Potential anti-AIDS Drugs Research Articles

ChemInform Abstract: Synthesis of 1-(3-R-Amino-4-hydroxybutyl)thymine Acylonucleoside Analogs as Potential Anti-Aids Drugs.

ChemInform Abstract: Synthesis of 1-(3-R-Amino-4-hydroxybutyl)thymine Acylonucleoside Analogs as Potential Anti-Aids Drugs.

ChemInform Abstract: Synthesis and Evaluation of New 2′,3′-Dideoxynucleoside Analogues as Potential Anti-AIDS and Anti-Herpes Drugs.

ChemInform Abstract: Synthesis and Evaluation of New 2′,3′-Dideoxynucleoside Analogues as Potential Anti-AIDS and Anti-Herpes Drugs.

Coumarins as Inhibitors of HIV Reverse Transcriptase

Acquired immunodeficiency syndrome (AIDS), a degenerative disease of the immune and central nervous systems, is an enormous world-wide health threat. No cure has been found, and research is aimed at developing chemotherapy against the causative agent, human immunodeficiency virus (HIV). Chemotherapy for AIDS has progressed steadily in the past decade. However, new, effective, and less toxic chemotherapeutic agents are still needed. Plants, particularly anti-infective or immunomodulating herbal medicines, can serve as sources of new active leads to be further developed as anti-AIDS drug candidates. A lot of structurally different natural coumarins were found to display potent anti-HIV activity and continued progress is anticipated in the discovery of new leads and in the development of these agents as potential anti-AIDS drug candidates. Recent studies based on the account of various coumarins from plant sources and their analogs--synthetic coumarins, indicate that some of them serve as potent nonnucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The current review demonstrates the variety of coumarins of natural plant origin and synthetic coumarins having unique mechanism of action to one of the most important stage of HIV replication (RT-inhibition). The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure-activity relationships are discussed. The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against drug-resistant mutants.

Molecular modeling, design, synthesis, and biological evaluation of novel 3′,4′-dicamphanoyl-(+)- cis-khellactone (DCK) analogs as potent anti-HIV agents

Our current studies aimed at developing new potential anti-AIDS drug candidates have focused on the design and synthesis of new DCK analogs with improved molecular water solubility. Based on the structures and biodata of previous DCK analogs, 3D-QSAR studies have been performed which resulted in two reliable computational models, CoMFA and CoMSIA, with r 2 values of 0.995 and 0.987, and q 2 values of 0.662 and 0.657, respectively. In accord with these 3D-QSAR models, 15 new DCK analogs with polar functional groups at the 3-position were subsequently designed, synthesized, and evaluated against HIV-1 replication in H9 and MT4 cell lines. New DCK analogs 3b, 3c, 4b, 4c, 6a, 7c, and 9a showed promising potency with EC 50 values ranging from 0.09 to 0.0002 μM in both assays. Meanwhile, these promising compounds also showed a wide range of predicted log P values from 0.90 to 5.19, which increased the probability of identifying anti-HIV drug candidates from this class of compounds for clinical trials. Furthermore, both experimental and predicted values matched well, corroborating the reliability of the established 3D-QSAR models.

Binding of the Second Generation Non-nucleoside Inhibitor S-1153 to HIV-1 Reverse Transcriptase Involves Extensive Main Chain Hydrogen Bonding

S-1153 (AG1549) is perhaps the most promising non-nucleoside inhibitor of HIV-1 reverse transcriptase currently under development as a potential anti-AIDS drug, because it has a favorable profile of resilience to many drug resistance mutations. We have determined the crystal structure of S-1153 in a complex with HIV-1 reverse transcriptase. The complex possesses some novel features, including an extensive network of hydrogen bonds involving the main chain of residues 101, 103, and 236 of the p66 reverse transcriptase subunit. Such interactions are unlikely to be disrupted by side chain mutations. The reverse transcriptase/S-1153 complex suggests different ways in which resilience to mutations in the non-nucleoside inhibitors of reverse transcriptase binding site can be achieved.

Recent advances in the discovery and development of plant-derived natural products and their analogs as anti-HIV agents

Abstract

Evaluation of anti-AIDS drugs in conventional mice implanted with a permeable membrane device containing human T cells infected with HIV

We now report the confirmation of the work of Hollingshead et al. (1995) on development of a cell based hollow fiber (HF) system for evaluating potential anti-AIDS drugs in vivo using conventional mice rather than SCID mice. CD4+, CEM-SS cells infected with HIV 1 , strain RF, at a multiplicity of infection of 0.1 were placed into HFs. The fibers were implanted into the peritoneal cavity of outbred Swiss mice. Using this model, the antiviral activity of azidothymidine (AZT) at doses of ∼ 150, 75 and 37.5 mg/kg/day was evaluated by administering AZT to the mice in drinking water. Upon fiber removal on day 6, AZT treatment was shown to significantly increase CEM cell viability over the untreated, virus control group and significantly reduced the levels of HIV p24 and HIV RT activity.

Synthesis,In VitroBiological Stability, and Anti-HIV Activity of 5-Halo (or Methoxy)-6-Alkoxy (Azido or Hydroxy)-5,6-Dihydro-2′,3′-Didehydro-3′-Deoxythymidine Diastereomers as Potential Prodrugs of 2′,3′-Didehydro-3′-deoxythymidine (D4T)

Abstract A new class of 5-halo (or methoxy)-6-alkoxy (azido or hydroxy)-5,6-dihydro-2′,3′-didehydro-3′-deoxythymidines (4–17) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodmgs of 2′,3′-didehydro-3′-deoxythymidine (D4T) were designed to have properties which would enhance their duration of action, lipophilicity and cephalic delivery to the central nervous system. The 5,6-dihydro derivatives of D4T (4–15), which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = OMe, OEt, N3, OH) to the 5,6-olefinic bond of D4T. These 5,6-disubstituted-5,6-dihydro analogs of D4T are more lipophilic (P = 0.70 – 4.0 range) than D4T (P = 0.12) and are stable to E. coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give D4T, upon incubation of the 5-bromo- and 5-iodo-6-methoxy-5,6-dihydro derivatives (6, 7, 10, 11) with glutathione or a mouse liver soluble enzyme fraction,...

Pyrrolobenzothiazepinones and pyrrolobenzoxazepinones: novel and specific non-nucleoside HIV-1 reverse transcriptase inhibitors with antiviral activity.

Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepinones were investigated as potential anti-AIDS drugs. These compounds were found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appreciable activity on HIV-2 cytopathic effects, and against HBV as well as calfthymus DNA alpha-polymerase. Their potency is influenced by substituents at position 6 and on the fused aromatic ring. Specifically, small lipophilic substituents at C-6 were preferred, whereas substitutions on the benzo-fused ring were found to be detrimental to activity, with respect to the unsubstituted compounds. Modification of the pie-system at C-6 is well tolerated, although the replacement of the benzo-fused with a [2,3]naphtho-fused ring leads to a less active compound. Maximum potency and specificity is achieved with a phenyl and an ethyl group at position 6 of the pyrrolobenzoxazepinone system. In the enzymatic assay the oxazepinone derivative (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5] benzoxazepin-7(6H)-one 16e (IC50 = 0.25 microM) was found to be more potent than nevirapine (IC50 = 0.5 microM), tested in the same experimental conditions using rC.dG as a template-primer. In cell culture assay benzoxazepine 16e was active against HIV-1, both wild type and AZT-sensitive, and HIV-1 (IIIB) strains, but not against HIV-2. In enzyme assay although 16e inhibited HIV-1 RT, it was inactive against the nevirapine-resistant recombinant RT Y181C at 50 microM. Molecular modeling studies suggest that these derivatives present a 3D pharmacophoric arrangement similar to that of other non-nucleoside inhibitors such as nevirapine.

Clinical trials to begin on designed AIDS drug

Researchers have used structure-based drug design to successfully engineer greater bioavailability and increased potency into a potential anti-AIDS drug. The drug, designated VX-478, is an orally bioavailable inhibitor of human immunodeficiency virus (HIV) protease, a key enzyme in the life cycle of the virus. VX-478 was designed by scientists at Vertex Pharmaceuticals, Cambridge, Mass. Researchers from Burroughs Well-come, Research Triangle Park, N.C., and Vertex presented detailed preclinical data on the drug for the first time last month at the 2nd National Conference on Human Retroviruses & Related Infections, in Washington, D.C. (C&EN, Feb. 6, page 7). Burroughs is Vertex's development partner for VX-478. In addition, Vertex scientists recently reported the X-ray crystal structure of the inhibitor bound to HIV protease [ J. Am. Chem. Soc., 117 ,1181 (1995)]. The structure determination was carried out by Vertex scientists Eunice E. Kim, Chris T. Baker, Maureen D. Dwyer, Mark A. Murcko, B. Govinda Rao...

Synthesis and evaluation of new 2′,3′-dideoxynucleoside analogs as potential anti-AIDS and anti-herpes drugs

Based on the known structure-activity relationships for the active anti-HIV, a series of 3′-deoxy-3′- N-functionalized thymidine analogs has been synthesized from thymidine. Evaluation for inhibitory activity against human immunodeficiency virus (HIV) replication in CEM cells and against herpes simplex virus in MRC-5 cells is reported.

A molecular modeling study of nucleoside analogues as potential anti-AIDS drugs

Cyclic and acyclic thymidine analogues may act as anti-human immunodeficiency virus agents. Several structures have been optimized using molecular mechanics, and electronic properties calculated using the modified neglect of differential overlap method. Introduction of an unsaturated bond into the ribose ring leads to a large increase in strain energy, but the quantum mechanical heat of formation remains reasonable. Electrostatic potentials were calculated based on partial atomic charges, and compared with the potential around thymidine. It is found that a common region of positive potential exists in the C3' region for the active compounds, and on this basis the unsynthesized acyclic compounds studied here may be active. In azidothymidine (AZT) the extent of twist around the N1-C1' bond determines the presence or absence of this feature. A relationship is found to exist between the molecular mechanics energy and the EC50 activity data for the azido-substituted compounds.

Potential anti-AIDS drugs. Lipophilic, adenosine deaminase-activated prodrugs

Selected acid-stable (2'-fluoro-2',3'-dideoxyarabinofuranosyl)adenine nucleosides containing methyl groups and other lipophilic functions at various positions in the adenine ring were prepared and evaluated as anti-HIV agents. The N6-methyl (1f), N6-benzoyl (1g), and 6-chloro (1i) analogues had modest activity, giving 30-50% protection to ATH8 cells infected with HIV. 2-Methyl (1d), 8-methyl (1h), and 2,N6-dimethyl (1e) substitution, as well as N1-oxide (21) formation, abolished the activity of the parent compound (1a). Several of these compounds, originally designed as agents for treating HIV in the central nervous system, were further investigated as substrates for adenosine deaminase (ADA). Kinetic experiments showed that ADA catalyzed the formation of the anti-HIV active inosine compound 1b from the N6-methyl analogue 1f in a quantitative manner. The anti-HIV activity of 1f and 1i was abolished when the ADA inhibitor, 2'-deoxycoformycin, was added to the test mixture. In contrast, the activity of 1f was significantly enhanced when ADA was added to the test system. These data indicate that 1f and 1i are prodrug forms of 1b in systems containing ADA.

Aurin tricarboxylic acid, the anti-AIDS compound, prevents the binding of interferon-α to its receptor

Binding of HIV to its receptor, the CD4 molecule of lymphocytes, can be prevented by chemical agents. These agents could be considered as potential anti-AIDS drugs. We have shown that aurin tricarboxylic acid (ATA, 3 μM) specifically blocks the binding of gp120, the HIV coat protein, to the CD4 molecule. We have also found that ATA prevents the binding of interferon-α to its receptor in a dose-dependent manner (12–50 μM range). Membrane potential shift, associated with binding of interferon-α to its receptor, was also blocked by ATA in a dose-dependent fashion. Our results indicate that potential anti-AIDS drugs should be screened for such undesired side effects.

Carbocyclic Nucleoside Analogues. Synthesis and Properties of 1-(4-Hydroxymethyl-2-cyclopenten-1-YL)-Thymine

Abstract The title compound, a potential anti-Aids drug, was prepared via construction of the thymine ring on a suitably substituted aminocyclopentene. NOE difference spectroscopy was used for establishing the stereochemistry of the products.

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

The reaction of thymidine with diethyl, dipropyl, and dibutyl phosphorochloridates yields novel 5′-(dialkyl phosphates), characterized by spectroscopic and analytical data. These are readily mesylated at the 3′-position. Similar reaction of 3′- O-acetyl and 3′- O-ethyl thymidine with dialkyl phosphorochloridates gives an analogous series of compounds. Lastly, reaction of the anti-AIDS drug AZT with these phosphorylating agents gives the corresponding 3′-azido products. It was hoped that these might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT and that the alternative 3′-substituents might also confer similar activity. In fact, none of the compounds studied displayed any anti-HIV activity in vitro. This is attributed to the metabolic stability of the trialkyl phosphate moiety.

Synthesis of 1-(3-R-amino-4-hydroxy butyl)thymine acyclonucleoside. Analogs as potential anti-aids drugs

The 1-(3-R-amino-4-hydroxybutyl)thymine acyclonucleoside analogs 8 – 12 , 14 , 16 , 19 , and the corresponding 3-aminomethyl derivatives 24 – 26 were prepared from the din-butyl ester of R-(−)-aspartic acid.

Sugar and Base-Modified 2',3'-Dideoxynucleosides as Potential Anti-Aids Drugs

Abstract Several 2′,3′-dideoxynucleosides have proven to be effective against HIV-1 in cell culture. The 2′,3-unsaturated analogues dideoxycytidinene (D4C) and dideoxythymidinene (D4T) are among the most potent and selective inhibitors of HIV-1 replication in vitro. However, 2′,3′-didehydro-2′,3′-dideoxynucleosides are relatively unstable. A chlorine substituent at the 2′-position increases the stability, and, therefore, some 2′-chloro-2′,3′-didehydro-2′,3′-dideoxynucleosides were synthesized and evaluated for anti-HIV-1 activity.

Synthesis of 3′-substituted-2′,3′-dideoxynucleoside analogs as potential anti-aids drugs

3′-Amino-3′-deoxythymidine 9 was prepared in six steps and in 67% overall yield from thymidine. Five derivatives of 9 and compound 17 were tested for their anti-HIV activity.

Synthesis of iso-ddA, member of a novel class of anti-HIV agents

Iso-ddA ( 3) represents a new class of potential anti-AIDS drugs. Synthetic approaches to this compound involving nucleophilic additions to a novel carbohydrate framework are discussed.