In situ microemulsion-gel obtained from bioadhesive hydroxypropyl methylcellulose films for transdermal administration of zidovudine.

This study aims to develop in situ microemulsion-gel (ME-Gel) obtained from hydroxypropyl methylcellulose (HPMC) films for transdermal administration of Zidovudine (AZT). Firstly, HPMC films containing propylene glycol (PG) and eucalyptus oil (EO) were obtained and characterized. Later, a pseudo-ternary phase diagram composed of water, EO, tween 80 and PG was obtained and one microemulsion (ME) with a similar proportion of the film components was obtained. ME was transformed in ME-Gel by the incorporation of HPMC. Finally, HPMC films were hydrated with Tween 80 solution to yield in situ ME-Gel and its effect on AZT skin permeation was compared with HPMC film hydrated with water (F5hyd). The results showed that the ME and ME-Gel presented a droplet size of 16.79 and 122.13 µm, respectively, polydispersity index (PDI) < 0.39 and pH between 5.10 and 5.40. The incorporation of HPMC resulted in viscosity about 2 times higher than the use of ME. The presence of AZT did not alter the formulation properties. The in situ ME-Gel promoted a two-fold increase in the permeated amount of AZT compared to F5hyd. The results suggest that it was possible to obtain an ME-Gel in situ from HPMC films and that its effect on transdermal permeation of AZT was significant.

Inhibition of UGT2B7 Enzyme Activity in Human and Rat Liver Microsomes by Herbal Constituents.

The co-use of conventional drug and herbal medicines may lead to herb-drug interaction via modulation of drug-metabolizing enzymes (DMEs) by herbal constituents. UDP-glucuronosyltransferases (UGTs) catalyzing glucuronidation are the major metabolic enzymes of Phase II DMEs. The in vitro inhibitory effect of several herbal constituents on one of the most important UGT isoforms, UGT2B7, in human liver microsomes (HLM) and rat liver microsomes (RLM) was investigated. Zidovudine (ZDV) was used as the probe substrate to determine UGT2B7 activity. The intrinsic clearance (Vmax/Km) of ZDV in HLM is 1.65 µL/mg/min which is ten times greater than in RLM, which is 0.16 µL/mg/min. Andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone inhibited ZDV glucuronidation in HLM with IC50 values of 6.18 ± 1.27, 18.56 ± 8.62, 8.11 ± 4.48 and 4.57 ± 0.23 µM, respectively, hence, herb-drug interactions are possible if andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone are taken together with drugs that are highly metabolized by UGT2B7. Meanwhile, only mitragynine and zerumbone inhibited ZDV glucuronidation in RLM with IC50 values of 51.20 ± 5.95 µM and 8.14 ± 2.12 µM, respectively, indicating a difference between the human and rat microsomal model so caution must be exercised when extrapolating inhibitory metabolic data from rats to humans.

Poly(ethylene glycol) enclatherated pectin-mucin submicron matrices for intravaginal anti-HIV-1 drug delivery.

This paper explores the potential of polyethylene glycol enclatherated pectin-mucin (PEG-encl-PEC:MUC) submicron matrices (SMMs) as an intravaginal drug delivery system capable of delivering an anti-HIV-1 agent (zidovudine; AZT) over a prolonged duration. A three factor and three level (3(3)) Box-Behnken statistical design was employed to optimize the SMMs. Optimized PEG-encl-PEC:MUC SMMs prepared as a stable W/O emulsion (determined by the degree of reversible colloidal phenomena) were spherical with a mean particle size of 270.6 ± 5.533 nm and mean zeta potential of -34.4 ± 0.539 mV. The microencapsulation of AZT and the hydrogen bonding mediated shielding of AZT by SMMs was confirmed by Fourier Transform Infrared (FTIR) analysis. The thermochemical (differential scanning calorimetry and thermogravimetric analysis) data proposed that Ca(2+)-based macromolecular ionic crosslinking as well as the intermolecular interactions may be responsible for the thermal stability of the delivery system. The partially amorphous nature of drug-loaded SMMs, as confirmed by X-ray diffraction patterns, further strengthened the matricization of AZT into the pectin-mucin matrix. In vitro drug release studies from the SMMs showed approximately 91% zidovudine release in simulated vaginal fluid (SVF) and 94% in phosphate buffered saline (PBS) in 24h. The mean dissolution time (MDT) of zidovudine from the SMMs was 5.974 h. The attainment of required dimensional structure and drug release profiles from SMMs highlights the potential of their inclusion into a secondary carrier system for extended and controlled intravaginal stay.

Synthesis and Cytotoxic Evaluation of Artemisinin-triazole Hybrids.

Dihydroartemisinin was converted to its corresponding alkyne-functionalized esters, which were subsequently deployed as substrates for a 'click' chemistry-mediated coupling-with 3'-azido-3'-deoxythydimine (AZT) to furnish novel triazole-artesunate-AZT hybrid compounds. Moreover, various substituted triazole-artemisinin :hybrids were synthesized based on 'click' chemistry between propargyl-substituted derivatives and artemisinin containing a 2-hydroxypropane unit. Fourteen new hybrids were thus successfully prepared and evaluated as cytotoxic agents, revealing an interesting anticancer activity of four triazole-artemisinin derivative hybrids in KB and HepG2 cancer cell lines.

A new antiviral: chimeric 3TC-AZT phosphonate efficiently inhibits HIV-1 in human tissues ex vivo.

Although more-recently developed antivirals target different molecules in the HIV-1 replication cycle, nucleoside reverse transcriptase inhibitors (NRTIs) remain central for HIV-1 therapy. Here, we test the anti-HIV activity of a phosphonate chimera of two well-known NRTIs, namely AZT and 3TC. We show that this newly synthesized compound suppressed HIV-1 infection in lymphoid tissue ex vivo more efficiently than did other phosphonates of NRTIs. Moreover, the new compound was not toxic for tissue cells, thus making the chimeric phosphonate strategy a valid approach for the development of anti HIV-1 compound heterodimers.

Development and evaluation of a floating multiparticulate gastroretentive system for modified release of AZT.

The aim of this study was to develop and evaluate a floating multiparticulate gastroretentive system for the modified release of zidovudine (AZT). AZT was used as a model drug water-soluble at therapeutic doses. The floating gastroretentive system was obtained by co-precipitation, after solvent diffusion and evaporation. The proposed system was evaluated in vitro for particle morphology, lag time and floating time, loading rate, release profile, and the release kinetic of AZT release. AZT's physico-chemical characteristics were evaluated by differential scanning calorimetry (DSC), X-ray diffraction (XDR) and infrared spectroscopy (IR). The particles obtained were sphere-shaped, hollow, and had porous walls. The floating was immediate, and floating time was higher than 12 h. The loading rate was 34.0 ± 9.0%. The system obtained had an extended release. DSC and XDR results showed a modification in AZT's solid state. IR spectroscopy revealed that the chemical structure of the AZT was unchanged. The hollow microballoons presented gastroretentive, floating, and extended-release properties.

The influence of the compression force on zidovudine release from matrix tablets.

The aim of the present work is the study of different zidovudine (AZT) formulations containing polymers (both cellulosic and acrylic), in order to evaluate the influence of the compression force on the antiviral release from the matrix tablets. The results evidenced that the formulations compressed at 500 and 1,000 MPa exhibit a higher hardness than those prepared at 100 MPa. The effect of the compression force on the drug release was analyzed and a statistically significant difference was observed (P < 0.05). Using lower compression forces leads to slightly better release profiles, i.e., profiles close to an ideal Higuchi kinetics for a total release of drug in a 12-h period, allowing to conclude that a compression force higher than 100 MPa is unnecessary.

Oral sustained release tablets of zidovudine using binary blends of natural and synthetic polymers.

Oral sustained release matrix tablets of zidovudine (ZDV) were prepared using different types, proportions and blends of carbopol 71G (C71) and a plant gum obtained from Abelmoschus esculentus (AEG). The effect of various formulation factors like polymer proportion, polymer type and pH of the dissolution medium on the in vitro release of the drug was studied, using the half change technique, in 900 ml of dissolution medium, at 100 rpm. Release kinetics were analyzed using Zero-order, Higuchi's square-root and Ritger-Peppas' empirical equations. In vitro release performance as revealed by the time taken for 70% of the drug to be released (t70%), showed that the release rate decreased with increase in polymer proportion. Matrix tablets containing 10 and 20% AEG were found to exhibit immediate-release characteristics. Matrix tablets containing 30% AEG showed t70% value of 204 min and extended the release up to 5 h, while matrix tablets containing 30% carbopol showed t70% value of 234 min and extended the release up to 6 h. Three blends of AEG and C71 at the ratio of 1:2, 2:1 and 1:3 showed t70% values of 132, 312 and 102 min respectively and extended the release up to 8 h. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets followed Fickian and anomalous release. Drug release from matrix tablets of zidovudine containing blends of AEG and C71 demonstrates the advantage of blending a natural and synthetic polymer over single polymer use.

Controlled release matrix tablets of zidovudine: effect of formulation variables on the in vitro drug release kinetics.

The purpose of this research was to design oral controlled release (CR) matrix tablets of zidovudine (AZT) using hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC) and carbopol-971P (CP) and to study the effect of various formulation factors on in vitro drug release. Release studies were carried out using USP type 1 apparatus in 900 ml of dissolution media. Release kinetics were analyzed using zero-order, Higuchi's square root and Ritger-Peppas' empirical equations. Release rate decreased with increase in polymer proportion and compression force. The release rate was lesser in formulations prepared using CP (20%) as compared to HPMC (20%) as compared to EC (20%). No significant difference was observed in the effect of pH of dissolution media on drug release from formulations prepared using HPMC or EC, but significant difference was observed in CP based formulations. Decrease in agitation speed from 100 to 50 rpm decreased release rate from HPMC and CP formulations but no significant difference was observed in EC formulations. Mechanism of release was found to be dependent predominantly on diffusion of drug through the matrix than polymer relaxation incase of HPMC and EC formulations, while polymer relaxation had a dominating influence on drug release than diffusion incase of CP formulations. Designed CR tablets with pH independent drug release characteristics and an initial release of 17-25% in first hour and extending the release up to 16-20 h, can overcome the disadvantages associated with conventional tablets of AZT.

Dipeptide derivatives of AZT: synthesis, chemical stability, activation in human plasma, hPEPT1 affinity, and antiviral activity.

5'-O-Dipeptide ester prodrugs of antiviral zidovudine (AZT) were designed to target the human intestinal oligopeptide transporter, hPEPT1, and were evaluated for their stability at pH 7.4 in buffer and in human plasma, affinity toward hPEPT1, cytotoxicity, and antiretroviral activity. The dipeptide esters of AZT undergo cyclization in buffer at pH 7.4 to release the parent drug at a rate that depends on the size of the side chains of the peptide carrier; the prodrug is considerably more stable if bulky beta-branched amino acids such as Ile and Val are present, particularly as C-terminal residues. Incubation in human plasma showed that most of the dipeptide esters of AZT release the parent drug through two aminopeptidase-mediated pathways: 1) stepwise cleavage of each of the amino acids and 2) direct cleavage of the dipeptide-drug ester bond. However, the plasma hydrolysis of Gly-Gly-AZT and Phe-Gly-AZT showed only direct cleavage of the dipeptide-drug ester bond. Substrate half-lives in plasma were again remarkably high when hydrophobic beta-branched amino acids (Val, Ile) were present. The esters were also good substrates for the intestinal oligopeptide transporter hPEPT1 in vitro, with Val-Gly-AZT and Val-Ala-AZT presenting the highest affinity toward the transporter (IC(50): 0.20 and 0.15 mM, respectively). The AZT dipeptide esters were assayed against the IIIB and ROD strains of HIV, and their cytotoxicity was evaluated in MT-4 cells. The selectivity index of the prodrugs was two- to threefold higher than that of AZT for all compounds analyzed. These results point to the potential of dipeptide-based carriers for the development of effective antiviral drug-delivery systems. Val-Ala-AZT appears to combine chemical stability with good affinity for the hPEPT1 transporter and an improved cytotoxicity/antiretroviral index relative to AZT.

Synthesis, characterization, and in vitro assay of folic acid conjugates of 3'-azido-3'-deoxythymidine (AZT): toward targeted AZT based anticancer therapeutics.

Conjugates of three components namely folic acid, poly(ethyleneglycol) and 3 '-azido-3 '-deoxythymidine (AZT) are presented. Folate-PEG units were coupled to AZT to facilitate delivery of the nucleoside into the cell. A convenient separation of the polydisperse PEGylated-folic acid regioisomers produced upon conjugation is described. This is to select for the active gamma-regioisomer over the inactive alpha-regioisomer. In vitro cytotoxicity assays were conducted against an ovarian cell line (A2780/AD) that overexpresses the folate receptor (FR) and compared to a FR free control cell line. Compared to AZT a approximately 20-fold greater potency against the resistant ovarian line was observed for the conjugates.

Effects of the translocation status of human immunodeficiency virus type 1 reverse transcriptase on the efficiency of excision of tenofovir.

The ATP-dependent phosphorolytic excision of nucleoside analogue reverse transcriptase inhibitors can diminish their inhibitory effects on human immunodeficiency virus replication. Previous studies have shown that excision can occur only when the reverse transcriptase complex exists in its pretranslocational state. Binding of the next complementary nucleotide causes the formation of a stable dead-end complex in the posttranslocational state, which blocks the excision reaction. To provide mechanistic insight into the excision of the acyclic phosphonate nucleotide analog tenofovir, we compared the efficiencies of the reaction in response to changes in the translocation status of the enzyme. We found that rates of excision of tenofovir with wild-type reverse transcriptase can be as high as those seen with 3'-azido-3'-deoxythymidine monophosphate (AZT-MP). Thymidine-associated mutations, which confer >100-fold and 3-fold decreased susceptibility to AZT and tenofovir, respectively, caused substantial increases in the efficiency of excision of both inhibitors. However, in contrast to the case for AZT-MP, the removal of tenofovir was highly sensitive to dead-end complex formation. Site-specific footprinting experiments revealed that complexes with AZT-terminated primers exist predominantly pretranslocation. In contrast, complexes with tenofovir-terminated primers are seen in both configurations. Low concentrations of the next nucleotide are sufficient to trap the complex posttranslocation despite the flexible, acyclic character of the compound. Thus, the relatively high rate of excision of tenofovir is partially neutralized by the facile switch to the posttranslocational state and by dead-end complex formation, which provides a degree of protection from excision in the cellular environment.

Evaluation of a basic physiologically based pharmacokinetic model for simulating the first-time-in-animal study.

The objective of this study was to evaluate a physiologically based pharmacokinetic (PBPK) approach for predicting the plasma concentration-time curves expected after intravenous administration of candidate drugs to rodents. The predictions were based on a small number of properties that were either calculated based on the structure of the candidate drug (octanol:water partition coefficient, ionization constant(s)) or obtained from the typical high-throughput screens implemented in the early drug discovery phases (fraction unbound in plasma and hepatic intrinsic clearance). The model was tested comparing the predicted and the observed pharmacokinetics of 45 molecules. This dataset included six known drugs and 39 drug candidates from different discovery programs, so that the performance of the model could be evaluated in a real discovery case scenario. The plasma concentration-time curves were predicted with good accuracy, the pharmacokinetic parameters being on average two- to three-fold of actual values. Multivariate analysis was used for identifying the candidate properties which were likely associated to biased predictions. The application of this approach was found useful for the prioritization of the in vivo pharmacokinetics screens and the design of the first-time-in-animal studies.

Evaluating the utility of ion mobility separation in combination with high-pressure liquid chromatography/mass spectrometry to facilitate detection of trace impurities in formulated drug products.

Many formulated products contain complex polymeric excipients such as polyethylene glycols (PEGs). Such excipients can be readily ionized by electrospray and may be present at very high concentrations, thus making it very difficult to identify trace level impurities such as degradants in samples, even if hyphenated techniques such as liquid chromatography/mass spectrometry (LC/MS) are used. Ion mobility (IM) spectrometry is a very rapid gas-phase separation technique and offers additional separation capability within the LC timeframe. This work investigates the use of an IM separator in combination with high-pressure liquid chromatography (HPLC) and MS, to improve the separation of drug-related materials from excipients, thus aiding the identification of trace-level impurities in an anti-HIV medication, Combivir.

Effect of change in nucleoside structure on the activation and antiviral activity of phosphoramidate derivatives.

Changing the nucleoside group of a series of phosphoramidate derivatives affects the enzyme mediated hydrolysis rate of the compounds. d4T and AZT-substituted analogs were activated by enzymes such as lipases, esterases, and proteases. On the other hand, 3dT-substituted derivatives were comparatively less prone to hydrolysis under similar experimental conditions. From the experimental results, we propose that the most preferable nucleoside group for enzyme activation is d4T rather than AZT or 3dT. Additionally, we also observed that depending on the enzymes used the chiral selectivity of the enzymes for the phosphorus center of these phosphoramidate derivatives differed, demonstrating the importance of the nucleoside structure for this class of compounds.

Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action.

The effect of various oxygen-containing monoterpenes such as cineole, menthol, alpha-terpineol, menthone, pulegone and carvone was investigated on ex vivo permeation of zidovudine (AZT) across rat skin. Furthermore, saturation solubility of AZT, its stratum corneum (SC)/vehicle partition coefficient and activation energy for diffusion across skin with or without terpene(s) in vehicle (66.6% ethanol in water) were determined to understand their mechanism of action. All the terpenes studied significantly increased transdermal flux of AZT in comparison to vehicle (p<0.05) and their enhancement activities are in the following decreasing order: cineole>menthol>menthone approximately pulegone approximately alpha-terpineol>carvone>vehiclewater. On the other hand, saturation solubility and SC/vehicle partition coefficient of AZT were not significantly altered (p>0.05) by terpenes. Activation energies of AZT permeation across rat skin from water, vehicle and cineole in vehicle were measured to be 20.4, 18.6 and 10.6 kcal/mol, respectively. Interactions between terpenes and SC lipids were studied with molecular modeling and found that terpenes form hydrogen bonds (bond lengths<2 A) with lipid head groups. The mechanism of permeation enhancement of AZT by terpenes was explained with thermodynamic activity, SC/vehicle partition coefficient, activation energy and molecular modeling studies.

Pre-clinical safety evaluation of novel nucleoside analogue-based dual-function microbicides (WHI-05 and WHI-07).

Compounds WHI-05 [5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl)-methoxyalaninyl phosphate] and WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate] are aryl phosphate derivatives of zidovudine (ZDV) with anti-HIV and contraceptive activity. WHI-05 and WHI-07 differ fundamentally from currently used surfactant microbicides that are cytotoxic to genital tract epithelial cells at spermicidal concentrations. These drugs were rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions, as well as to achieve spermicidal activity. WHI-05 and WHI-07 were formulated via a non-toxic gel-microemulsion for intravaginal use as potential anti-HIV spermicides. Pre-clinical safety studies of intravaginally administered WHI-05 and WHI-07 gel-microemulsions were performed in mice and rabbits to mimic closely the intravaginal application of a microbicidal preparation in women. In addition, systemic toxicity studies were performed in mice and non-human primates. The LD10 doses for WHI-05 and WHI-07 when administered intravenously or intraperitoneally were >500 mg/kg for mice. Female cynomolgus monkeys treated with 20 mg/kg WHI-05 and WHI-07 intravenously developed no grade 2-4 systemic toxicities. Repetitive intravaginal administration of 2% WHI-05 and WHI-07 via a gel-microemulsion to achieve concentrations as high as 6.1 x 10(4) and 5.7 x 10(6) times their respective in vitro anti-HIV IC50 values, and 1200 and 5700 times their spermicidal EC50 values, for up to 13 weeks, was not associated with mucosal, systemic or reproductive toxicity. Furthermore, long-term (2 years) intravaginal administration of 2% WHI-07 gel-microemulsion was not associated with systemic toxicity or increased carcinogenicity in mice. The improved potency, as well as the lack of mucosal, systemic and reproductive toxicity of WHI-05 and WHI-07, means that these compounds have clinical potential as safe, prophylactic contraceptives in addition to their microbicide activity to curb the sexual transmission of HIV.

Design, synthesis, and biological evaluation of anti-HIV double-drugs. conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor through spontaneously cleavable linkers.

Based on the prodrug concept as well as the combination of two different classes of anti-HIV agents, we designed and synthesized a series of anti-HIV double-drugs consisting of HIV protease inhibitors conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoins the two different classes of inhibitors has been investigated. Double-drugs using a succinyl amino acid linker were shown to release the parent drugs via spontaneous imide formation at a faster rate compared to compounds using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Among the double-drugs, KNI-1039 (3b) with a glutarylglycine linker exhibited extremely potent anti-HIV activity compared with that of the individual components. Double-drug 3b was relatively stable in culture medium, whereas it regenerated active species in cell homogenate. These results suggested that the synergistic enhancement of anti-HIV activities of 3b may be due to their ability to penetrate into the target cell and subsequent regeneration of two different classes of anti-HIV agents in the cytoplasm.

Synthesis, characterization and preclinical formulation of a dual-action phenyl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07) with potent anti-HIV and spermicidal activities.

In a systematic effort to develop a microbicide contraceptive capable of preventing transmission of human immunodeficiency virus (HIV), as well as providing fertility control, we have previously identified novel phenyl phosphate derivatives of zidovudine (ZDV) with 5-halo 6-alkoxy substitutions in the thymine ring and halo substitution in the phenyl moiety respectively. Here, we describe the synthesis, characterization, and successful preclinical formulation of our lead compound, 5-bromo-6-methoxy-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), which exhibits potent anti-HIV and sperm immobilizing activities. The anti-HIV activity of WHI-07 was tested by measuring viral p24 antigen production and reverse transcriptase activity as markers of viral replication in HIV-1 infected human peripheral blood mononuclear cells (PBMC). WHI-07 inhibited replication of HIV in a concentration-dependent fashion with nanomolar IC50 values. The effects of WHI-07 on human sperm motion kinematics were analysed by computer-assisted sperm analysis (CASA), and its effects on sperm membrane integrity were examined by confocal laser scanning microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy (HR-LVSEM). WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion. The in-vitro cytotoxicities of WHI-07 and nonoxynol-9 (N-9) were compared using normal human ectocervical and endocervical epithelial cells by the MTT cell viability assay. Unlike N-9, WHI-07 had no effect upon sperm plasma and acrosomal membrane integrity. N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, whereas WHI-07 was selectively spermicidal. The in-vivo vaginal absorption and vaginal toxicity of 2% gel-microemulsion of WHI-07 was studied in the rabbit model. The sperm immobilizing activity of WHI-07 was 18-fold more potent than that of N-9. Over a 10 day period, there was no irritation or local toxicity to the vaginal epithelia or systemic absorption of WHI-07. Therefore, as a potent anti-HIV agent with spermicidal activity, and lack of mucosal toxicity, WHI-07 may have the clinical potential to become the active ingredient of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.

Synthesis and anti-HIV activity of steroidal prodrugs of 3'-azido-3'-deoxythymidine (AZT).

A total of seven steroidal prodrugs of AZT were synthesized and tested in vitro for their anti-HIV activity. Three of them were steroidal carboxylic esters prepared from steroidal 17 beta-carboxylic acids and AZT. The remaining four were alkyl steroidal phospho-triesters of AZT. These prodrugs were synthesized using known procedures. Preliminary results of in vitro anti-HIV activity screening showed that all of these prodrugs were active against HIV. While carboxylic esters showed comparable anti-HIV activity to that of AZT, phosphotriesters were less active than AZT. The therapeutic indices of all these prodrugs are comparable to that of AZT.