RESUMO
The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition, and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. We have synthesized and identified a novel series of 4-aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonists. Among all the synthesized compounds, in vitro and docking studies suggested that the 4-methoxy-phenyl-substituted tetrahydroquinazolinamine compound 4c has potent and selective H3R antagonist activity (IC50 < 0.04 µM). Compound 4c did not exhibit any activity on the hERG ion channel and pan-assay interference compounds liability. Pharmacokinetic studies showed that 4c crosses the blood brain barrier, and in vivo studies demonstrated that 4c induces anorexia and weight loss in obese, but not in lean mice. These data reveal the therapeutic potential of 4c as an anti-obesity candidate drug via antagonizing the H3R.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Obesidade/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptores Histamínicos H3/metabolismo , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Glicemia/metabolismo , Dieta Hiperlipídica , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Proteínas Proto-Oncogênicas c-fos/metabolismo , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacosRESUMO
In an attempt to develop new antimalarial drugs, we have synthesized a new class of N-alkylated 3-glycoconjugated-oxopropylidene oxindoles starting from substituted isatins and glucopyranosyl propanone via a well-known cross-aldol reaction followed by dehydration. The newly synthesized compounds were screened for their in vitro antiplasmodial activity, and among all the compounds 9g, 9f, 9b, 8d, 9d, 9c, and 9e displayed potent activity with the IC50 values in the range of 0.1-0.3⯵M against Chloroquine (CQ) sensitive Pf3D7 strain, while compounds 9d, 9b, 9e, 8c, 8f, 9c, and 9a have shown promising activity having IC50 values in 0.1-0.4⯵M range against CQ resistant PfK1 strain, which is even better than the standard drug chloroquine with IC50 value of 0.5⯵M.
Assuntos
Antiprotozoários/síntese química , Isatina/química , Oxindóis/síntese química , Antimaláricos/síntese química , Antiprotozoários/farmacologia , Concentração Inibidora 50 , Relação Estrutura-AtividadeRESUMO
A small library of 36 new glycohybrids of phenylhydrazono-indolinones was synthesized employing glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-diones and different phenylhydrazines via acid catalyzed reaction. All the compounds were screened for their antiplasmodial activity in vitro. Compounds 6c, 7c, and 7b showed significant activity with the IC50 values 1.27, 1.64 and 1.96⯵M, respectively against CQ sensitive Pf3D7 strain while compounds 7b and 6f showed good activity with IC50 1.61 and 1.93⯵M, respectively against CQ resistant PfK1 strain.
Assuntos
Antimaláricos/farmacologia , Hidrazonas/farmacologia , Indóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Triazóis/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Glicosilação , Hidrazonas/química , Indóis/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
A novel and efficient Cu(I)-catalyzed ligand- and base-free multipathway domino strategy has been developed for the synthesis of 2-substituted quinazolinones. The reaction utilizes 2-bromobenzamide and multiform substrates such as aldehydes, alcohols, and methyl arenes for a one-pot protocol, whereas TMSN3 is used as a nitrogen source. A wide range of substrate scope, functional group tolerance, and operational simplicity are synthetically useful features.