Search results for: pyridazin

Authors: Zineb Ouahdi

Abstract:

Spirocyclic compound derivatives, with their unique heterocyclic motifs, serve as a continual source of inspiration in the pursuit of developing potential therapeutic agents. These compounds are diverse in their chemical structures; some have fully saturated skeletons, while others are partially unsaturated. Nevertheless, these compounds share a characteristic feature with natural products - the presence of at least one heteroatom in one of their rings. The inclusion of a C = O dipolarophile in pyridazinones imparts an exciting aspect for 1,3-dipolar cycloaddition reactions, the focal point of our study. Our research has involved a detailed theoretical investigation of the reaction between ethyl (Z)-2-bromo-2-(2-(p-tolyl)hydrazono)acetate and 6-methyl-4,5-dihydropyridazine-3(2H)-one. This has been accomplished using the DFT/B3LYP/6-31g(d,p) method, intending to illuminate the chemical pathway of this reaction. The chemical reactivity theories we used for this purpose included FMO, TS, and local and global indices derived from conceptual DFT. The theoretical framework outlined in this study allowed us to propose a reaction mechanism for cycloaddition reactions. It also enabled the identification of the potential activities of the analyzed compounds (P1, P2, P3, P4, P5, and P6) against the major protease of the coronavirus disease (COVID-19). This was achieved using various computational tools, including AutoDock Tools, Autodock Vina, Autodock 4, and PYRX.

Keywords: MEDT, pyridazin, cycloaddition, FMO, DFT, docking

Procedia PDF Downloads 101

Authors: Jyoti Singh, Ranju Bansal

Abstract:

Fighting pain and inflammation is a common problem faced by physicians while dealing with a wide variety of diseases. Since ancient time nonsteroidal anti-inflammatory agents (NSAIDs) and opioids have been the cornerstone of treatment therapy, however, the usefulness of both these classes is limited due to severe side effects. NSAIDs, which are mainly used to treat mild to moderate inflammatory pain, induce gastric irritation and nephrotoxicity whereas opioids show an array of adverse reactions such as respiratory depression, sedation, and constipation. Moreover, repeated administration of these drugs induces tolerance to the analgesic effects and physical dependence. Further discovery of selective COX-2 inhibitors (coxibs) suggested safety without any ulcerogenic side effects; however, long-term use of these drugs resulted in kidney and hepatic toxicity along with an increased risk of secondary cardiovascular effects. The basic approaches towards inflammation and pain treatment are constantly changing, and researchers are continuously trying to develop safer and effective anti-inflammatory drug candidates for the treatment of different inflammatory conditions such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriasis and multiple sclerosis. Synthetic 3(2H)-pyridazinones constitute an important scaffold for drug discovery. Structure-activity relationship studies on pyridazinones have shown that attachment of a lactam at N-2 of the pyridazinone ring through a methylene spacer results in significantly increased anti-inflammatory and analgesic properties of the derivatives. Further introduction of the heterocyclic ring at lactam nitrogen results in improvement of biological activities. Keeping in mind these SAR studies, a new series of compounds were synthesized as shown in scheme 1 and investigated for anti-inflammatory, analgesic, anti-platelet activities and docking studies. The structures of newly synthesized compounds have been established by various spectroscopic techniques. All the synthesized pyridazinone derivatives exhibited potent anti-inflammatory and analgesic activity. Homoveratryl substituted derivative was found to possess highest anti-inflammatory and analgesic activity displaying 73.60 % inhibition of edema at 40 mg/kg with no ulcerogenic activity when compared to standard drugs indomethacin. Moreover, 2-substituted-4-benzo[d][1,3]dioxole-6-phenylpyridazin-3(2H)-ones derivatives did not produce significant changes in bleeding time and emerged as safe agents. Molecular docking studies also illustrated good binding interactions at the active site of the cyclooxygenase-2 (hCox-2) enzyme.

Keywords: anti-inflammatory, analgesic, pyridazin-3(2H)-one, selective COX-2 inhibitors

Procedia PDF Downloads 200