title: Synthesis of zidovudine prodrugs with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS.
abstract: A series of prodrugs of zidovudine has been synthesized in an effort to enhance spectrum of chemotherapeutic properties for the effective treatment of HIV/AIDS. The 5'-OH function of zidovudine was esterified with ciprofloxacin, norfloxacin, isoniazide, pyrazinamide acetic acid. The anti-HIV-1 activity of the esters was determined in CEM cell-line and zidovudine ester bearing pyrazinamide acetic acid was found to be the most potent compound with EC50 of<0.0636 microM, CC50 of>1000 microM and selectivity index (SI) of>15,723. Zidovudine prodrug bearing ciprofloxacin and norfloxacin moiety showed 100% inhibition against Mycobacterium tuberculosis H37Rv at 6.25 microg/ml. The prodrugs were also found to exhibit antibacterial activity against 24 pathogenic bacteria. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterase with t1/2 ranging from 20 to 240 min.
authors.affiliation: Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031, India. dsriram@bits-pilani.ac.in
authors.forename: D
authors.initials: D
authors.lastname: Sriram
authors.forename: N
authors.initials: N
authors.lastname: Srichakravarthy
authors.forename: T R
authors.initials: TR
authors.lastname: Bal
authors.forename: P
authors.initials: P
authors.lastname: Yogeeswari
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004950:Esterases / Q000378:metabolism; D004952:Esters; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D004952:Esters; D011355:Prodrugs; D015215:Zidovudine; D004950:Esterases