RESUMO
In vitro ADME characterization of the lead compound 1 identified for visceral leishmaniasis was undertaken and further structural analogs were synthesized for antileishmanial screening. Compound 1 was highly permeable in intestinal PAMPA model (31 × 10(-6)cm/s) and was moderately bound to mouse and human plasma proteins (% bound 85-95%), its blood to plasma concentration ratio was less than 1, but the compound was unstable in blood. Compound 1 was found to have no CYP450 liability with CYP2C9, 2C19, 2D6 and 3A4. It showed inhibition with CYP1A2 with an IC50 value of 0.50 µM. Analogs of 1 were synthesized and subsequently characterized for in vitro activity against the intracellular form of Leishmania donovani. Resulting quinolines were found to have similar efficacy as 1 against the parasite. Compounds 8b and 8f were found to be the most active with IC50 values of 0.84 µM and 0.17 µM, respectively compared to 0.22 µM for compound 1. Of all the analogs tested, 8d was stable in hamster, mouse and human liver microsomes but lost the efficacy with an IC50 of 6.42 µM. Based on the in vitro efficacy and DMPK profile, compounds 8b and 8f seem the best candidates to be screened in further assays.
Assuntos
Desenho de Fármacos , Leishmania donovani/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Animais , Cricetinae , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Leishmaniose Visceral/tratamento farmacológico , Camundongos , Microssomos Hepáticos/metabolismo , Testes de Sensibilidade Parasitária , Quinolinas/metabolismo , Quinolinas/farmacocinética , Tripanossomicidas/metabolismo , Tripanossomicidas/farmacocinéticaRESUMO
Lewis acid catalyzed addition of active methylene compounds to mucochloric acid (1) and mucobromic acid (2) affording Knoevenagel aldol adducts, gamma-substituted gamma-butenolides, has been explored. Catalytic efficiencies of various Lewis acids have been compared. Indium acetate (0.25-5 mol %) was found to be the most efficient catalyst.
RESUMO
Novel strategies are required to combat pox virus infections, whether caused by escape of viruses such as monkeypox from indigenous areas or intentional release of smallpox. Anti-smallpox drugs with a unique mode of antiviral action, inhibition of transcription termination, were known but not therapeutically useful. Using a combinatorial method, variants of the basic isatin-beta-thiosemicarbazone structure were prepared and examined for cytotoxicity and antiviral activity in vaccinia virus- and cowpox virus-infected human cells. Potent and much more selective N-aminomethyl-isatin-beta-thiosemicarbazones were discovered.
Assuntos
Antivirais/síntese química , Isatina/análogos & derivados , Isatina/síntese química , Orthopoxvirus/efeitos dos fármacos , Tiossemicarbazonas/síntese química , Antivirais/farmacologia , Linhagem Celular , Técnicas de Química Combinatória , Vírus da Varíola Bovina/efeitos dos fármacos , Humanos , Isatina/farmacologia , Relação Estrutura-Atividade , Tiossemicarbazonas/farmacologia , Vaccinia virus/efeitos dos fármacos , Ensaio de Placa ViralRESUMO
Two multicomponent reactions, the Ugi and Passerini reactions, are accelerated by the use of aqueous solutions. The rate enhancements compared to those by organic solvents can approach 300-fold. Reactions performed in water offer another advantage that products are often insoluble, permitting direct isolation by precipitation. The methods were applied to the preparation of three small combinatorial libraries.
