Synthesis and pharmacological investigation of novel 4-(3-ethylphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-ones as a new class of H1-antihistaminic agents
A series of novel 4-(3-ethylphenyl)-1-substituted-4H-[1,2,4] triazolo[4,3-a]quinazolin-5-ones (4a-j) were synthesized by the cyclization of 3-(3-ethylphenyl)-2-hydrazino-3H-quinazolin-4-one (3) with various one-carbon donors. The starting material, compound 3, was synthesized from 3-ethyl aniline by a new innovative route with improved yield. When tested for their in vivo H1-antihistaminic activity on conscious guinea pigs, all test compounds protected the animals from histamine induced bronchospasm significantly. Compound 4-(3-ethylphenyl)-1-methyl-4H - [1,2,4]triazolo[4,3-a]quinazolin-5-one (4b) emerged as the most active compound of the series and it is more potent (74.6 % protection) compared to the reference standard chlorpheniramine maleate (71 % protection). Compound 4b shows negligible sedation (10 %) compared to chlorpheniramine maleate (30 %). Therefore compound 4b can serve as the leading compound for further development of a new class of H1-antihistamines.
F. E. Simons and K. J. Simons, The pharmacology and use of H1-receptor-antagonist drugs, N. Engl. J. Med.330 (1994) 1663-1670; DOI: 10.1056/NEJM199406093302307.
H. Van der Goot, A. Bast and H. Timmerman, Structural Requirements for Histamine H2 Agonists and H2 Antagonists, in Histamine and Histamine Antagonists (Ed. B. Uvniis), Springer, Berlin 1991, pp. 573-748.
A. A. Carr and D. R. Meyer, Synthesis of terfenadine, Arzneimittelforsch.32 (1982) 1157-1159.
R. J. Hopp, A. Bewtra, N. M. Nair and R. G. Townley, The effect of age on methacholine response, J. Allergy Clin. Immunol.76 (1985) 609-613; DOI: 10.1016/0091-6749(85)90783-3.
N. Chairungsrilerd, K. Furukawa, T. Ohta, S. Nozoe and Y. Ohizumi, Pharmacological properties of alpha-mangostin, a novel histamine H1 receptor antagonist, Eur. J. Pharmacol.314 (1996) 351-356.
F. Estelle, R. Simons and K. Simons, Pharmacokinetic optimisation of histamine H1-receptor antagonist therapy, Clin. Pharmacokin.21 (1991) 372-393.
H. Renner, S. Schnitzler, V. Hagen, K. Kottke and H. Kuehmstedt, Antianaphylactic effects of 2-hydrazino-3-arylquinazol-4-ones and 4-aryl-5-oxo-4,5-dihydro-sym-triazolo[4,3-a]quinazolines, Pharmazie35 (1980) 801-802.
V. Alagarsamy, R. Venkatesaperumal, S. Vijayakumar, T. Angayarkanni, P. Pounammal, S. Senthilganesh and S. Kandeeban, Synthesis and pharmacological investigation of some novel 2-phenyl-3-(substituted methyl amino) quinazolin-4(3H)-ones as H1-receptor blockers, Pharmazie57 (2002) 306-307.
V. Alagarsamy, Synthesis and pharmacological investigation of some novel 2-methyl-3-(substituted methylamino)-(3H)-quinazolin-4-ones as histamine H1-receptor blockers, Pharmazie59 (2004) 753-755.
J. Van Wauwe, F. Awouters, C. J. E. Niemegeers, F. Janssens, J. M. Van Nueten and P. A. Janssen, In vivo pharmacology of astemizole, a new type of H1-antihistaminic compound, J. Arch. Pharmacodyn. Ther.251 (1981) 39-51.
G. B. Shah and N. S. Parmar, Antiasthmatic property of polyherbal preparation E-721 B, Phytother Res.17 (2003) 1092-1097; DOI: 10.1002/ptr.1344.
B. N. Suhagia, M. T. Chhabria and A. G. Makwana, Design, synthesis and pharmacological screening of a series of N1-(substituted) aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)-pyrimidin-4(3H)-ones as potential histamine H1-receptor antagonists, J. Enzyme Inhib. Med. Chem.21 (2006) 681-691.