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Synthesis and Anti-HIV-1 Activity of a Novel Series of Aminoimidazole Analogs.

ABSTRACT: There is still an urgent need to develop nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) with a high-genetic barrier to resistance that facilitate patient adherence and allow durable suppression of HIV-1 replication. In this study, we describe the synthesis of a novel series of N-aminoimidazole (NAIM) analogs. Each of the NAIM analogs display potent activity against wild-type recombinant purified HIV-1 RT as well as RTs containing the K103N or Y181C resistance mutations. The analogs, however, do not exhibit significant antiviral activity in cell culture and were, in general, cytotoxic. Nevertheless, these data suggest that the NAIM backbone may provide a suitable scaffold from which inhibitors active against NNRTI-resistant HIV-1 could be developed.

SUBMITTER: Ganguly S

PROVIDER: S-EPMC2882308 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Synthesis and Anti-HIV-1 Activity of a Novel Series of Aminoimidazole Analogs.

Ganguly Swastika S Murugesan Sankaran S Prasanthi Naru N Alptürk Onur O Herman Brian B Sluis-Cremer Nicolas N

Letters in drug design & discovery 20100601 5

There is still an urgent need to develop nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) with a high-genetic barrier to resistance that facilitate patient adherence and allow durable suppression of HIV-1 replication. In this study, we describe the synthesis of a novel series of N-aminoimidazole (NAIM) analogs. Each of the NAIM analogs display potent activity against wild-type recombinant purified HIV-1 RT as well as RTs containing the K103N or Y181C resistance mutations. The analogs, ...[more]

PMID: 20535242

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Project description:The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives were synthesized, and their inhibitory activities in TrkA overexpressing cells, U87 and MEF cells were investigated. The cytotoxic effect of benzenesulfonamide derivatives and cisplatin was determined using trypan blue exclusion assays. The mode of interaction of benzenesulfonamides with TrkA was predicted by docking and structural analysis. ADMET profiling was also performed for all compounds to calculate the drug likeness property. Appropriate QSAR models were developed for studying structure-activity relationships. Compound 4-[2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfon-amide (AL106) and 4-[2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (AL107) showed acceptable binding energies with the active sites for human nerve growth factor receptor, TrkA. Here, AL106 was identified as a potential anti-GBM compound, with an IC50 value of 58.6 µM with a less toxic effect in non-cancerous cells than the known chemotherapeutic agent, cisplatin. In silico analysis indicated that AL106 formed prominent stabilizing hydrophobic interactions with Tyr359, Ser371, Ile374 and charged interactions with Gln369 of TrkA. Furthermore, in silico analysis of all benzenesulfonamide derivatives revealed that AL106 has good pharmacokinetics properties, drug likeness and toxicity profiles, suggesting the compound may be suitable for clinical trial. Thus, benzenesulfonamide analog, AL106 could potentially induce GBM cell death through its interaction with TrkA and might be an attractive strategy for developing a drug targeted therapy to treat glioblastoma.

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Synthesis and Anti-HIV-1 Activity of a Novel Series of Aminoimidazole Analogs.

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Synthesis and Anti-HIV-1 Activity of a Novel Series of Aminoimidazole Analogs.

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