Syntheses and Biological Evaluation of 5′-O-Myristoyl Derivatives of Thymidine against Human Immunodeficiency Virus (original) (raw)
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Antimicrobial Agents and Chemotherapy, 1990
Three analogs of thymidine, D4T [2',3'-didehydro-2',3'-dideoxythymidine; 1-(2,3-dideoxy-beta-D-glyceropent-2-enofuranosyl)thymine], FddT (3'-fluoro-3'-deoxythymidine), and AZT (3'-azido-3'-deoxythymidine), were compared in biological tests designed to assess their potential utility as anti-human immunodeficiency virus (HIV) agents. The in vitro potencies of these compounds against HIV infection in CEM cells were measured, with FddT and AZT being more potent than D4T. The cytotoxicities of D4T, FddT, and AZT for CEM cells were comparable. The triphosphates of these three derivatives inhibited purified HIV reverse transcriptase, and their affinities for this polymerase were found to be 1 or 2 orders of magnitude greater than that for the normal substrate, dTTP. D4T was less toxic than FddT or AZT for cultured human and mouse bone marrow cells (granulocyte-macrophage CFU). The three compounds had similar toxicities for human progenitor erythrocyte burst-...
Antiviral Chemistry and Chemotherapy, 1998
5′- O-Myristoyl analogue derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT), designed as potential double-barrelled prodrugs to AZT and the myristic acid analogues, were synthesized. Their ability to protect CEM cells against human immunodeficiency virus (HIV)-induced cytopathogenicity was determined and structure–activity paradigms were developed. 3′-Azido-2′,3′-dideoxy-5′- O-(4-oxate-tradecanoyl)thymidine (EC50=1.4 nM) and 3′-azido-2′,3′-deoxy-5′- O-(12-bromododecanoyl)thymidine (EC50=3.2 nM) were the most effective anti-HIV-1 agents, relative to AZT (EC50=10 nM). These myristoyl analogue derivatives were more lipophilic (calculated log P=4.5–8.1 range) than the parent compound AZT (log P=0.06), and a linear correlation between their log P and HPLC log retention timeswas observed. The ester cleavage half-lives ( t1/2) for esters upon in vitro incubation with porcine liver esterase, rat plasma or rat brain homogenate was dependent on the steric bulk, and electronegative inductive...
Journal of Medicinal Chemistry, 1994
A new class of 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines was investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodrugs to 3'-azido-3'-deoxythymidine (AZT), were designed in an effort to enhance the duration of action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines, which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, C1, I; R = alkoxy, azido) to the 5,6-olefinic bond of AZT. The 5-halo-6-methoxy-5,6-dihydro derivatives of AZT are more lipophilic (P = 3.3-18.8 range) than the parent compound AZT (P = 1.29). These 5-halo-6-methoxy-5,6-dihydro compounds, like AZT, did not undergo glycosidic bond cleavage upon incubation with Escherichia coEi thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give AZT, upon incubation of the 5-halo-6-methoxy-5,6-dihydro compounds with glutathione, mouse blood, or mouse liver homogenate, was dependent upon the nature of the 5-halo substituent (I > Br). No 5,6-olefinic bond regeneration was observed for the 5-chloro analogs. The ability of these 5-halo-6-alkoxy (or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines to protect CEM cells against HIV-induced cytopathogenicity was evaluated. Structure-activity studies showed that the C-5 substituent (I, Br, C1) was a determinant of anti-HIV-1 activity where the potency order was I 1 Br > C1. In the 5-bromo series of compounds, the C-6 substituent was also a determinant of activity where 6-OMe and 6-OEt substituents exhibited a greater potency than the corresponding 6-i-Pro, 6-(l-octyloxy), 6-(l-hexadecyloxy), and 6-azido analogs. All of the 5-chloro-6-substituted-5,6-dihydro compounds were inactive, except for the approximately equipotent 6-OMe and 6-azido diastereomeric mixtures which were 2-3 log units less active than the reference drug AZT. The configuration at the C-5 and C-6 positions also influenced potency where the activity of the 5R,GR-diastereomer was generally greater than that of the corresponding 5S,GS-diastereomer. The most potent anti-HIV-1 agents, which included the (5R,GR)-5-brom0-6-methoxy, (5R,GR)-5-iodo-6-methoxy, (5S,GS)-5-iodo-6-methoxy, and (5R,GR)-5-brom0-6-ethoxy analogs of AZT, were equipotent to the reference drug AZT. These 5-iodo(bromo)-6-methoxy-5,6-dihydro derivatives of AZT are potential prodrugs to AZT that provide a rapid release of AZT in vivo.
Journal of Medicinal Chemistry, 1994
Several 4-, 5-, and 6-substituted pyrimidine analogues of the new anti-HIV-1 lead compound [ 1-[2',5'bis-0-(tert-butyldimethylsilyl)-~-~-ribofuranosyll thymine]-3'-spiro-5''-"''-amino-l''"''oxathiole 2",2"-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1 and HIV-2 replication in cell cultures. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with 5-substituted pyrimidine bases, followed by treatment with Cs2CO3, afforded, stereoselectively, ~-~-ribofuranosyl-3'-spironucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the TSAO-5-substituted pyrimidine derivatives. Reaction of 5-halogen-TSAO derivatives with nucleophiles gave 6-substituted-TSAO analogues. Treatment of TSAO-pyrimidine analogues with POC13/1,2,4-triazole and methylamine or dimethylamine afforded the 4-substituted pyrimidine compounds. Several substituted TSAOthymine, TSAO-uracil, and TSAO-cytosine derivatives were found to be superior to their unsubstituted TSAO congeners with regard to their antiviral and/or cytotoxic properties. Chemistry The 3'-spironucleosides were stereoselectively prepared, following our previously reported method? by glycosylation of trimethylsilylated heterocyclic bases with the suitably functionalized and protected ribofuranosyl sugar intermediate 5,8 followed by basic treatment of the cyanomesyl nucleosides thus obtained, to give, exclusively, 0-D-ribospironucleosides. The ribo configuration of the
Synthesis and Modeling Study of Some Potential Pyrimidine Derivatives as HIV Inhibitors
Zeitschrift für Naturforschung B, 2014
A new series of 2-amino-6-((4-aryldiazenyl)benzyloxy)-4-chloropyrimidine derivatives 4 - 13 and 2,6-diamino-5-arylazo-4-chloro-pyrimidine analogs 15 - 20 were synthesized from the pyrimidine scaffolds 3 and 14, respectively, via diazotization with various amines. Nucleophilic displacement at the 2,4-diamino-5-arylazo-6-chloro-pyrimidine 16 by different amines afforded the 4-alkylamino analogs 21 - 27. All new compounds were evaluated for their in vitro anti-HIV activity in MT-4 cells as non-nucleoside reverse transcriptase inhibitors on the basis of our previous work. Screening results indicated that 10 and 11 were found to be the only compounds in the series inhibiting HIV-1 replication in cell cultures with EC
Synthesis, anti-HIV activity and molecular modeling study of some new pyrimidine analogues
European Journal of Chemistry, 2014
A new series of 2-amino-6-((4-aryldiazenyl)benzyloxy)-4-chloropyrimidine derivatives 4-13 and 2,6-diamino-5-arylazo-4-chloro-pyrimidine analogs 15-20 were synthesized from the pyrimidine scaffolds 3 and 14, respectively, via diazotization with various amines. Nucleophilic displacement at the 2,4-diamino-5-arylazo-6-chloro-pyrimidine 16 by different amines afforded the 4-alkylamino analogs 21-27. All new compounds were evaluated for their in vitro anti-HIV activity in MT-4 cells as non-nucleoside reverse transcriptase inhibitors on the basis of our previous work. Screening results indicated that 10 and 11 were found to be the only compounds in the series inhibiting HIV-1 replication in cell cultures with EC 50 of > 1.23 and > 2.92 µg mL −1 of a CC 50 of 12.30 and 17.52 µg mL −1 , resulting in a selectivity index of 10 and 6, respectively. In addition, preliminary structure-activity relationships and molecular modeling of these new analogs are detailed in this manuscript.
ACTA Pharmaceutica Sciencia, 2018
INTRODUCTION Nucleosides are key compounds involved in major biological processes, such as nucleic acids and proteins synthesis, cell signaling, enzyme regulation, and metabolism. Nucleoside and their derivatives have emerged as molecules with ABSTRACT In search of new leads toward potent antibacterial agents; therefore, a series of thymidine analogues were synthesized by direct acylation method and furnished the 5´-O-acyl thymidine derivatives in good yield. A number of acyl derivatives were prepared in order to obtain a series of newer components for antibacterial screening experiments. The synthesized compounds were characterized by their FTIR, 1 HNMR spectral data and elemental analysis. These thymidine derivatives were evaluated for in vitro antibacterial screening studies against a number of human pathogenic microorganisms by disc diffusion method. The study revealed that most of the tested chemicals exhibited moderate to good antibacterial activities. It was also observed that the test chemical 2-bromobenzoyl derivative 11 very significantly inhibited the growth of all Gram-positive and Gram-negative bacterial strains used. For comparative studies, antibacterial activity of standard antibiotics, Azithromycin was also carried out against these microorganisms. Hence, these thymidine derivatives can be used to discover antibacterial agents that may serve as leads in the development of new pharmaceuticals research activities.