RESUMEN
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.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Obesidad/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptores Histamínicos H3/metabolismo , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Glucemia/metabolismo , Dieta Alta en Grasa , Células HEK293 , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Proteínas Proto-Oncogénicas c-fos/metabolismo , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Estereoisomerismo , Relación Estructura-Actividad , Pérdida de Peso/efectos de los fármacosRESUMEN
In a quest to discover new drugs, we have synthesized a series of novel ß-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 µM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 µM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity.
Asunto(s)
Antimaláricos/química , Antimaláricos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Triazoles/química , Triazoles/uso terapéutico , Amino Alcoholes/química , Amino Alcoholes/farmacocinética , Amino Alcoholes/farmacología , Amino Alcoholes/uso terapéutico , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Chlorocebus aethiops , Humanos , Células MCF-7 , Malaria Falciparum/metabolismo , Masculino , Ratones , Ratas Sprague-Dawley , Triazoles/farmacocinética , Triazoles/farmacología , Proteína p53 Supresora de Tumor/genética , Regulación hacia Arriba/efectos de los fármacos , Células VeroRESUMEN
A new series of C-linked phenyl butenonyl glycosides bearing ureidyl(thioureidyl) and sulfonamidyl moieties in the phenyl rings were designed, synthesized, and evaluated for their in vitro antimalarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains. Among all the compounds screened the C-linked phenyl butenonyl glycosides bearing sulfonamidyl moiety (5a) and ureidyl moiety in the phenyl ring (7d and 8c) showed promising antimalarial activities against both 3D7 and K1 strains with IC50 values in micromolar range and low cytotoxicity offering new HITS for further exploration.