Scientia Pharmaceutica (Sci. Pharm.) 69, 351-366 (2001) 35 1 0 Osterreichische Apotheker-Verlagsgesellschaft m. b. H., Wien, Printed in Austria Substituted Quinazolines, 1. Synthesis and Antitumor Activity of Certain Substituted 2-Mercapto-4(3H)-quinazolinone Analogs. S.G. Abdel Hamid*, H.A. El-Obeid, K.A. Al-Rashood, A.A. Khalil and H.I. El-Subbagh.* Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh-11451 Saudi Arabia. A new series of 4(3H)-quinazolinone analogs bearing 6-iodo and 2-thioether functions were synthesized and screened for their in vitro antitumor activity. Eight compounds were identified as active anticancer agents. 2-Mercapto-3-benzyl-4-thioxo-6-iodo-3H-quinazoline (2) and 2-(2,4- dinitrophenyl)-3-benzyl-6-iodo-4-(3H)-quinazolinone (9) proved to be the most active compounds in this study. They showed MG-MID (3150, TGI, LC50 values of 3.9, 25.2, 82.3 and 2.7, 12.3, 38.7 pM, respectively. The detailed synthesis and biological screening data are reported. (Keywords: Synthesis, 4(3H)-quinazolinone, Antitumor testing). Introduction Quinazolines have been reported to be biologically versatile compounds possessing variety of activity including anticancer potency.' An extensive interest in quinazolines has been increased since the discovery of raltitrexed (A) and thymitaq (B) and their activity as thymidylate enzyme inhibitors.233 Overexpression of the epidermal growth factor receptor (EGFR) tyrosine kinase is associated with poor prognosis in a significant proportion of human turn or^.^." 4-Anilinoquinazolines proved to inhibit EGFR autophosphorylation and EGF-stimulated signal transduction and considered as a new class of anticancer d r~~s.~-'~ Quinazoline analogs also showed a remarkable activity against the opportunistic infections of Pnc~m~ocystis cc~rinii and Toxoplusmu gondii through the inhibition of dihydrofolate reductase