SYNTHESIS OF NEW 1,2,4-TRIAZOLOQUINAZOLINE DERIVATIVES AS CNS MODULATORS

Ziedan, Noha; El-Shanawani, Abdalla; El-Adl, Sobhy; Sakr, Samy

doi:10.21608/zjps.2006.169423

SYNTHESIS OF NEW 1,2,4-TRIAZOLOQUINAZOLINE DERIVATIVES AS CNS MODULATORS

Document Type : Original Article

Authors

¹ Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

² Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazige University, Zagazig, Egypt

10.21608/zjps.2006.169423

Abstract

A series of 1,2,4-triazolo4,3-cJquinazoline-3-thiol was synthesized by reacting isatoic anhydrides (I_a, I_b) with thiosemicarbazide to yield the appropriate 2-acylhydrazinocarbothioamides (II_ab ,II_b) which were cyclized to afford 5-(2- substituted aminophenyl)-1,2,4-triazol-3-thiols (III_ab ,III_b) using sodium hydroxide. The triazol derivatives (III_ab,III_b) were cyclized to the new 1,2,4-riazolo4,3-cquinazoline-3-thiol (IV) upon condensation with aromatic aldehydes. Whereas, cyclization of (III_ab,III_b) with formaldehyde unexpectedly afforded 3-hydroxymethyl-1,2,4-triazolo1,5-cquinazolin-2-thione (VI_a, VI_b). The last reaction is the role-play to the formation of a series of 1,2,4-triazolo 1,5-cquinazoline-2-thiol (VL_c, VI_d, VII) upon boiling of the appropriate 1,2,4-triazolo4,3-cquinazoline-3-thiol in ethanol with acidified formaldehyde. Also, alkylation of 3-thiol derivatives (IV) with the appropriate alkyl halide in alkaline medium afforded a new series of 3-alkyl (or 3-aralkyl) thio-1,2,4-triazolo4,3-cquinazolines (V_a-b). Otherwise, alkylation of 5-(2-methylaminophenyl)-1,2,4-triazol-3-thiol (III_a) was affected firstly and followed by condensation with either carbon disulfide or hydroxybenzaldehyde to produce 3-alkylthio-6- methyl-1,2,4-triazolo(4,3-cquinazolin-5(6H)-thione (IX) or 3-alkylthio-5-(hydroxyphenyl)-6-methyl-1,2,4-triazolo4,3- c]quinazoline (V_1-1) respectively. Oxo-desulfuration was the key-procedure for preparation of 3-hydroxy-6-methyl-5-(4- nitrophenyl)-1,2,4-triazolo4,3-cquinazoline (X) from its thione analogue. The new triazoloquinazoline derivatives were subjected to preliminary pharmacological screening, where compounds (VI_f, V_b, VI_a, VI_b, VI_d, X) produced a moderate to high CNS stimulant effect when tested on mice. Furthermore, compound (VI_a) was tested by recording the electroencephalographic changes induced by its intravenous injection in conscious rabbits which gave noticeable results.