Design, Synthesis and Pharmacological Investigation of Some Novel Quinazolines, Thiosemicarbazides/Thiosemicarbazones

Abstract

A series of novel 2-(3-substitutedpropylthio)-3-(substitutedphenyl) quinazolin-4(3 H)-ones were synthesized by the reaction of 2-(3-bromopropylthio)-3-(substitutedphenyl) quinazolin-4(3 H)-one with a variety of amines. The starting material, 2-(3-bromopropylthio)-3-(substitutedphenyl) quinazolin-4(3 H)-one was synthesized from substituted aniline. The title compounds containing substituted propylthio group at C-2 and substituted phenyl group at N-3 of quinazolines were evaluated for their in vivo antihistaminic activity adopting the protection against histamine induced bronchospasm on conscious guinea pigs method. While the test compounds exhibited good antihistaminic activity, percentage protection data showed that all compounds of the series found to possess significant protection in the range of 64-77%. Structure activity relationship (SAR) studies indicated that the electronic nature of the substituent group of N-3 aromatic ring led to a significant variation in antihistaminic activity. For example electron withdrawing group (chloro substituent) enhanced the biological activity, whereas electron releasing groups (methyl) made the compounds less active. From the SAR studies it is also revealed that different substituent over the C-2 position of quinazoline ring exerted varied biological activity. The presence of N-methyl piperazinyl group showed most significant activity, among the test compounds, 2-(3-(4-methyl piperazin-1-yl)propylthio)-3-(4-chloro phenyl) quinazolin-4(3 H)-one (PC5) exhibited the most potent activity of the series with the percentage protection of 77.53 % which is more potent than that of standard chlorpheniramine maleate (percentage protection 70.09 %). As sedation is one of the major side effects associated with antihistamines, the test compounds were also evaluated for their sedative potentials, by measuring the reduction in locomotor activity using actophotometer on Albino Swiss mice. The results of sedative-hypnotic activity indicate that the test compounds were found to exhibit only negligible sedation (6-12%), whereas the reference standard chlorpheniramine maleate showed 33% sedation. Hence the compound PC5 series as a lead molecule of the present study which is more potent 77.53% then the standard chlorpheniramine maleate 70.09%. Interestingly this lead compound exhibited lesser sedation (7%) than the standard chlorpheniramine maleate (33%).