RESUMEN
Condensation of 5-nitro, 3-chloro-, and 5-chlorosalicylic acid with formaldehyde afforded dimeric disalicylmethanes which were O-methylated with dimethyl sulfate and oxidized with chromium(VI) oxide to give the diarylketones 10, 11, 12. Wittig reaction with ylides obtained by deprotonation of alkyltriphenylphosphonium salts with sodium bis (trimethylsilyl)amide yielded a series of diarylalkenes. Some of the obtained compounds showed high antimicrobial activity in vitro against Bacillus subtilis and Mycobacterium smegmatis.
Asunto(s)
Alquenos/síntesis química , Antibacterianos/síntesis química , Bacillus subtilis/efectos de los fármacos , Mycobacterium smegmatis/efectos de los fármacos , Alquenos/química , Alquenos/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Evaluación Preclínica de Medicamentos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
The effects of linker chain modifications were investigated in a series of cosalane analogues. The modifications investigated included: (1) shortening the three-carbon linker chain between the dichlorodisalicylmethane and the cholestane moiety by one carbon atom; (2) lengthening the linker chain by one carbon; (3) hydrogenation of the double bond in the linker chain; (4) changing the point of attachment of the linker chain from C-3 to C-6; (5) insertion of a phosphate between the steroid and the linker chain. With the exception of the phosphate modification, which abolished anti-HIV activity and increased cytotoxicity, the linker chain modifications produced relatively minor changes in anti-HIV activity and increased cytotoxicity, the linker chain modifications produced relatively minor changes in anti-HIV potency. The steroid and attached linker chain of cosalane therefore appear only to provide a general lipophilic appendage for the dichlorodisalicylmethane pharmacophore.
Asunto(s)
Fármacos Anti-VIH/química , Antivirales/química , Ácido Aurintricarboxílico/análogos & derivados , Ácido Aurintricarboxílico/química , Modelos Moleculares , Fosforilación , Relación Estructura-ActividadRESUMEN
Several novel alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors were synthesized. The most potent of these proved to be 3',3"-dibromo-4',4"-dimethoxy-5'5"-bis(methoxycarbonyl)-1,1-diphenyl-1-+ ++heptene (8) ADAM 8 inhibited the cytopathic effect of HIV-1 in CEM cell culture with an EC50 value of 7.1 microM and was active against an array of laboratory strains of HIV-1 in CEM-SS and MT-4 cells, but was inactive as an inhibitor of HIV-2. In common with the other known non-nucleoside reverse transcriptase inhibitors, ADAM 8 was an effective inhibitor of HIV-1 reverse transcriptase (IC50 1 microM) with poly(rC).oligo(dG), but not with poly(rA).oligo(dT), as the template/primer. ADAM 8 was inactive against HIV-1 reverse transcriptases containing non-nucleoside reverse transcriptase inhibitor resistance mutations at residues 101, 106, 108, 139, 181, 188, and 236, while it remained active against enzymes with mutations at residues 74, 98, 100, 103, and at 103/181. An AZT-resistant virus having four mutations in reverse transcriptase was more sensitive to inhibition by ADAM 8 than the wild-type HIV-1. In addition, ADAM 8 displayed synergistic activity with AZT, but lacked synergy with ddI. ADAM 8 or a structurally related analog may therefore be useful as an antiviral agent in combination with AZT or with other NNRTIs that are made ineffective by mutations at residues which do not confer resistance to ADAM 8.
Asunto(s)
Antivirales/síntesis química , Benzoatos/síntesis química , Compuestos de Bifenilo/síntesis química , VIH-1/efectos de los fármacos , ADN Polimerasa Dirigida por ARN/metabolismo , Inhibidores de la Transcriptasa Inversa/síntesis química , Secuencia de Aminoácidos , Antivirales/farmacología , Ácido Aurintricarboxílico/análogos & derivados , Ácido Aurintricarboxílico/farmacología , Benzoatos/farmacología , Sitios de Unión , Compuestos de Bifenilo/farmacología , Células Cultivadas , Didanosina/farmacología , Farmacorresistencia Microbiana , Proteína p24 del Núcleo del VIH/análisis , Transcriptasa Inversa del VIH , VIH-1/enzimología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Datos de Secuencia Molecular , Estructura Molecular , Mutagénesis Sitio-Dirigida , Inhibidores de la Transcriptasa Inversa/farmacologíaRESUMEN
In order to define the role of the cholestane moiety in the anti-HIV agent cosalane, a series of cosalane analogs was synthesized in which the cholestane ring system was replaced by normal alkenyl and phosphodiester substituents having varied chain lengths and lipophilicities. The compounds containing simple alkenyl substituents were found to be more potent as inhibitors of the cytopathic effect of HIV-1 in cell culture than the phosphodiesters. In addition, the potencies of the alkene congeners correlated positively with chain length and lipophilicity of the alkene. The results indicate that the cholestane moiety of cosalane functions as a lipophilic accessory appendage to escort the dichlorodisalicylmethane pharmacophore to a lipid environment.
Asunto(s)
Antivirales/farmacología , Ácido Aurintricarboxílico/análogos & derivados , VIH-1/efectos de los fármacos , Metabolismo de los Lípidos , Antivirales/química , Antivirales/metabolismo , Ácido Aurintricarboxílico/química , Ácido Aurintricarboxílico/metabolismo , Ácido Aurintricarboxílico/farmacología , Células Cultivadas , Efecto Citopatogénico Viral/efectos de los fármacos , VIH-1/patogenicidad , Humanos , Análisis EspectralRESUMEN
Several new analogues of the novel anti-HIV agent cosalane have been synthesized and evaluated as inhibitors of HIV-1 integrase and protease, HIV-1 replication, HIV-1 and HIV-2 cytopathicity, HIV-1- and HIV-2-mediated syncytium formation, and cytopathicity of a variety of human pathogenic viruses. The congeners displayed enhanced potencies relative to cosalane itself as inhibitors of HIV-1 integrase and protease. The two most potent analogues against HIV-1 integrase displayed IC50 values of 2.2 microM, while the three most potent compounds against HIV-1 protease had IC50 values in the 0.35-0.39 microM range. In addition to its activity against HIV-1 and HIV-2 cytopathicity, cosalane inhibited the cytopathic effects of herpes simplex virus-1, herpes simplex virus-2, and human cytomegalovirus at concentrations that were well below the cytotoxic concentrations. Potentially useful antiviral activities were also revealed for some of the new cosalane congeners against influenza virus, Junin virus, and Tacaribe virus.
Asunto(s)
Antivirales/farmacología , Ácido Aurintricarboxílico/análogos & derivados , ADN Nucleotidiltransferasas/antagonistas & inhibidores , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Secuencia de Aminoácidos , Ácido Aurintricarboxílico/química , Ácido Aurintricarboxílico/farmacología , Línea Celular , VIH-1/enzimología , VIH-1/fisiología , Herpesviridae/efectos de los fármacos , Humanos , Integrasas , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Replicación Viral/efectos de los fármacosRESUMEN
Cosalane (3), a novel anti-HIV agent having a disalicylmethane unit linked to C-3 of cholestane by a three-carbon linker, was synthesized from commercially available starting materials by a convergent route. Cosalane proved to be a potent inhibitor of HIV with a broad range of activity against a variety of laboratory, drug-resistant, and clinical HIV-1 isolates, HIV-2, and Rauscher murine leukemia virus. The cytotoxicity of cosalane is relatively low as reflected by an in vitro therapeutic index of > 100. Although cosalane inhibits HIV-1 reverse transcriptase and protease, time of addition experiments indicate that it prevents the cytopathic effect of HIV by acting earlier than reverse transcription in the viral replication cycle. The available evidence indicates that the primary mechanism of action of cosalane involves inhibition of gp120-CD4 binding as well as inhibition of a postattachment event prior to reverse transcription.