RESUMEN
Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.
Asunto(s)
Bencimidazoles/farmacología , Receptores Opioides kappa/agonistas , Secuencia de Aminoácidos , Simulación por Computador , Humanos , Datos de Secuencia Molecular , Receptores Opioides kappa/química , Homología de Secuencia de Aminoácido , Relación Estructura-ActividadRESUMEN
Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.
Asunto(s)
Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Bencimidazoles/química , Bencimidazoles/uso terapéutico , Obesidad/tratamiento farmacológico , Receptores de Somatostatina/antagonistas & inhibidores , Receptores de Somatostatina/metabolismo , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Unión Proteica , Pérdida de Peso/efectos de los fármacosRESUMEN
In an effort to discover potent antibacterials based on the entropically favored 'bioactive conformation' approach, a series of novel tricyclic molecules mimicking the conformationally constrained structure of Linezolid is reported. Based on the initial tricyclic molecule 1, the benzazepine derivative 2 was designed where the tricyclic structure had more flexibility around C-N bond compared to 1. While, the molecule 2 was less active, the molecule 3 showed promising antibacterial activity presumably after having obtained rigidity due to pyrrole ring. The syntheses, SAR studies, and evaluation of 3 as a lead compound are reported.
Asunto(s)
Antibacterianos/síntesis química , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Antibacterianos/farmacología , Benzazepinas/química , Imitación Molecular , Pirroles/química , Relación Estructura-ActividadRESUMEN
Some novel oxazolidinone derivatives with benzotriazole as pendant have been synthesized and tested for antibacterial activity. Linearly attached benzotriazole derivative showed more potency compared to angular one in vitro. Out of E/Z-isomers of angularly attached derivatives E-isomer was found to be more potent than Z-isomer. Either less active or inactive molecules were obtained, when benzotriazole was replaced with benzimidazole, benzthiazole, or benzoxazole. Finally, thioacetamide analogue of linear compound gave a lead having activity similar to linezolid in vitro.