Substituted Isoquinolines and Quinazolines as Potential Antiinflammatory Agents. Synthesis and Biological Evaluation of Inhibitors of Tumor Necrosis Factor α

Abstract

A series of isoquinolin-1-ones and quinazolin-4-ones and related derivatives were prepared and evaluated for their ability to inhibit tumor necrosis factor alpha (TNFalpha) production in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). In an effort to optimize the TNFalpha inhibitory activity, a homologous series of N-alkanoic acid esters was prepared. Several electrophilic and nucleophilic substitutions were also carried out. Alkanoic acid esters of four carbons were found to be optimum for activity in both the isoquinoline and quinazoline series. Ring substituents such as fluoro, bromo, nitro, acetyl, and aminomethyl on the isoquinoline ring resulted in a significant loss of activity. Likewise, similar groups on the quinazoline ring also reduced inhibitory activity. However, the 6- and 7-aminoquinazoline derivatives, 75 and 76, were potent inhibitors, with IC(50) values in the TNFalpha in vitro assay of approximately 5 microM for each. An in vivo mouse model of pulmonary inflammation was then used to evaluate promising candidate compounds identified in the primary in vitro assay. Compound 75 was selected for further study in this inhalation model, and was found to reduce the level of TNFalpha in brochoalveolar lavage fluid of LPS-treated mice by about 50% that of control mice. Thus, compounds such as 75, which can effectively inhibit proinflammatory cytokines such as TNFalpha in clinically relevant animal models of inflammation and fibrosis, may have potential as new antiinflammatory agents. Finally, a quinazoline derivative suitable to serve as a photoaffinity radiolabeled compound was prepared to help identify the putative cellular target(s) for these TNFalpha inhibitors.

Synthesis and Antifungal Bioactivities of 3-Alkylquinazolin- 4-one Derivatives

“…When the reaction time was prolonged further to 2 h, tiny improvement (83.8 %, entry 13) was obtained, as compared to that of 1 h (83.0 %, entry 8). As for the reaction temperature, it could be seen that the yield was relatively low when the reaction was carried out at 20-65°C (Table 1, entries [10][11][12] than that at 88-90 °C (entry 8). The effect of different organic phase was also investigated.…”

Synthesis and Antimicrobial Activity of Amino Linked Heterocycles

“…The synthetic intermediate 2,4-dichloroquinazoline (3) was obtained by the reaction of substituted anthranilic acid with urea followed by chlorination with POCl 3 in the presence of N,N-dimethylaniline.…”

“…As an important pharmacophore, quinazoline has a variety of biological activities such as anticancer, 1) antibacterial 2) and anti-inflammatory. 3) Different azoles, benzoxazoles, benzothiazoles and benzimidazoles are associated with diverse pharmacological activities viz., analgesic, antituberculosis, 4) antimicrobial, 5,6) anti-inflammatory, antioxidant and antiviral. 7) Synthetic analogues possessing these core structures have considerable medicinal interest and are identified as the important heterocyclic motifs for the development of novel therapeutics.…”

Synthesis of Novel 6,7,8,9-Tetrahydro-5H-5-hydroxyphenyl-2-benzylidine-3-substituted Hydrazino Thiazolo (2,3-b) Quinazoline as Potent Antinociceptive and Anti-inflammatory Agents

“…Therefore, the discovery of new safer anti-inflammatory drugs represents a challenging goal for such a research area, the quinazolines and condensed quinazolines exhibit antinociceptive, anti-inflammatory activities. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] On the other hand, the considerable biological and medicinal activities of thiazole derivatives have attracted continuing interest over the years because of their varied biological activities. 15,16 These observation led to the conception that a novel series of 6,7,8,9-tetrahydro-5H-5-hydroxy phenyl-2-benzylidine-3-substituted hydrazino thiazolo (2,3-b) quinazoline derivatives were synthesized using appropriate ketones/aldehydes by Schiff base mechanism and their chemical structure were confirmed by IR, H-NMR spectra of final compounds confirms the secondary NH proton in thiazolo quinazoline moiety.…”