RESUMEN
Drug-drug interactions are sometimes considered to be detrimental and responsible for adverse effects. In some cases, however, some are stakeholders of the efficiency of the treatment and this combinatorial strategy is exploited by some drug associations, including levodopa (L-Dopa) and dopadecarboxylase inhibitors, ß-lactam antibiotics and clavulanic acid, 5-fluorouracil (5-FU) and folinic acid, and penicillin and probenecid. More recently, some drug-drug combinations have been integrated in modern drug design strategies, aiming to enhance the efficiency of already marketed drugs with new compounds acting not only as synergistic associations, but also as real boosters of activity. In this review, we provide an update of examples of such strategies, with a special focus on microbiology and oncology.
Asunto(s)
Antiinfecciosos/administración & dosificación , Antineoplásicos/administración & dosificación , Diseño de Fármacos , Animales , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Interacciones Farmacológicas , Sinergismo Farmacológico , Quimioterapia Combinada , HumanosRESUMEN
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM).
Asunto(s)
Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Donepezilo/síntesis química , Donepezilo/uso terapéutico , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/uso terapéutico , Donepezilo/química , Donepezilo/farmacología , Humanos , Modelos Moleculares , Conformación Molecular , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/uso terapéutico , EstereoisomerismoRESUMEN
A series of substituted 3-trifluoromethylpyrroles was obtained from trifluoromethylamino-ynol derivatives via a gold-catalyzed cyclization. Using fluorinated starting materials, after mesylation, allowed for the desired compounds to be obtained in good yields under mild conditions.