RESUMEN
A uHTS campaign led to the discovery of a 5-(5-furan-2-ylpyrazol-1-yl)-1H-benzimidazole series that inhibits assembly of HIV-1 capsid. Synthetic manipulations at N1, C2 and C16 positions improved the antiviral potency by a . The X-ray structure of 33 complexed with the capsid N-terminal domain allowed identification of major interactions between the inhibitor and the protein.
Asunto(s)
Antivirales/farmacología , Bencimidazoles/farmacología , Proteínas de la Cápside/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure-activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity.
Asunto(s)
Fármacos Anti-VIH/química , Benzodiazepinonas/química , Proteínas de la Cápside/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacología , Proteínas de la Cápside/metabolismo , Evaluación Preclínica de Medicamentos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , Humanos , Imidazoles/química , Pirazoles/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
The role of the tetrazole moiety in the binding of aryl thiotetrazolylacetanilides with HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases was explored. Different acyclic, cyclic and heterocyclic replacements were investigated in order to evaluate the conformational and electronic contribution of the tetrazole ring to the binding of the inhibitors in the NNRTI pocket. The replacement of the tetrazole by a pyrazolyl group led to reversal of selectivity, providing inhibitors with excellent potency against the double mutant reverse transcriptase.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/genética , Tetrazoles/síntesis química , Tetrazoles/farmacología , Fármacos Anti-VIH/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , VIH-1/efectos de los fármacos , VIH-1/genética , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tetrazoles/químicaRESUMEN
A series of novel 8-substituted dipyridodiazepinone-based inhibitors were investigated for their antiviral activity against wild type human immunodeficiency virus (HIV-1) and the clinically prevalent K103N/Y181C mutant virus. Our efforts have resulted in a series of benzoic acid analogues that are potent inhibitors of HIV-1 replication against a panel of HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Furthermore, the combination of good antiviral potency, a broad spectrum of activity, and an excellent pharmacokinetic profile provides strong justification for the further development of compound (7) as a potential treatment for wild type and NNRTI-resistant HIV-1 infection.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Azepinas/síntesis química , Farmacorresistencia Viral , VIH-1/efectos de los fármacos , Piridinas/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Azepinas/química , Azepinas/farmacología , Células CACO-2 , Perros , VIH-1/genética , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Microsomas Hepáticos/metabolismo , Mutación , Permeabilidad , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
High-throughput screening hit 1 was identified as a potent, broad-spectrum, non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 replication. Analysis of the bound conformation of analogs of this inhibitor via molecular modeling and NMR contributed to the design of novel tertiary amide, carbamate, and thiocarbamate based NNRTIs.
Asunto(s)
Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Inhibidores de la Transcriptasa Inversa/farmacología , Replicación Viral/efectos de los fármacos , Amidas/química , Fármacos Anti-VIH/síntesis química , Carbamatos/química , Diseño de Fármacos , Farmacorresistencia Viral , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Inhibidores de la Transcriptasa Inversa/síntesis química , Relación Estructura-Actividad , Tiocarbamatos/químicaRESUMEN
A series of aryl thiotetrazolylacetanilides were synthesized and found to be potent inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases. The incorporation of an alkynyl fragment on the aniline provided inhibitors with excellent cellular activity and extensive SAR led to the identification of one inhibitor having good oral bioavailability in rats.
Asunto(s)
Acetanilidas/farmacología , Antivirales/química , Antivirales/farmacología , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Acetanilidas/química , Animales , Disponibilidad Biológica , Modelos Moleculares , Estructura Molecular , Mutación , Ratas , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
An indandione-containing class of inhibitors abrogates DNA replication of human papillomavirus (HPV) types 6 and 11 by binding reversibly to the transactivation domain (TAD) of the viral E2 protein and inhibiting its interaction with the viral E1 helicase. To locate the binding site of this class of protein-protein interaction inhibitors, a benzophenone derivative was used to generate an irreversibly labeled E2-TAD polypeptide. The single site of covalent modification of the E2-TAD was identified by proteolytic digestions using trypsin, LysC, and V8 proteases and characterization of the resulting peptides by LC-MS procedures. Through this methodology, the benzophenone attachment point was located at the terminal methyl of residue Met101. Evidence further pinpointed the site of photoaffinity attachment to the terminal carbon atom, which is significant in providing a definitive example of the ability to locate photoinduced cross-linking to a polypeptide with atomic resolution using solely mass spectrometric detection. The location of the inhibitor binding site vis-à-vis the Glu39 and Glu100 residues sensitive to mutation for HPV 11 E2-TAD is discussed in relation to the crystal structure of the E2-TAD from the related HPV type 16.