New bronchodilators. 1. 1,5-Substituted 1H-imidazo[4,5-c]quinolin-4(5H)-ones

Abstract

A series of novel xanthine-based tricyclic heterocycles in 1H-imidazo[4,5-c]quinolin-4(5H)-ones was designed, synthesized, and tested as potential active bronchodilators. Inhibition of the Schulz-Dale (SD) reaction-induced contraction in trachea and inhibition of antigen inhalation-induced bronchospasm in passively sensitized guinea pigs served as primary in vitro and in vivo assays, respectively. Simultaneous measurement of acute lethal toxicity (minimum lethal dose; MLD, po) in mice allowed determination of a safety margin. The bronchodilatory activity of these heterocycles was considerably varied with the nature of substituents at the 5-position. The most active substituents at the 2- and 5-positions and on the aromatic ring were found to be hydrogen, n-butyl, and hydrogen, respectively. There was a bulk tolerance for lipophilic substituents at the 1-position. 5-Butyl-substituted compounds appeared to be less toxic than theophylline on the basis of MLD data. Thus 5-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-4(5H)-one (10) (IC50 value of the SD assay = 0.25 microM, MLD > 300 mg/kg) was selected for further studies. Compound 10 (KF15570) reduced bronchoconstriction produced by antigen (Konzett-Rössler preparation in anesthetized guinea pigs, ED50 = 0.42 mg/kg, iv) more effectively than aminophylline (ethylenediamine salt of theophylline, ED50 = 7.8 mg/kg, iv) but had fewer side effects on the heart and CNS than theophylline. Compound 10 and its derivatives showed weak adenosine antagonism and phosphodiesterase (PDE) inhibition which could not account for their potent bronchodilation. Although their precise mechanism of action remains unclear, this series of novel tricyclic heterocycles represents a new class of bronchodilator.

A new therapeutic approach in Parkinson’s disease: Some novel quinazoline derivatives as dual selective phosphodiesterase 1 inhibitors and anti-inflammatory agents

“…When compared the effect of bromo substituent on the quinazolinone ring of title compounds, it was found that non bromo analogues have shown potent anti-inflammatory activity than the bromo analogues. The order of activity in this series was non-bromo analogues (1-5) > monobromo analogues (11)(12)(13)(14)(15) > dibromo analogues (6)(7)(8)(9)(10).…”

“…For example electronic withdrawing group (mainly bromo substitutions) enhanced the PDE1 inhibitory activity whereas non bromo analogues have shown less activity. The order of activity was dibromo analogues (6-10) > monobromo analogues (11)(12)(13)(14)(15) > non bromo analogues (1)(2)(3)(4)(5). The substituent over thiophene nucleus also led to significant variation in PDE1 inhibitory activity.…”

“…The quinazolinone moiety is a building block for approximately 150 naturally occurring alkaloids and drugs. 10 The natural quinazolinones and their synthetic analogs possess a variety of biological activities, including PDE inhibitory activity, [11][12][13][14][15] anticonvulsant, 16,17 bronchodilator, 18 anti-inflammatory, 19,20 antimalarial, 21 antituberculous, 22 anti-HIV, 23 narcotic antagonist, 24 anti-tumor, 25 tyrosine kinase inhibitor, 26 adenosine antagonist, 27 antimicrobial, 19 etc. Along with these activities, quinazoline derivatives showed a very prominent activity in PD.…”

“…Considering that quinazolines are promising compounds for anti-inflammatory 19,20 and PDE1 inhibitors 11,40 and in the light of aforementioned findings, we aimed to synthesize novel series of 7H-thieno[2 0 ,3 0 :4,5]pyrimido[6,1-b]-quinazolin-7-one 41 and 8H-pyrido[2 0 ,3 0 :4,5]pyrimido[6,1-b]quinazolin-8-ones (see Fig. 2).…”

Synthesis and Antimicrobial Evaluation of Some New Thiazolo Imidazole Analogs

“…Imidazoles are more vital in many biological processes since they are present in many natural compounds. Many synthetic pyrimidine analogs are also known to exhibit a variety of therapeutic uses including antiviral [9], antimycobacterial [10], antitumor [11], anti-inflammatory [12], antidepressant [13], branchodilatory [14], antifungal activity [15], etc.…”