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

İzole kurbağa özofagus striplerinde nitrerjik mekanizma aracılığı ile oluşturulan gevşemeler üzerinde uvabain,sodyum metavanadat ve Amilorid'in etkileri

TEZ3466Tez (Doktora) -- Çukurova Üniversitesi, Adana, 2000.Kaynakça (s. 49-53) var.xi, 53 s. ; 30 cm.

EFFECTS OF SODİUM-POTASSİUM - EXCHANGİNG ATPASE AND NİTRİC OXİDE ON ETHANOL INDUCED RELAXATİONS

Alkol (etanol) dünyada yaygın olarak kullanılmakta olup gastrointestinal (GI) rahatsızlıklara neden olabilmektedir. Etanolün GI sistemde oluşturduğu etkilerin moleküler mekanizmasını aydınlatmak alkole bağlı GI sistem rahatsızlıklarının tedavi yaklaşımlarına katkı sağlayabilir. Bundan dolayı şimdiki çalışmada, GI sistem düz kas dokusu olan izole fare gastrik fundusunda etanolün oluş- turduğu etkilerin moleküler mekanizmasını araştırmayı amaçladık. Bu amaçla, ilgili dokuda etanol ile indüklenen gevşeme cevapları üzerinde nitrik oksid ve sodyum-potasyum değiştirici ATPaz'ın rolünü araştırdık. Gereç ve Yöntemler: Bu çalışmada her iki cinsten beyaz fare (Swiss albino) kullanıldı. Fareler servikal dislokasyon ile öldürüldükten sonra gastrik funduslar izole edildi. İzole edilen gastrik fundus dokuları longitudinal olarak kesilmek suretiyle gastrik fundus şeritleri hazırlandı ve içinde Tyrode solüsyonu bulunan organ banyosuna 0.5 g tansiyon altında asıldı. Banyo ortamı 37°C'de sabit tutuldu ve %95 O2 ve %5 CO2 ile gazlandırıldı. Deneysel veriler izometrik transduser vasıtasıyla kaydedildi. Bir saatlik dengelenme periyodundan sonra, izole fare gastrik fundus şeridinin bazal tonusu 5 dakika boyunca kaydedildi ve etanol organ banyosuna uygulandı (etanolun organ banyosu ortamındaki nihai konsantrasyonu 164 mM idi). Bulgular: Etanol (164 mM) izole fare mide fundus şeritlerinde tekrarlanabilir gevşemelere neden oldu. Bu gevşemeler NO sentaz enziminin potent ve spesifik inhibitörü olan N?-nitro-L-arginin (L-NOARG; 10-5 -5x10-4 M) tarafından konsantrasyona bağımlı bir şekilde inhibe edildi. Bu inhibisyon istatistiksel olarak anlamlı idi. Buna karşılık, sodyum-potasyum değiştirici ATPaz'ın potent ve spesifik inhibitörü olan uvabain (10-5 -10-4 M), izole fare gastrik fundus şeritlerinde etanol (164 mM) ile indüklenen gevşemeleri etkilemedi. Sonuç: Deneysel sonuçlar, izole fare gastrik fundus düz kasında etanol ile indüklenen gevşemelerde nitrik oksidin rolünün olabileceğini göstermektedir. Deneysel çalışma sonuçları aynı zamanda, ilgili dokuda etanol ile indüklenen gevşeme yanıtlarında sodyum-potasyum değiştirici ATPaz'ın rolünün olmadığını telkin etmektedir.Alcohol is widely used in the world and can cause gastrointestinal (GI) disturbances. Elucidating the molecular mechanism of alcohol in the GI tract may contribute to the therapeutic approaches on GI diseases caused by alcohol. So in the present study we aimed to elucidate the molecular mechanism of ethanol on isolated mouse gastric fundus. We investigated the role of nitric oxide and sodium-potassium-exchanging ATPase on relaxations induced by ethanol in the related tissue. Material and Methods: Mice (Swiss albino) of either sex were used in this study. After killing the mice by cervical dislocation the gastric fundal strips were prepared by longitudinal incision and mounted under 0.5 g tension in an organ bath filled with Tyrode’s solution. The bath medium was maintained at 37°C and gassed with 95% O2 and 5% CO2. After equlibrium period of an hour, the basal tonus of isolated mouse gastric fundal strip was recorded for 5 minutes and ethanol was applied into organ bath (the final concentration of ethanol in the organ bath medium was 164 mM). Results: Ethanol (164 mM) caused reproducible relaxations in isolated mouse gastric fundal strips. These relaxations were statistically significantly inhibited by N?-Nitro-L-arginine (L-NOARG; 10-5 -5x10-4 M), a potent and specific inhibitor of nitric oxide synthase, in a concentration dependent manner. On the other hand ouabain (10-5 -10-4M), a potent and specific inhibitor of the sodium-potassium-exchanging ATPase, failed to affect the relaxations induced by ethanol (164 mM) in the mouse gastric fundus. Conclusion: The results of experimental data suggest that nitric oxide may play a role on relaxations induced by ethanol in the isolated mouse gastric fundal smooth muscle. The results also suggest that sodium-potassiumexchanging ATPase may not have a role on relaxations induced by ethanol in the related tissue

N-Benzoylthiourea-pyrrolidine carboxylic acid derivatives bearing an imidazole moiety: Synthesis, characterization, crystal structure, in vitro ChEs inhibition, and antituberculosis, antibacterial, antifungal studies

A series of novel N-benzoylthiourea-pyrrolidine carboxylic acid derivatives bearing an imidazole moiety has been prepared and their various biological activities are evaluated. The ability of forming intermolecular hydrogen-bonds of these molecules was pursued in the search of the best antimicrobial activity. The synthesized compounds were tested to search whether they had an enzyme inhibitory potency against AChE and BChE, which are the main targets for Alzheimer's disease. The prepared compounds were also screened for antituberculosis activity against M. tuberculosis H37Rv strain and the antibacterial activity against E. coli, A. baumannii, S. aureus, B. subtilis, A. hydrophila, bacteria. In addition, their antifungal activities are also evaluated against C. tropicalis, C. albicans, C. glabrata strains.This work is a part of Samet POYRAZ's Ph.D. thesis granted by Mersin University (Project no: 2019-1-TP3-3463) and (Project no: 2020-1 AP4-3982). We also gratefully acknowledge support from Çukurova University (Project no: TSA-2021-13814), Alicante University and Mersin University

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

AIM: To evaluate the impact of extracellular and intracellular Ca(2+) 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 μmol/L), a local anesthetic agent, and hexamethonium (100 and 500 μmol/L), a ganglionic blocking agent, failed to affect these contractions, verapamil (1–50 μmol/L) and nifedipine (1–50 μmol/L), selective blockers of L-type Ca(2+) 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 μmol/L) and ruthenium red (10–100 μmol/L), selective blockers of intracellular Ca(2+) channels/ryanodine receptors; cyclopiazonic acid (CPA; 1–10 μmol/L), a selective inhibitor of sarcoplasmic reticulum (SR) Ca(2+)-ATPase; and caffeine (0.5–5 mmol/L), a depleting agent of intracellular Ca(2+) stores, significantly inhibited the contractile responses induced by ethanol. In addition, the combination of caffeine (5 mmol/L) plus CPA (10 μmol/L), and ryanodine (10 μmol/L) plus CPA (10 μmol/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 μmol/L) and CPA(10 μmol/L) eliminated the contractions induced by ethanol in isolated gastric fundal strips of mice. CONCLUSION: Both extracellular and intracellular Ca(2+) may have important roles in regulating contractions induced by ethanol in the mouse gastric fundus