Green Synthetic and Pharmacological Developments in the Hybrid Quinazolinone Moiety: An Updated Review.

Bicyclic quinazolinone constitutes an important class of organic framework enveloping numerous biological properties which enthused organic and medicinal chemists to explore green synthetic strategies for the construction of quinazolinone hybrids with significantly improved pharmacodynamics and pharmacokinetic profiles. In this perspective, the present review summarizes the most recent green synthetic strategies, biological properties, structure-activity relationship, and molecular docking studies of the 4-quinazolinone-based scaffold. This review provides deeper insight into the hit-to-lead synthesis of quinazolinone derivatives in the development of clinically important therapeutic candidates.

Water-assisted cascade synthesis of trifluoromethylated dipyridodiazepinone analogues: in vitro and in silico antibacterial studies.

A base-promoted palladium-catalyzed cascade reaction is described to access trifluoromethylated dipyridodiazepinone derivatives in an aqueous system (1,4-dioxane-H2O). This methodology uses simple chemicals, has a broad substrate scope, is waste minimized (E-factor = 0.3-0.9) and produces 11-CF3-tethered dipyridiodiazepinone derivatives in good to excellent yields. All the synthesized analogues were preliminarily examined for antibacterial activity against E. coli and S. aureus and compared to the reference drugs. Furthermore, inhibition of the peptide deformylase enzyme and antibiofilm studies were performed and compound 5i exhibited the best inhibitory effect among the other analogues. Furthermore, these analogues were in silico analysed via molecular docking, molecular simulation, drug-likeness, physicochemical and ADMET studies. Results from biological evaluation and computational studies revealed that compound 5i could be used as a lead molecular structure for the development of novel antibacterial agents. In conclusion, the green metrics evaluation of the defined protocol provides advantages in the synthesis of biologically active compounds.

Tetrazole derivatives in the management of neurological disorders: Recent advances on synthesis and pharmacological aspects.

Neurological disorders are the leading cause of a large number of mortalities and morbidities. Nitrogen heterocyclic compounds have been pivotal in exhibiting wide array of therapeutic applications. Among them, tetrazole is a ubiquitous class of organic heterocyclic compounds that have attracted much attention because of its unique structural and chemical properties, and a wide range of pharmacological activities comprising anti-convulsant effect, antibiotic, anti-allergic, anti-hypertensive to name a few. Owing to significant chemical and biological properties, the present review aimed at highlighting the recent advances in tetrazole derivatives with special emphasis on their role in the management of neurological diseases. Besides, in-depth structure-activity relationships, molecular docking studies, and associated modes of action of tetrazole derivatives evident in in vitro, in vivo preclinical, and clinical studies have been discussed.

Development of novel bosentan analogues as endothelin receptor antagonists for pulmonary arterial hypertension.

Since decades, bosentan has been in use for the treatment of pulmonary arterial hypertension (PAH). However, chronic exposure to bosentan leads to the development of resistance, tolerance, and serious adverse effects that have restricted its usage in clinical practices. To surmount these limitations, some new bosentan derivatives have been synthesized and evaluated for their therapeutic efficacy in PAH. Molecular docking analyses of all the synthesized derivatives were carried out using the endothelin (ET) receptor. In addition, the inhibitory ability of synthesized derivatives was determined in in vitro assay employing an ET-1 human ELISA kit. Among the synthesized derivatives, three derivatives namely 17d, 16j, and 16h with higher docking scores and lower IC50 values were selected for determination of the magnitude of the binding force between the derivative and ET receptor using molecular dynamics (MD) simulations study. Further, these derivatives were subjected to in vivo studies using monocrotaline (MCT) induced PAH in rat model. Results of in vivo studies inferred that the derivatives exhibit impressive ability to reduce PAH. Besides, its protective role was also evidenced in hemodynamic and right ventricular hypertrophy analyses, histological analysis, cardiac biomarkers, hypoxia-inducible factor 1 alpha (HIF1α) levels, and biochemical studies. Furthermore, gene quantification by quantitative RT-PCR and Western blot analysis was also performed to examine its effect on the expression of key proteins in PAH. Notably, amongst three, derivative 16h exhibited the most encouraging results in molecular docking analysis, in vitro, in vivo, histopathological, biochemical, protein expression, and MD studies. Besides, derivative 16h also showed impressive pharmacokinetic features in ADMET analysis. In conclusion, derivative 16 h could act as a reliable ET receptor antagonist and requires further exploration to attain its therapeutic utility in PAH management.

Synthesis and Theoretical Studies of Biologically Active Thieno Nucleus Incorporated Tri and Tetracyclic Nitrogen Containing Heterocyclics Scaffolds via Suzuki Cross-Coupling Reaction.

A new series of thieno nucleus embellished trinuclear (19, 20) and tetranuclear (21-24) nitrogen heteroaryl have been synthesized by the Suzuki cross-coupling reaction using bis(triphenylphosphine)palladium(II) dichloride. All the synthesized compounds were characterized by IR, 1 H-NMR, 13 CNMR and Mass spectral properties. In vitro antibacterial studies of the synthesized compound were conducted using broth microdilution assay employing Gram-positive and Gram-negative strains and half-maximal inhibitory concentration (IC50 ) was determined. The result showed that compound 20 possess best antibacterial activity against S. aureus and E. coli with IC50 values of 60 µg mL-1 and 90 µg mL-1 . Further to determine the mode of antibacterial action, compounds 20 and 21 were examined for in vitro bacterial dehydrogenase inhibitory assay. To understand the binding affinity of the synthesized compounds, the docking study was performed in the bacterial dehydrogenase enzyme by AutoDock Vina software and structure was confirmed by Discovery Studio Visualizer. All the synthesized compounds were docked in a good manner within the active sites of the bacterial dehydrogenase enzyme and exhibited good binding energies.

Synthetic and Biological Attributes of Pyrimidine Derivatives: A Recent Update.

Nitrogen-containing heterocycles attract the attention of chemists due to their multifarious activities. Amongst all, pyrimidine plays a central role and exhibits a broad spectrum of biological activities. Literature is replete with various aspects of synthetic development in the chemistry of pyrimidine for a wide array of applications. It aroused our interest to compile various novel and efficient synthetic approaches towards the synthesis of pyrimidine and its derivatives. Pyrimidine derivatives are broadly useful as therapeutic agents, owing to their high degree of structural diversity. They have been recorded to possess a diverse range of therapeutic activities viz. anticancer, anti-inflammatory, anti-HIV etc.