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1.
Molecules ; 25(10)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32429580

RESUMO

Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5'-O-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC50 value of 0.07 µM against HCoV-229E with TC50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5'-O-fatty acyl conjugates of NRTIs, 5'-O-tetradecanoyl ester conjugate of FTC showed modest activity with EC50 and TC50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Coronavirus Humano 229E/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Fármacos Anti-HIV/química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Linhagem Celular , Coronavirus Humano 229E/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA Replicase/metabolismo , Inibidores da Transcriptase Reversa/química
2.
Artigo em Inglês | MEDLINE | ID: mdl-32164970

RESUMO

Emtricitabine (Emtriva, FTC) is an antiviral medicine which decreases the body's amount of HIV. Emtricitabine on of Anti-HIV drugs slow down or protect the immune system against damage and reduce the risk of diseases related to developing of AIDS. Emtricitabine use also for treatment of hepatitis B virus. Emtricitabine is a drug class known as nucleoside reversing transcriptase inhibitors (NRTIs). In view of Emtricitabine's clinical significance, a thorough review of the physical and pharmaceutical characteristics and details of the multiple analytical techniques used to test the drug in pharmaceutical and biological systems was conducted. The methods investigated include identification test, Spectroscopy, chromatography, electrochemicals, and Thermal. Beside the analytical profile, the degradation and stability of Emtricitabine, its pharmacology and pharmacokinetics, Pharmaceutical Applications, Mechanism of Action, dosage forms and dose, ADME profile, and interactions have been debated.


Assuntos
Fármacos Anti-HIV/farmacologia , Emtricitabina/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Infecções por HIV/tratamento farmacológico , Hepatite B/tratamento farmacológico , Humanos
3.
Nucleic Acids Res ; 48(5): 2709-2722, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-31943114

RESUMO

RNA aptamers that bind HIV-1 reverse transcriptase (RT) inhibit RT in enzymatic and viral replication assays. Some aptamers inhibit RT from only a few viral clades, while others show broad-spectrum inhibition. Biophysical determinants of recognition specificity are poorly understood. We investigated the interface between HIV-1 RT and a broad-spectrum UCAA-family aptamer. SAR and hydroxyl radical probing identified aptamer structural elements critical for inhibition and established the role of signature UCAA bulge motif in RT-aptamer interaction. HDX footprinting on RT ± aptamer shows strong contacts with both subunits, especially near the C-terminus of p51. Alanine scanning revealed decreased inhibition by the aptamer for mutants P420A, L422A and K424A. 2D proton nuclear magnetic resonance and SAXS data provided constraints on the solution structure of the aptamer and enable computational modeling of the docked complex with RT. Surprisingly, the aptamer enhanced proteolytic cleavage of precursor p66/p66 by HIV-1 protease, suggesting that it stabilizes the productive conformation to allow maturation. These results illuminate features at the RT-aptamer interface that govern recognition specificity by a broad-spectrum antiviral aptamer, and they open new possibilities for accelerating RT maturation and interfering with viral replication.


Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Protease de HIV/metabolismo , Transcriptase Reversa do HIV/metabolismo , Aptâmeros de Nucleotídeos/química , Simulação de Acoplamento Molecular , Mutagênese/genética , Proteínas Mutantes/metabolismo , Ligação Proteica , Multimerização Proteica , Inibidores da Transcriptase Reversa/farmacologia
4.
Eur J Med Chem ; 186: 111864, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31767136

RESUMO

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064 µM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 µM), Y181C (EC50 = 0.11 µM), E138K (EC50 = 0.057 µM), and moderate activity against double mutants RES056 (EC50 = 8.7 µM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , Indazóis/farmacologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Indazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 186: 111900, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771827

RESUMO

Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 µM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 185: 111874, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31735575

RESUMO

The fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less potent anti-viral activity, they showed much lower cytotoxicity. Further optimization on the sulfur led to the sulfinylacetamide-DAPYs exhibiting improved anti-viral activity and a higher selectivity index especially toward the K103N mutant strain. The most potent compound 12a displayed EC50 values of 0.0249 µM against WT and 0.0104 µM against the K103N mutant strain, low cytotoxicity (CC50 > 221 µM) and a high selectivity index (SI WT > 8873, SI K103N > 21186). In addition, this compound showed a favorable in vitro microsomal stability across species. Computational study predicted the binding models of these potent compounds with HIV-1 reverse transcriptase thus providing further insights for new developments.


Assuntos
Acetamidas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Acetamidas/síntese química , Acetamidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
8.
Commun Biol ; 2: 469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31872074

RESUMO

Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (-)-FTC-TP and (-)-3TC-TP and drug resistance by M184V. (-)-FTC-TP and (-)-3TC-TP have higher binding affinities (1/K d) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (-)-FTC-TP and (-)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3'-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold) K d for the L-nucleotides and moderately higher (>9-fold) K d for the D-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (-)-FTC-TP and shifts its triphosphate into a non-productive conformation.


Assuntos
Farmacorresistência Viral , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Nucleotídeos/química , Inibidores da Transcriptase Reversa/química , Alelos , Substituição de Aminoácidos , Bases de Dados Genéticas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Mutação , Nucleotídeos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia
9.
Pan Afr Med J ; 33: 222, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31692792

RESUMO

Introduction: HIV-2, endemic in West Africa, has a natural resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) which makes it difficult to treat it in developing countries. Methods: We conducted a descriptive, longitudinal, prospective study over the period November 2005-June 2017. Virologic failure has been defined as any viral load greater than 50 copies/ml after 6 months of ARV treatment administered twice. Assays for detecting drug-resistance mutations was performed in the protease-coding region and in the reverse transcriptase-coding region. Results: Data from a total of 110 patients were collected. The patients had a median age of 46 years (ranging from 18 to 67) with a sex-ratio F/M of 2.54. At inclusion, viral load could be assessed in 44% of cases with a median of 935cp/ml (ranging from 17 to 144038). Antiretroviral regimen consisted of a combination of 2 NRTIs and 1IP in 94% of cases. The median follow-up was 1200 days (ranging from 1 to 3840); 94 then 76 patients completed their 12-month and 24-month assessments respectively. At 24-month follow-up, 39 patients had virologic failure, reflecting a prevalence of 39% estimated at 33% at 12-month follow-up and at 11% at 24-month follow-up; NRTIs resistance was observed in 45% of patients, IP resistance in 41% of patients while multi-NRTIs resistance and multi-IP resistance in 30% of patients. Conclusion: Currently, there is an urgent need to make available the new therapeutic classes of ARV for second line ART for patients living with HIV-2 with therapeutic failure in resource-limited settings.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , HIV-2/isolamento & purificação , Inibidores da Transcriptase Reversa/administração & dosagem , Adolescente , Adulto , Idoso , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , HIV-2/efeitos dos fármacos , HIV-2/genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Transcriptase Reversa/farmacologia , Senegal/epidemiologia , Carga Viral , Adulto Jovem
10.
Drug Res (Stuttg) ; 69(12): 671-682, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31698495

RESUMO

In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(A-D): interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though π-π stacking in HIV-1 RT. Furthermore, 8A: and 8D: were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 µM concentration. Interestingly, 8A: was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC50 of 4.63±0.62 µg/mL, which was similar with that in EFV and TMC278 (IC50 7.76±0.37 and 1.57±0.20 µg/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.


Assuntos
Diarilquinolinas/química , Diarilquinolinas/farmacologia , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzoxazinas/química , Benzoxazinas/farmacologia , Linhagem Celular Tumoral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Nevirapina/química , Nevirapina/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Rilpivirina/química , Rilpivirina/farmacologia
11.
PLoS One ; 14(11): e0225575, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31751428

RESUMO

BACKGROUND: Antiretroviral therapy (ART) has improved the survival of HIV infected persons. However, rapid scale-up of ART and the high HIV-1 genetic variability, has greatly influenced the emergence of drug-resistant strains. This constitutes a potential threat to achieving the UNAIDS' 90-90-90 goals by 2020. We investigated the prevalent HIV-1 genotypes, drug resistance-associated mutations and assessed some predictors of the occurrence of these mutations. METHODS: This was a hospital-based cross-sectional study conducted between October 2010 and June 2012. Participants were consecutively enrolled from selected HIV treatment centers of the Southwest and Northwest regions of Cameroon. Viral load was determined with the automated Abbott Real-time HIV-1 m2000rt System. HIV genotyping and antiretroviral resistance mutations analysis were performed using Bayer's HIV-1 TRUGENE™ Genotyping Kit and OpenGene DNA Sequencing system. The drug resistance mutation was interpreted with the Stanford HIV database. Epidemiological data were obtained using pre-tested semi-structured questionnaires. RESULTS: Of the 387 participants, 239 were successfully genotyped. The median age of these participants was 33 years (interquartile range, IQR: 28-40 years), and a majority (65.7%) were female. A total of 29.3% of the participants were receiving ART. The median duration of ART was 10.5 months (IQR: 4-17.25 months). The median CD4 count and log10 viral load of study participants were 353.5 cells/ml (IQR:145-471) and 4.89 copies/ml (IQR: 3.91-5.55) respectively. CRF02 (A/G) (69%) was the most prevalent subtype followed by G (8.2%) and F (6.7%). Overall, resistance mutations were present in 37.1% of ART-experienced and 10.7% of ART-naive patients. Nucleoside reverse transcriptase inhibitors (NRTI) mutations occurred in 30% of ART-experienced and 2.4% of ART-naïve patients, while non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations occurred in 34.2% of ART-experienced and 10.1% of -naïve patients. M184V (8.4%, 20/239) and K103N (5.4%, 13/239) were the most prevalent mutations. Major protease inhibitor mutations occurred in 3 (1.3%) out of the 239 sequences. The duration of ART independently predicted the occurrence of resistance mutation among ART-experienced patients. CONCLUSION: The high resistance to NNRTIs, which are the main support to the backbone (NRTIs) first-line antiretroviral regimen in Cameroon, has prompted the need to rollout an integrase strand transfer inhibitor regimen (containing Dolutegravir) with a higher genetic barrier to resistance as the preferred first line regimen.


Assuntos
Farmacorresistência Viral , Infecções por HIV/virologia , HIV-1/genética , Mutação , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Camarões , Estudos Transversais , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Inibidores da Transcriptase Reversa/farmacologia , Carga Viral
12.
Top Antivir Med ; 27(3): 111-121, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31634862

RESUMO

The 2019 edition of the IAS-USA drug resistance mutations list updates the Figure last published in January 2017. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The Figure is designed to assist practitioners in identifying key mutations associated with resistance to antiretroviral drugs, and therefore, in making clinical decisions regarding antiretroviral therapy.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Substituição de Aminoácidos , Fármacos Anti-HIV/uso terapêutico , Genes Virais/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , Humanos , Inibidores da Transcriptase Reversa/farmacologia , Estados Unidos
13.
Molecules ; 24(21)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652782

RESUMO

BACKGROUND: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research for the development of new inhibitors continues as the virus develops resistant strains. METHODS: The best features of available NNRTIs were taken into account for the design of novel inhibitors. PASS (Prediction of activity spectra for substances) prediction program and molecular docking studies for the selection of designed compounds were used for the synthesis. Compounds were synthesized using conventional and microwave irradiation methods and HIV RT inhibitory action was evaluated by colorimetric photometric immunoassay. RESULTS: The evaluation of HIV-1 RT inhibitory activity revealed that seven compounds have significantly lower ΙC50 values than nevirapine (0.3 µΜ). It was observed that the activity of compounds depends not only on the nature of substituent and it position in benzothiazole ring but also on the nature and position of substituents in benzene ring. CONCLUSION: Twenty four of the tested compounds exhibited inhibitory action lower than 4 µΜ. Seven of them showed better activity than nevirapine, while three of the compounds exhibited IC50 values lower than 5 nM. Two compounds 9 and 10 exhibited very good inhibitory activity with IC50 1 nM.


Assuntos
Síndrome de Imunodeficiência Adquirida , Fármacos Anti-HIV , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa , Tiazóis , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/enzimologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Transcriptase Reversa do HIV/metabolismo , Humanos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
14.
SAR QSAR Environ Res ; 30(10): 697-714, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31542957

RESUMO

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most promising anti-AIDS agents that target the HIV-1 reverse transcriptase enzyme (RT). However, the efficiency of approved NNRTI drugs has decreased by the appearance of drug-resistant viruses and side effects upon long-term usage. Thus, there is an urgent need for developing new, potent NNRTIs with broad spectrum against HIV-1 virus and with improved properties. In this study, a series of thiazolidinone derivatives was designed based on a butterfly mimicking scaffold consisting of a substituted benzothiazolyl moiety connected with a substituted phenyl ring via a thiazolidinone moiety. The most promising derivatives were selected using molecular docking analysis and PASS prediction program, synthesized and evaluated for HIV-1 RT inhibition. Five out of fifteen tested compounds exhibited good inhibitory action. It was observed that the presence of Cl or CN substituents at the position 6 of the benzothiazole ring in combination with two fluoro atoms at the ortho-positions or a hydrogen acceptor substituent at the 4-position of the phenyl ring are favourable for the HIV RT inhibitory activity.


Assuntos
Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 183: 111714, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557609

RESUMO

In our continuing efforts to find novel anti-HIV compounds, we have synthesized sixteen novel pyrazolo[4,3-c]pyridin-4-one derivatives. All the synthesized compounds were screened for anti-HIV activity against HIV-1VB59 (R5, subtype C). Compounds 12a-12c and 12e were also tested against HIV-1UG070 (X4, subtype D) in TZM-bl cell line. Compound 12c was found to be the most active against HIV-1VB59 and HIV-1UG070 with IC50 value 3.67 µM and 2.79 µM, and therapeutic indices 185 and 243, respectively. The lead compound 12c inhibited the HIV-192/BR/018 (R5, subtype B) and drug resistant isolates, NIH-119 (X4/R5, subtype B) and NARI-DR (R5, subtype C) effectively. The activity of the lead compound was further confirmed by PBMC assays. The molecular docking data showed that the most active compound 12c binds in the non-nucleoside binding pocket of HIV-1 reverse transcriptase, which was confirmed by the ToA assay. Thus the study indicated that 12c may be considered as a NNRTI and further explored as a lead for anti-HIV drug development.


Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirazóis/síntese química , Piridinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/farmacologia , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Pirazóis/farmacologia , Piridinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 182: 111619, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31434039

RESUMO

For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0.0043 µM to 4.42 µM. Notably, compound 27 (EC50 = 4.7 nM, SI = 5183) and 33 (EC50 = 4.3 nM, SI = 7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103 N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC50 values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC50 = 0.094 µM), and also showed exceptional activity against E138K (EC50 = 0.014 µM), L100I (EC50 = 0.011 µM) and K103 N (EC50 = 0.025 µM). Additionally, most compounds showed markedly reduced cytotoxicity (CC50) compared to lead compounds, especially 36 (CC50 > 234.91 µM, SI > 18727) and 37 (CC50 > 252.49 µM, SI > 15152). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Sulfonas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , HIV-1/genética , Humanos , Indóis/síntese química , Indóis/química , Masculino , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química
18.
Eur J Med Chem ; 182: 111603, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421633

RESUMO

Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2'-fluoro and 3'-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2'-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC50 = 14 and 17 nM, respectively) and RT enzyme (EC50 = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC50 = 264.19 µM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.


Assuntos
Fármacos Anti-HIV/farmacologia , Compostos de Bifenilo/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Compostos de Bifenilo/química , Linhagem Celular , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiofenos/química
19.
Eur J Med Chem ; 182: 111617, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442684

RESUMO

A number of compounds targeting different processes of the Human Immunodeficiency Virus type 1 (HIV-1) life cycle have been developed in the continuing fight against AIDS. Coumarin-based molecules already proved to act as HIV-1 Protease (PR) or Integrase (IN) inhibitors and also to target HIV-1 reverse transcriptase (RT), blocking the DNA-dependent DNA-polymerase activity or the RNA-dependent DNA-polymerase activity working as common NNRTIs. In the present study, with the aim to exploit a coumarin-based scaffold to achieve the inhibition of multiple viral coded enzymatic functions, novel 4-hydroxy-2H, 5H-pyrano (3, 2-c) chromene-2, 5-dione derivatives were synthesized. The modeling studies calculated the theoretical binding affinity of the synthesized compounds on both HIV-1 IN and RT-associated Ribonuclease H (RNase H) active sites, which was confirmed by biological assays. Our results provide a basis for the identification of dual HIV-1 IN and RT RNase H inhibitors compounds.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , HIV-1/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 179: 423-448, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265935

RESUMO

HIV infection is a major challenge to mankind and a definitive cure or a viable vaccine for HIV is still elusive. HIV-1 is constantly evolving and developing resistant against clinically used anti-HIV drugs thus posing serious hurdles in the treatment of HIV infection. This prompts the need to developed new anti-HIV drugs; preferentially adopting intelligent ways to counteract an evolving virus. Highly Active Anti-Retroviral Therapy (HAART): a strategy involving multiple targeting through various drugs has proven beneficial in the management of AIDS. However, it is a complex regimen with high drug load, increased risk of drug interactions and adverse effects, which lead to poor patient compliance. Reverse transcriptase (RT) and Integrase (IN) are two pivotal enzymes in HIV-1 lifecycle with high structural and functional analogy to be perceived as drug-able targets for novel dual-purpose inhibitors. Designed multi-functional ligand (DML) is a modern strategy by which multiple targets can be exploited using a single chemical entity. A single chemical entity acting on multiple targets can be much more effective than a complex multi-drug regimen. The development of such multifunctional ligands is highly valued in anti-HIV drug discovery with the proposed advantage of being able to stop two or more stages of viral replication cycle. This review will encompass the evolution of the RT-IN dual inhibitory scaffolds reported so far and the contribution made by the leading research groups over the years in this field.


Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Inibidores de Integrase de HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Estrutura Molecular , Inibidores da Transcriptase Reversa/química
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