A novel series of 5-(4-(benzyloxy)substituted phenyl)-3-((phenyl amino)methyl)-1,3,4-oxadiazole-2(3H)-thione Mannich bases 6a-o were synthesized in good yield from the key compound 5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazole-2(3H)-thione by aminomethylation with paraformaldehyde and substituted amines using molecular sieves and sonication as green chemistry tools. The antifungal activity of the new products was evaluated against seven human pathogenic fungal strains, namely, Candida albicans ATCC 24433, Candida albicans ATCC 10231, Candida glabrata NCYC 388, Cryptococcus neoformans ATCC 34664, Cryptococcus neoformans PRL 518, Aspergillus fumigatus NCIM 902 and Aspergillus niger ATCC 10578. The synthesized compounds 6d, 6f, 6g, 6h and 6j exhibited promising antifungal activity against the tested fungal pathogens. In molecular docking studies, derivatives 6c, 6f and 6i showed good binding at the active site of C. albicans cytochrome P450 enzyme lanosterol 14 α-demethylase. The in vitro antifungal activity results and docking studies indicated that the synthesized compounds have potential antifungal activity and can be further optimized as privileged scaffolds to design and develop potent antifungal drugs.
A series of 6-amino-4-substituted-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 5a–j were synthesized via one-pot, four-component condensation reactions of aryl aldehydes 1a–j, propanedinitrile (2), hydrazine hydrate (3) and ethyl acetoacetate (4) under solvent-free conditions. We report herein the use of the Brønsted acid ionic liquid (BAIL) triethylammonium hydrogen sulphate [Et3NH][HSO4] as catalyst for this multi-component synthesis. Compared with the available reaction methodology, this new method has consistent advantages, including excellent yields, a short reaction time, mild reaction conditions and catalyst reusability. Selected synthesized derivatives were evaluated for in vitro anticancer activity against four human cancer cell lines viz. melanoma cancer cell line (SK-MEL-2), breast cancer cell line(MDA-MB-231), leukemia cancer cell line (K-562) and cervical cancer cell line (HeLa). Compounds 5b, 5d, 5g, 5h and 5j exhibited promising anticancer activity against all selected human cancer cell lines, except HeLa. Molecular docking studies also confirmed 5b and 5d as good lead molecules. An in silico ADMET study of the synthesized anticancer agents indicated good oral drug-like behavior and non-toxic nature.
A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a–j were synthesized in good yield from the key compound 4-(benzyloxy)-N′-(substituted benzylidene) benzo hydrazide, called Schiff ’s bases 5a–j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6a–j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski’s rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6a–j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.
A series of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a-j were synthesized in good yield by cyclo-condensation of Schiff's bases with chloro acetyl chloride in the presence of tri ethylamine as catalyst and solvent DMF by using ultra-sonication as one of the green chemistry tool. Synthesis of these derivatives by a conventional method like stirring at room temperature required 20-28 hr and by refluxing nearly takes 8-10 hr whereas using ultra-sonication it requires only 2h for completion of the reaction. Use of ultrasound to promote chemical reactions is called Sono-chemistry, it is complementary technique for promoting chemical reactions by ecofriendly green synthetic protocol. Ultrasound assisted synthesis are used to reduce the amount of undesired hazardous chemicals and solvents, reduce energy consumption and increase the selectivity towards the given product. Schiff's bases are the compounds carrying imine or azomethine (-C=N-) functional group in which the electrophilic carbon and nucleophilic nitrogen confers the Schiff's bases possibility to interact with several biological targets and have gained importance in medicinal and pharmaceutical fields exhibiting broad spectrum of biological activities. The compounds 4-(benzyloxy)-N'-(substituted benzylidene) benzo hydrazide, i.e. Schiff's bases 5a-j were obtained by condensation of 4-(benzyloxy)benzo hydrazide with various aromatic aldehydes. The four-membered cyclic amides commonly known as 2-azetidinones or β-lactam occupy an eminent place in organic and medicinal chemistry since the structure of penicillin showed the presence of β-lactam ring in it and various potent activities of penicillin are due to the presence of β-lactam ring. Azetidinones are known to exhibit various biological activities like anti-tubercular, antibacterial and antifungal with β-lactam ring. Hence, we are introducing an eco-friendly protocol for the synthesis of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a-j. All the synthesized compounds were characterized by FTIR, 1 HNMR, 13 CNMR and mass spectral analysis.
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