ABSTRACT
A series of eight N1-(2'-O,4'-C-methylene-ß-D-ribofuranonucleoside-3'-yl)-C4-(coumarin-7-oxymethyl)-1,2,3-triazoles have been synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition reaction of 3'-azido-3'-deoxy-2'-O,4'-C-methyleneuridine and 3'-azido-3'-deoxy-2'-O,4'-C-methylene-5-methyluridine with 7-propargyloxy coumarins in 82-88% yields. The synthesized coumarintriazolyl-bicyclonucleoside conjugates possess an extra bridge between 2'-O and 4'-C in the nucleoside moiety, which facilitates its pre-organization into N-type sugar puckering. This was confirmed by X-ray crystal structure studies on one of the conjugates, i.e. on N1-(3'-deoxy-2'-O,4'-C-methylene-5-methyluridin-3'-yl)-C4-(4-phenylcoumarin-7-oxymethyl)-1,2,3-triazole. Photophysical studies carried out on the synthesized compounds demonstrate that they possess useful level of fluorescence with Stokes shift of approximately 70â¯nm.
Subject(s)
Alkynes/chemistry , Azides/chemistry , Coumarins/chemistry , Triazoles/chemical synthesis , Uridine/chemistry , Carbohydrate Conformation , Catalysis , Copper/chemistry , Cycloaddition Reaction , Photochemical Processes , Triazoles/chemistry , Uridine/analogs & derivativesABSTRACT
A series of ß-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, N1-(ß-d-ribofuranosyl)-C4-(4-methylcoumarin-7-oxymethyl)-1,2,3-triazole (6b) and its corresponding directly linked conjugate N1-(ß-d-ribofuranosyl)-C4-(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 MTT assay showed that the synthesized compounds were non-cytotoxic.
Subject(s)
Anti-Bacterial Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Triazoles/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Three LNA-based mercaptoacetamido-linked nonionic nucleoside dimers TL-S-T, T-S-TL, and TL-S-TL have been synthesized by HOBT and HBTU catalyzed condensation of silyl-protected 2-S-(thymidin-5 '-yl)mercaptoacetic acid or 2-S-(2 '-O,4 '-C-methylenethymidin-5 '-yl)mercaptoacetic acid with 3 '-amino-3 '-deoxy-5 '-O-DMT-2 '-O,4 '-C-methylenethymidine or with 3 '-amino-3 '-deoxy-5 '-O-DMT-ß-thymidine followed by desilylation of the protected dimers. The 3 '-O-phosphoramidite derivative of one of the nucleoside dimers was successfully prepared by condensation with [P(-Cl)(-OCH2CH2CN)-N(iPr)2}] in DCM in the presence of N,N-diisopropylethylamine (DIPEA), which is a building block for the preparation of mercaptoacetamido-linked oligonucleotides of therapeutic applications.
Subject(s)
Dimerization , Drug Design , Nucleosides/chemistry , Nucleosides/chemical synthesis , Oligonucleotides/chemistry , Sulfhydryl Compounds/chemistry , Chemistry Techniques, SyntheticABSTRACT
A Novozyme-435 catalytic methodology has been developed for selective deacylation of one of the acyloxy functions involving a primary -OH group over the other acyloxy functions involving primary and secondary -OH groups in 4'-C-acyloxymethyl-2',3',5'-tri-O-acyl-ß-D-xylofuranosyl nucleosides. Optimization of the biocatalytic reaction revealed that tetra-O-butanoyl-ß-D-xylofuranosyl nucleosides are the best substrates for the enzyme. The possibility of acyl migration during enzymatic deacylation reactions has been ruled out by carrying out biocatalytic deacylation reactions on mixed esters of 4'-C-hydroxymethyl-2',3',5'-tri-O-acetyl-ß-D-xylofuranosyl nucleosides. The developed methodology has been used for the efficient synthesis of xylo-LNA monomers T, U, A, and C in good yields.
