly inhibited the relaxations induced by ethanol. In contrast ouabain (10-100 microm), an inhibitor of Na(+)-K(+)-ATPase, failed to cause significant alteration on these relaxations in the same tissue. The results of the present study suggest that the inhibitory effect of ethanol on the mouse esophagus may be direct effect of ethanol on the muscle tissue rather than neuronal effect. In addition, intracellular but not extracellular Ca(2+) may have a role on ethanol-induced relaxations in isolated mouse esophageal strips. Potassium channels and nitric oxide may also have a role on these relaxations. Similarly, phospholypase C and arachidonic acid pathways may contribute the relaxations to ethanol. However Na(+)-K(+)-ATPase may not have a role on relaxations induced by ethanol in the mouse esophagus.