Synthesis and in vitro anti-HIV activities of didanosine prodrugs.
A series of prodrugs of didanosine were synthesized in an effort to enhance the anti-HIV activity. The 5'-OH function of didanosine was esterified with different aryl piperazine acetic acid derivatives and evaluated for anti-HIV-1 activity in MT-4 cell line using the MTT assay method. Among the synthesized compounds, (tetrahydro-5-(1,6-dihydro-6-oxopurin-9-yl)furan-2-yl)methyl 2-(4-(4-chlorophenyl)piperazin-1-yl)acetate (4b) was found to be the most potent compound with EC50 of 0.64 microM and was not toxic to the MT-4 cells up to 1000 microM with a selectivity index of > 1562. Compound 4b was found to be seven times more potent than the parent drug didanosine (EC50 of 4.8 microM) in vitro. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t1/2 ranging from 20-60 min.
Sriram
Dhrmarajan
D
Medicinal Chemistry Research Laboratory, Pharmacy group, Birla Institute of Technology and Science, Pilani 333031, India. dsriram@bits-pilani.ac.in
Yogeeswari
Perumal
P
Babu
Nagell Raveendra
NR
Kurre
Purna Nagashree
PN
D016049:Didanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D016049:Didanosine