Pyrimidine-based cationic amphiphiles (PCAms), i.e., di-trifluoroacetic acid salts of N1-[1′-(1″,3″-diglycinatoxy-propane-2″-yl)-1′,2′,3′-triazole-4′-yl]methyl-N3-alkylpyrimidines have been synthesized utilizing naturally occurring biocompatible precursors, like glycerol, glycine, and uracil/ thymine in good yields. Synthesized PCAms consist of a hydrophilic head group comprising TFA salt of glyceryl 1,3-diglycinate and hydrophobic tail comprising of C-7 and C-12 N3-alkylated uracil or thymine conjugated via a 4-methylene-1,2,3-triazolyl linker. The physicochemical properties of all PCAms, such as critical aggregation concentration, hydrodynamic diameter, shape, and zeta potential (surface charge) were analyzed. These PCAms were also evaluated for their anti-proliferative and anti-tubercular activities. One of the synthesized PCAm exhibited 4- to 75-fold more activity than first-line anti-tubercular drugs streptomycin and isoniazid, respectively, against the multidrug resistant clinical isolate 591 of Mycobacterium tuberculosis.

Synthesis of fifteen C-4-aroyl-C-5-aryl-N-1-(5 '-deoxythymidin-5 '-yl)-1,2,3-triazoles have been reported starting from azidation of 5 '-p-toluenesulfonyloxythymidine followed by azide-alkene oxidative cycloaddition reaction of the resulted 5 '-azido-5 '-deoxythymidine with 1,3-diarylpropenones in dimethylformamide (DMF) in the presence of tetra-n-butylammonium hydrogen sulfate (n-Bu4N+HSO4-, TBAHS) as catalyst in 60 to 79% overall yields. Further, they were also synthesized by one pot sequential reaction of tosylated thymidine with sodium azide in DMF and then with 1,3-diarylpropenones in presence of n-Bu(4)N(+)HSO(4)(-)in superior yield of 70 to 95% than 60 to 79% in two step procedure. All fifteen synthesized compounds were screened for theirin vitroantiMycobacterium tuberculosisactivity against sensitive reference strain H37Rv and multi drug resistant (MDR) clinical isolate 591, and found to exhibit minimum inhibitory concentration (MIC) ranging from 2 to 15 mu g/mL, which was equivalent to the MIC of first line anti-tubercular drug streptomycin. All compounds qualify for their drug likeness when their physicochemical parameters were assessed using online MolSoft and Lipinski filter software, except their molecular weight. The cytotoxicity of potent compounds evaluated human monocytic cell line THP-1 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was found to be less as compared to the first line drug, isoniazid.

The synthesis of novel 4-furano-coumarins and 3-furano-chromones has been achieved using silver-mediated oxidative C–H/C–H functionalization of 4-ethynylcoumarin/3-ethynylchromone with ethyl acetoacetate in 80%–90% and 82%–90% yields, respectively. The structure of the synthesized compounds was established on the basis of their spectral data analysis and the structure of one of the 4-furano-coumarins has been further confirmed on the basis of its X-ray crystallographic study. All eight synthesized 4-furano-coumarins and 3-furano-chromones exhibited moderate antitubercular activity against sensitive reference strain H37Rv of Mycobacterium tuberculosis.

A series of beta-D-ribofuranosyl coumarinyl-1,2,3-triazoles have been synthesized by Cu-catalyzed cycloaddition reaction between azidosugar and 7-O-/7-alkynylated coumarins in 62-70% overall yields. The in vitro antimycobacterial activity evaluation of the synthesized triazolo-conjugates against Mycobacterium tuberculosis revealed that compounds were bactericidal in nature and some of them were found to be more active than one of the first line antimycobacterial drug ethambutol against sensitive reference strain H37Rv, and 7 to 420 times more active than all four first line antimycobacterial drugs (isoniazid, rifampicin, ethambutol and streptomycin) against multidrug resistant clinical isolate 591. Study of in silico pharmacokinetic profile indicated the drug like characters for the test molecules. Further, transmission electron microscopic experiments revealed that these compounds interfere with the constitution of bacterial cell wall possibly by targeting mycobacterial InhA and DNA gyrase enzymes. Study conducted on the activities of the test compounds on bacterial InhA and DNA gyrase revealed that the most bactericidal test compound, N-1-(beta-D-ribofuranosyl)-C-4-(4-methylcoumarin-7-oxymethyl)-1,2,3-triazole (6b) and its corresponding directly linked conjugate N-1-(beta-D-ribofuranosyl)-C-4-(4-methylcoumarin-7-yl)-1,2,3-triazole (11b) significantly inhibited the activity of both the enzymes. The results were further supported by molecular docking studies of the compound 6b and 11b with bacterial InhA and DNA gyrase B enzymes. Further, the cytotoxicity study of some of the better active compounds on THP-1 macrophage cell line using MIT assay showed that the synthesized compounds were non-cytotoxic. (C) 2018 Elsevier Masson SAS. All rights reserved.