RESUMO
A series of novel 2,4-disubstituted-7-methyl-1,1,3-trioxo-2H,4H-pyrazolo[4,5-e][1,2,4]thiadiazines (PTDs) was prepared starting from a ring of pyrazolo[4,5-e][1,2,4]thiadiazine nuclei with two different alkyl halides obtained by a facile one-pot reaction. The structures of all synthesized compounds were confirmed by 1H- and 13C-NMR, infrared spectra (IR), and mass spectra (MS) spectroscopic analysis. Anti-HIV activity was evaluated and none of the compounds were found to inhibit HIV replication in human T-lymphocyte (MT-4) cell culture.
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Different extracts of leaf parts of Wrightia tinctoria and fruit powder of Morinda citrifolia have been studied against replication of HIV-1(IIIB) in MT-4 cells and HCV in Huh 5.2 cells. Chloroform extract of Wrightia tinctoria exhibited a maximum protection of 48% against the cytopathic effect of HIV-1(IIIB) in MT-4 cells. Fruit juice of Morinda citrifolia exhibited a displayed marked cytotoxic activity in lymphocyte (MT-4) cells (CC50: 0.19 mg/ml). The 50% effective concentration for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells by Morinda citrifolia was 0.98 mug/ml and by chloroform extract of Wrightia tinctoria was 10 mug/ml. The concentration that reduced the growth of exponentially proliferating Huh 5-2 cells by 50% was greater than 50 mug/ml.
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A series of novel N-Sulphonamidomethyl piperzinyl fluoroquinolones were synthesized and screened antiviral activity. Eight compounds were synthesized through modifying the N(4)-hydrogen of piperazine in fluoroquinolones with formaldehyde and sulphanomides by Mannich reactions. The structures of the synthesized compounds were characterized by means of their IR and (1)H-NMR spectral data. Synthesized compounds were screened for antiviral activity against influenza A (H1N1, H3N2, H5N1) and influenza B viruses in MDCK cell culture. The antiHIV activities of the new compounds were screened for antiviral activity against replication of HIV-1(III(B)) in MT-4 cells. Cytotoxicity of the synthesized compounds was also tested in mock-infected MDCK and MT-4 cells. Compound CF-SD and CF-SDM inhibits the influenza A (H1N1) and compound GF-SDM inhibit the replication of influenza A (H5N1) and B in MDCK cells. All compounds displayed cytostatic propertity in MT-4 cells. Among the compounds tested, GF-SDM (CC(50)=39.44 muM) most toxic compound in this series.
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A series of novel isatine-sulphonamide derivatives have been synthesized by combining isatin derivatives with sulphonamides. The structure of the synthesized compounds were elucidated by spectral analysis (IR, NMR and Mass). Investigation of anti-HIV activity was done against HIV-1(IIIB) in MT-4 cells and HIV integrase inhibitory activity. 4-(1-acetyl-5-methyl-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (SPIII-5ME-AC) inhibits the HIV Integrase enzymatic activity as both over all and strand transfer reaction and 4-(1-benzoyl-5-chloro-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzene sulfonamide (SPIII-5Cl-BZ) exhibits 36 percent maximum protection against HIV-1 at sub toxic concentration.
RESUMO
OBJECTIVES: We have previously identified the pyranodipyrimidines (PDPs) as a new class of integrase (IN) inhibitors. The most potent congener V-165 inhibits HIV-1 integration at low micromolar concentrations by inhibiting the binding of IN to the DNA. As part of pre-clinical studies with PDP, we wanted to investigate HIV resistance development against V-165 and to further characterize the physicochemical properties of the compound. METHODS: We selected PDP-resistant HIV-1 strains by growing the virus in the presence of increasing concentrations of V-165. The selected strains were analysed genotypically and phenotypically. Mutant IN enzymes were generated and evaluated in an enzymatic oligonucleotide-based assay for their activity and sensitivity to the different IN inhibitors. In addition, the antiviral effect of the compound on viral entry and integration was measured using quantitative PCR. RESULTS: Numerous mutations were detected in the RT, IN and env genes of the virus selected in the presence of V-165. Although V-165 inhibited integration in vivo as indicated by a decrease in the number of integrated proviruses, the compound also inhibited viral entry at a concentration of 19 microM. V-165 was poorly recovered from human hepatic microsomal matrix and 1% BSA. CONCLUSIONS: These data point to a multimodal mechanism of action. A quest for derivatives of V-165 that specifically target IN should be pursued.
Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/fisiologia , HIV-1/efeitos dos fármacos , Piranos/farmacologia , Pirimidinas/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular , Fenômenos Químicos , Físico-Química , DNA Viral/genética , Farmacorresistência Viral/genética , Ensaio de Imunoadsorção Enzimática , Proteína gp160 do Envelope de HIV/genética , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , Humanos , Integrases/genética , Lentivirus/genética , Oligonucleotídeos , Plasmídeos/genética , Piranos/química , Piranos/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Recombinação Genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução GenéticaRESUMO
Human immunodeficiency virus (HIV) is the etiological agent of the acquired immune deficiency syndrome (AIDS). The current strategy for the treatment of HIV infection is called Highly Active Antiretroviral Therapy (HAART) and is based on cocktails of drugs that are currently approved by the Food and Drug Administration. These drugs include compounds that target the viral entry step and the enzymes reverse transcriptase or protease. The introduction of HAART has dramatically changed the landscape of HIV disease. Death from AIDS-related diseases has been reduced significantly since HAART came into use. Nevertheless it is not clear how long clinical benefit will last taking into account the emergence of multiple drug-resistant viral strains. Addition of new anti-HIV drugs targeting other steps of the viral replication cycle may increase the potency of inhibition and delay resistance development. HIV integrase is an essential enzyme in the HIV life cycle and is an attractive target for new drug development. Despite years of intensive research, only two classes of compounds that inhibit integration have been identified until now, namely the diketo acids and the pyranodipyrimidines. In this review we will point to new potential antiviral targets related to retroviral integration that are amenable to drug development. We will describe the pitfalls of currently used integrase assays and propose new strategies and technologies for the discovery of HIV integration inhibitors. Furthermore, we will describe the two classes of integrase inhibitors and discuss their antiviral activity, molecular mechanism of anti-HIV action and the selection of HIV resistance against these drugs.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Integração Viral/efeitos dos fármacos , Animais , Infecções por HIV/enzimologia , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/enzimologia , HumanosRESUMO
Integration of the proviral DNA is a crucial step in the life cycle of the human immunodeficiency virus (HIV). Basic understanding of the cell biology of HIV integration will help the development of new antiviral drugs to complement the currently used cocktails of reverse transcriptase and protease inhibitors. Our research team has made major advancement in the field of antiviral research in recent years. The scientific-technological achievements were possible by the collaboration of a group of researchers with complementary research expertise. The integrase team is headed by Myriam Witvrouw and Zeger Debyser. After a general overview we summarized our most relevant publications. In the perspectives we referred to the ongoing work.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Inibidores de Integrase de HIV/uso terapêutico , HIV/enzimologia , Integração Viral/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , HumanosRESUMO
Selected plants used in Rwandan traditional medicine for the treatment of infections and/or rheumatoid diseases were investigated for antiviral activity in vitro against human immunodeficiency virus type-1 (HIV-1). Of the 38 tested 80% ethanolic extracts, belonging to plants of 21 different families only the extracts from the leaves of Aspilia pluriseta (Asteraceae) and Rumex bequaertii (Polygonaceae) had interesting selectivity indices (SI = ratio of the 50% cytotoxic concentration to the 50% effective antiviral concentration) higher than 1. Further fractionation of the initially antivirally inactive ethanolic extract of Tithonia diversifolia, however, led to an aqueous fraction with a high anti-HIV-1 activity (SI > 461), indicating that the cytotoxicity of some plant components may mask the antiviral properties of the active plant substances in total plant extracts.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Medicinas Tradicionais Africanas , Fitoterapia , Extratos Vegetais/farmacologia , Fármacos Anti-HIV/uso terapêutico , Linhagem Celular/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Extratos Vegetais/uso terapêutico , Estruturas Vegetais , RuandaRESUMO
The chemical synthesis of some 4-substituted 1-[1-(2-hydroxyethoxy)-methyl-1,2.3-triazol-(4 and 5)-ylmethyl]-1-H-pyrazolo[3,4-d]pyrimidines 12a,b, 13a,b and 14-23 as acyclic nucleosides is described. Treatment of (2-acetoxyethoxy)methylbromide with sodium azide afforded (2-acetoxyethoxy)methylazide 9. The heterocycles 6a,b were alkylated, separately, with propargyl bromide to obtain. regioselectively, 4-(methyl and benzyl)thio-1-(prop-2-ynyl)-1H-pyrazolo[3,4-d]pyrimidines 7a,b. These N-alkylated products were condensed with compound 9 via a 1,3-dipolar cycloaddition reaction to obtain, after separation and deprotection, 1,4- and 1,5-regioisomers 12a,b and 13a,b. The deprotected acyclic nucleosides 12a and 13a served as precursors for the preparation of 4-amino (14 and 15), 4-methylamino (16 and 17). 4-benzylamino (18 and 19), 4-methoxy (20 and 21) and 4-hydroxy (22 and 23) analogues. Compounds 7a,b and all deprotected acyclic nucleosides were evaluated for their inhibitory effects against the replication of HIV-(IIIB) and HIV-2(ROD) in MT-4 cells and for their anti-tumor activity. No marked activity was found. However, initial evaluation of 6a,b, 7a,b. 12a,b, 13a,b and 14-23 showed that compound 7b has marked activity against M. tuberculosis.
Assuntos
Nucleosídeos/química , Nucleosídeos/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Linhagem Celular , HIV/metabolismo , Humanos , Modelos Químicos , Nucleosídeos/síntese química , Pirimidinas/síntese química , TemperaturaRESUMO
The synthesis of 1-[1-(4-hydroxybutyl)-1,2,3-triazol-(4 and 5)-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidines 11a,b, 12a,b and 13-17 as carboacyclic nucleosides is described. The compounds 8a,b were condensed, separately, with compound 7 via 1,3-dipolar cycloaddition reaction to afford, after separation and deprotection. 1,4-regioisomers 11a,b and 1,5-regioisomers 12a,b. The deprotected carboacyclic nucleosides 11a served as precursor for the preparation of 4-amino 13. 4-methylamino 14, 4-benzylamino 15, 4-methoxy 16 and 4-hydroxy 17 analogues. All deprotected carboacyclic nucleosides were evaluated for their inhibitory effects against the replication of HIV-1(III), HIV-2(ROD), various DNA viruses, a variety of tumor-cell lines and tuberculosis. No marked biological activity was found.
Assuntos
Nucleosídeos/química , Nucleosídeos/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Linhagem Celular , Fibroblastos/metabolismo , HIV/metabolismo , Células HeLa , Humanos , Modelos Químicos , Nucleosídeos/síntese química , Pirimidinas/síntese química , Temperatura , Células Tumorais CultivadasRESUMO
4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, (1)H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Isatina/síntese química , Isatina/farmacologia , Sulfametazina/síntese química , Sulfametazina/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Linhagem Celular , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Isatina/análogos & derivados , Sulfametazina/análogos & derivados , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Zidovudina/química , Zidovudina/farmacologia , BenzenossulfonamidasRESUMO
A new series of cosalane analogues incorporating two fragments of the dichlorodisalicylmethane pharmacophore has been synthesized. In order to identify the position for the attachment of the pharmacophore fragments to the steroid ring that results in the most potent analogues, two types of compounds were designed. In the first type, the two pharmacophore fragments were attached at C-3 and C-17 of the steroid ring by using appropriate linker units. In the second type, both pharmacophore groups were connected to C-3 of the steroid through an alkenyl chain containing an amide moiety. All of the new compounds displayed antiviral activity versus HIV-1(RF), HIV-1(IIIB), and HIV-2(ROD) in cell culture. The relative potencies of the compounds resulting from the two attachment strategies were found to depend on the viral strain as well as the cell type. Overall, the attachment of the second pharmacophore did not result in either a large gain or a large loss in anti-HIV activity, and the results are therefore consistent with the hypothesis that the two pharmacophores act independently, and one at a time, with positively charged amino acid side chains present on the surface of gp120 and CD4.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Ácido Aurintricarboxílico/análogos & derivados , Ácido Aurintricarboxílico/farmacologia , Fármacos Anti-HIV/metabolismo , Ácido Aurintricarboxílico/síntese química , Ácido Aurintricarboxílico/metabolismo , Antígenos CD4/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Salicilatos/química , Salicilatos/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Synthesis of Z and E ethenyl acyclonucleosides (6a-e and 7a-e) via Michael addition of nucleobases with the diethyl acetylenedicarboxylate is described. The structures of compounds have been confirmed by spectral data. New compounds were found to be inactive against DNA and RNA viruses.
Assuntos
Vírus de DNA/efeitos dos fármacos , Hidrocarbonetos Acíclicos/síntese química , Hidrocarbonetos Acíclicos/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Vírus de RNA/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidrocarbonetos Acíclicos/química , Isomerismo , Espectroscopia de Ressonância Magnética , Nucleosídeos/química , Espectrofotometria Ultravioleta , Relação Estrutura-AtividadeRESUMO
Ten 2-aryl or heteroaryl-3-nitrosoimidazo[1,2-a]pyridine derivatives were synthesised as potential antiretroviral agents. The new compounds were characterized by elemental analysis, 1H NMR, and by crystallography for (14). The compounds were devoid of any activity against HIV-1 or HIV-2.
Assuntos
Fármacos Anti-HIV/síntese química , Antivirais/síntese química , Imidazóis/síntese química , Imidazóis/farmacologia , Compostos Nitrosos/síntese química , Compostos Nitrosos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Retroviridae/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância MagnéticaRESUMO
New 5'-O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HIV potency, and to optimize the intramolecular cyclic rearrangement process related to the 5'-O-(4-hydroxybutyl) carbonate moiety. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of the 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs with our thermodynamic predictions. Interestingly, these 5'-O-carbonate prodrug series show increased anti-HIV potencies in conjunction with, or without, reduced cytotoxicity as compared to AZT that lead to a gain in selectivity indexes. The cytotoxicity of AZT could be reduced with these 5'-O-carbonate prodrug series by delaying the 5'-O-glucuronidation of AZT, which is one of the major limitations of AZT.
Assuntos
Fármacos Anti-HIV/síntese química , Pró-Fármacos/síntese química , Zidovudina/análogos & derivados , Zidovudina/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Células Cultivadas , Estabilidade de Medicamentos , Humanos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Zidovudina/química , Zidovudina/farmacologiaRESUMO
Ten saponins isolated from the leaves of Maesa lanceolata were tested for their antiviral, haemolytic and molluscicidal activities. The influence of the substitution pattern of these acylated triterpenoid saponins on their biological activities was investigated and structure-activity relationships were established. Maesasaponin VI(2) (3 beta-O-[[alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D-galactopyranosyl-(1 --> 3)]-[beta-D-galactopyranosyl-(1 --> 2)]-beta-D-glucopyranuronyl]-21 beta,22 alpha-diangeloyloxy-13 beta,28-epoxyolean-16 alpha,28 alpha-diol), the most potent molluscicidal compound (LC(50) 0.5 ppm), also showed virucidal and haemolytic activity. In general, 21,22-diacylation appeared to be associated with a virucidal (reduction factor of the viral titer > or = 10(3) at 50 microg/ml) and haemolytic activity (HC(50) < or = 1 microg/ml).
Assuntos
Fármacos Anti-HIV/farmacologia , Antivirais/farmacologia , Hemólise/efeitos dos fármacos , Moluscocidas/farmacologia , Saponinas/farmacologia , Árvores/química , Animais , Antivirais/isolamento & purificação , Sequência de Carboidratos , HIV/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Técnicas In Vitro , Magnoliopsida/química , Medicinas Tradicionais Africanas , Dados de Sequência Molecular , Fitoterapia , Extratos Vegetais/farmacologia , Plantas Medicinais , Saponinas/isolamento & purificação , Caramujos/efeitos dos fármacos , Relação Estrutura-Atividade , Triterpenos/farmacologiaRESUMO
Design, synthesis and anti-HIV activity of a series of 2,3-diaryl-1,3-thiazolidin-4-ones are reported. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations thereby acting as non-nucleoside HIV-1 RT inhibitors (NNRTIs). SAR studies evidenced that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus largely influenced the in vitro anti-HIV activity of this new class of potent antiviral agents.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Tiazóis/farmacologia , Fármacos Anti-HIV/química , HIV-1/fisiologia , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiazóis/química , Replicação Viral/efeitos dos fármacosRESUMO
OBJECTIVES: To investigate the genotypic and phenotypic effects of in vitro resistance selection with lamivudine and/or the second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) quinoxaline HBY097 using HIV-1 isolates carrying the multi-nucleoside resistance pattern linked to the Q151M mutation. METHODS: Virus strains were selected in C8166 cells in the presence of increasing concentrations of lamivudine or HBY097. In parallel control experiments, the virus was cultured in C8166 cells in the absence of drugs. The entire reverse transcriptase encoding region was amplified using polymerase chain reaction and was subsequently sequenced. Antiviral activities of drugs were evaluated in C8166 cells. RESULTS: High-level resistant viruses were selected rapidly in the presence of lamivudine and quinoxaline (less than 10 passages). The multi-nucleoside resistance mutations were stable during in vitro resistance selection. Lamivudine elicited the acquisition of the M184I mutation. Phenotypic resistance to all nucleoside-analog reverse transcriptase inhibitors (NRTIs) was increased when M184I was added to the multi-nucleoside resistance background in the absence of NNRTI-resistance mutations. In most cases of HBY097 resistance selection, at least two mutations associated with NNRTI resistance resulted in high-level NNRTI resistance. The NNRTI resistance-related mutations partially reversed the phenotypic resistance to most NRTIs, except to abacavir. The addition of the M184I mutation to the NNRTI-multi-nucleoside resistance set abolished this antagonizing effect for didanosine, zalcitabine and lamivudine, but further potentiated the phenotypic reversal for zidovudine and stavudine. CONCLUSION: Changes in the non-nucleoside binding pocket must affect the conformation of residues at the dNTP binding site, and can result in a partial phenotypic reversal of the multi-nucleoside resistance phenotype.
Assuntos
Fármacos Anti-HIV/farmacologia , Antivirais/farmacologia , Resistência a Múltiplos Medicamentos/genética , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , Lamivudina/farmacologia , Mutação , Quinoxalinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/metabolismo , Antivirais/metabolismo , Sítios de Ligação , Resistência Microbiana a Medicamentos , Genótipo , Infecções por HIV/tratamento farmacológico , HIV-1/classificação , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Lamivudina/metabolismo , Nucleosídeos/metabolismo , Nucleosídeos/farmacologia , Fenótipo , Quinoxalinas/metabolismo , Inibidores da Transcriptase Reversa/metabolismoRESUMO
Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6--12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, beta-alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.
Assuntos
Fármacos Anti-HIV/síntese química , Ácido Aurintricarboxílico/síntese química , HIV-1/efeitos dos fármacos , Ânions/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Ácido Aurintricarboxílico/análogos & derivados , Ácido Aurintricarboxílico/química , Ácido Aurintricarboxílico/farmacologia , Antígenos CD4/química , Linhagem Celular , Humanos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5'-OH function of AZT was functionalized with various enzymatically labile alkyl groups using specific procedures. The prodrug moieties included 5'-O-carbonate, 5'-O-carbamate, and 5'-O-ester. Analogues of the 3'-azido-3'-deoxythymidin-5'-yl O-(omega-hydroxyalkyl) carbonate series were particularly interesting since they were rearranged through an intramolecular cyclic process during their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5'-O-carbonate prodrugs with their corresponding 5'-O-ester- and 5'-O-carbamate-AZT prodrugs. Interestingly, the anti-HIV-1 activities (EC(50)) of 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in peripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respectively. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associated with the 3'-azido-3'-deoxythymidin-5'-yl O-(omega-hydroxyalkyl) carbonate prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential than AZT for the treatment of AIDS.