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We report on the synthesis of 4-hydroxycoumarin dimers 1-15 bearing an aryl substituent on the central linker and fused benzopyranocoumarin derivatives 16-20 and on their in vitro broad anti-DNA and RNA virus activity evaluations. The chemical identities and structure of compounds 1-20 were deduced from their homo- and heteronuclear NMR measurements whereas the conformational properties of 5, 14 and 20 were assessed by the use of 1D difference NOE enhancements. Unequivocal proof of the stereostructure of compounds 7, 9, 16 and 18 was obtained by single crystal X-ray diffraction method. The X-ray crystal structure analysis revealed that two 4-hydroxycoumarin moieties in the 4-trifluoromethylphenyl- and 2-nitrophenyl derivatives (compounds 7 and 9, respectively) are intramolecularly hydrogen-bonded between hydroxyl and carbonyl oxygen atoms. Consequently, the compounds 7 and 9 adopt conformations in which two 4-hydroxy-coumarin moieties are anti-disposed. Antiviral activity evaluation results indicated that the 4-bromobenzylidene derivative of bis-(4-hydroxycoumarin) (compound 3) possesses inhibitory activity against HSV-1 (KOS), HSV-2 (G), vaccinia virus and HSV-1 TK⁻ KOS (ACVr) at a concentration of 9-12 μM and at a minimum cytotoxic concentration (MCC) greater than 20 μM. Compounds 4-6, 8, and 20 were active against feline herpes virus (50% effective concentration, EC₅₀ = 5-8.1 μM), that is at a 4-7-fold lower concentration than the MCC.

Isatin (2,3-dioxoindole) has been reacted with N-(6-chloro benzothiazol-2-yl) thiosemicarbazide to form Schiff base and the N-Mannich bases of the above Schiff base were synthesized by reacting with formaldehyde and several secondary amines. The chemical structures of N-Mannich bases have been confirmed by means of IR, 1H-NMR data and by elemental analysis. Investigation of antimicrobial activity of compounds was done by agar dilution method against 25 pathogenic bacteria, 8 pathogenic fungi and anti-HIV activity against replication of HIV-1 (Ill B) in MT-4 cells. Among the compounds tested 1-[N,N-dimethylaminomethyl] isatin-3-[1'(6-chlorobenzothiazoI-2-yl) thiosemicarbazone] showed the highest antimicrobial activity.

Ribavirin enhances the anti-human immunodeficiency virus activity of 2',3'-dideoxyinosine (ddIno) in MT-4, CEM and peripheral blood lymphocyte cells. Ribavirin causes an increase in the levels of IMP, the presumed phosphate donor for the conversion of ddIno to ddIMP by 5'-nucleotidase. Consequently, ribavirin stimulates the conversion of ddIno to its antivirally active metabolite ddATP. Ribavirin also causes a marked depletion of the guanine nucleotide pools. The increase in IMP pool levels may result from (i) a direct inhibitory effect of ribavirin 5'-monophosphate on IMP dehydrogenase (which converts IMP to XMP) and (ii) an indirect inhibition of adenylosuccinate synthetase by the decreased GTP and dGTP pools (since GTP is an obligatory cofactor in the conversion of IMP to succinyl AMP). GTP depletion plays a key role in the accumulation of IMP and the resultant higher rate of ddIno phosphorylation to ddIMP and eventually ddATP. Our findings are in agreement with the observations that guanosine and 2'-deoxyguanosine, but not 2'-deoxyadenosine, reverse (i) the stimulatory effect of ribavirin on the anti-human immunodeficiency virus activity of ddIno and (ii) the accumulation of endogenous IMP pools as well as accumulation of [3H]IMP from exogenous [3H]hypoxanthine in ribavirin-treated cells.

A series of new 5-alkyl-2-phenylaminocarbonylmethylthiopyrimidin-4(3H)-ones bearing variously substituted arylmethyl moieties at the C6 position of the pyrimidine ring were synthesized and evaluated for anti-HIV activity in MT-4 cells. Most of these new congeners exhibited moderate to good activities against the wild-type virus, with EC(50) values in the range of 1.40-0.19 μM. Among them, 2-[(4-cyanophenylamino)carbonylmethylthio]-6-(2-chloro-6-fluorobenzyl)-5-ethylpyrimidin-4(3H)-one 4 b6 is one of the compounds endowed with the highest broad-spectrum HIV-1 inhibitory activity, with EC(50) values of 0.19±0.005 μM against the wild-type virus, 1.05±0.24 μM (twofold resistance) against the E138K strain, and 2.38±0.13 μM (4.5-fold resistance) against the Y181C strain. Furthermore, reverse transcriptase (RT) inhibition assays against wild-type HIV-1 RT were performed with selected derivatives, confirming that the main target of these compounds is HIV-1 RT and that these new S-DABO analogues act as non-nucleoside RT inhibitors (NNRTIs). Structure-activity relationship and molecular modeling analyses of these new congeners are also discussed.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of the replication of human immunodeficiency virus (HIV) in vitro in human T-lymphocyte MT-4, H9, and ATH8 cells. PMEA also inhibits Moloney murine sarcoma virus (Mo-MSV)-induced transformation of murine C3H embryo fibroblasts. Moreover, PMEA causes a dose-dependent suppression of tumor formation and associated mortality in mice inoculated with Mo-MSV. At a dose of 50 or 20 mg/kg per day PMEA effected a 90-100% protection of the mice against Mo-MSV-induced tumor formation and mortality. Even with a PMEA dose as low as 1 to 5 mg/kg per day, tumor formation was significantly delayed and the survival rate was significantly enhanced. In parallel experiments, azidothymidine exhibited a comparable inhibitory effect on Mo-MSV-induced tumor formation and associated death only at a 25-fold higher dose than PMEA. Because PMEA has stronger in vivo antiretrovirus potency and selectivity than azidothymidine and various other compounds currently being subjected to clinical trials, PMEA studies should be pursued to assess the potential of this compound in the treatment of acquired immunodeficiency syndrome (AIDS) and other retrovirus infections in humans.

Methyl 2,3-O-isopropylidene-D-ribofuranoside ( IV ) was alkylated with alkyl halides in the presence of sodium hydride and the products were transformed by acid hydrolysis and glycosylation into methyl 5-O-alkyl-D-ribofuranosides VII . Benzoylation of VII followed by acetolysis afforded 1-O-acetyl-2,3-di-O-benzoyl-5-O-alkyl-D-ribofuranoses IX which on reaction with 2,4-bis(trimethylsilyloxy)pyrimidine in the presence of tin tetrachloride in acetonitrile and subsequent hydrolysis gave 5'-O-alkyl-2',3'-di-O-benzoyluridines XIa-XIe . Methanolysis of compounds XI furnished 5'-O-alkyluridines III . The 5-O-allyl derivative XII was hydroxylated in the presence OsO 4 and transformed further to 5'-O-( RS )-(2,3-dihydroxypropyl)uridine ( IIIg ) and its tetrabenzoate XVI . Compounds XI and XVI on reaction with elemental fluorine in acetic acid afforded benzoyl derivatives of 5'-O-alkyl-5-fluorouridines XVIIa-XVIIe and XIX which were methanolyzed to give 5'-O-alkyl-5-fluorouridines II . This procedure afforded 5'-O-methyl ( IIa ), ethyl ( IIb ), n-butyl ( IIc ), n-hexyl ( IId ), n-octyl ( IIe ), and ( RS )-(2,3-dihydroxypropyl) ( IIf ) derivatives of 5-fluorouridine. None of the compounds II exhibited antibacterial effect on Escherichia coli B or antiviral activity against HSV-1, HSV-2, vaccinia virus or vesicular stomatitis viruses. Compounds IIc,d,e suppressed the growth of L 1210 mice leukemic cells at concentrations of 10 -5 to 10 -6 mol l -1 ; the 5'-O-n-butyl derivative IIc has the highest activity (ID 50 2·8 μmol l -1 ) but does not prolong the life span of L 1210 leukemia bearing mice following repeated daily doses of 80 mg/kg.

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