RESUMO
2-Amino-3-cyanothiophenes were successfully condensed with a number of cycloalkanones to afford tacrine analogues in a one-step reaction mediated with Lewis acid. The newly synthesized compounds have been tested for their ability to inhibit acetylcholine esterase (AChE) activity using tacrine as standard drug. Some of the tested compounds showed moderate inhibitory activity in comparison with tacrine, especially compounds 6a which displayed the highest inhibitory activity. Furthermore, molecular-modeling studies were performed in order to rationalize the obtained biological results.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Tacrina/análogos & derivados , Tienopiridinas/síntese química , Inibidores da Colinesterase/metabolismo , Desenho de Fármacos , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Tacrina/metabolismo , Tacrina/farmacologia , Tienopiridinas/metabolismo , Tienopiridinas/farmacologiaRESUMO
Several triazenoindazoles 3a-e and triazinopyrazolopyridines 6a-i were prepared through the reaction of the corresponding 3-amino-4-chloroindazole and 3-aminopyrazolopyridine diazonium salts 2 and 5 with a number of secondary amines. All compounds were evaluated for their in vitro cytotoxic activity on three cell lines, HepG2, MCF7, and HeLa. Most compounds inhibited cell growth with IC(50) less than 0.1 microM. Compound 6d was the most potent, with an IC(50) of 0.03 microM against HepG2 and 0.05 microM against MCF7 and HeLa cells.
Assuntos
Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/farmacologia , Desenho de Fármacos , Indazóis/síntese química , Indazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Triazenos/síntese química , Triazenos/farmacologia , Antineoplásicos Alquilantes/química , Linhagem Celular Tumoral , Dacarbazina/química , Dacarbazina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Células Hep G2 , Humanos , Indazóis/química , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Piridinas/química , Espectrofotometria Infravermelho , Temperatura de Transição , Triazenos/químicaRESUMO
In an attempt to identify potential vasodilator-cardiotonic lead compounds, three series of pyridazinones were designed using three-dimensional pharmacophore developed with CATALYST software from a set of potent cyclic nucleotide phosphodiesterase III, cAMP PDEIII inhibitors. The features of the target compounds were based on the structures of many biologically active lead compounds with cAMP phosphodiesterase III inhibiting activity such as Milrinone and others. Compounds with higher fit scores to the developed pharmacophore were synthesized namely; 6-(3-ethoxycarbonyl-4-oxo-1,4-dihydroquinolin-6-yl)-4,5-dihydro-3(2H)-pyridazinones (3a and 3b), 6-[4-(2,6-disubstituted-quinolin-4-ylamino)phenyl]-4,5-dihydropyridazin-3(2H)-ones (5a-f), and 6-[3-(5-cyano-6-oxo-4-aryl-1,6-dihydro-2-pyridyl)phenylamino]-3(2H)pyridazinone (8a and 8b). The vasodilator activity of the newly synthesized compounds was examined on the isolated main pulmonary artery of the rabbit. Some of the tested compounds showed moderate vasorelaxant activity compared with standard drug, Milrinone.
