Research Article Synthesis and Biological Evaluation of 2,4-Diaminoquinazolines as Potential Antitumor Agents Mohammad A. Alassaf , Khalid B. Selim, and Magda N. A. Nasr Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Wataniya Private University, Hama 264-2007, Syria Correspondence should be addressed to Mohammad A. Alassaf; mohammad.alassaf@wpu.edu.sy Received 4 June 2022; Revised 5 September 2022; Accepted 14 October 2022; Published 25 October 2022 Academic Editor: Dharmendra Kumar Yadav Copyright © 2022 Mohammad A. Alassaf et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In the present study, a set of 2-anilino-4-alkylaminoquinazoline derivatives were synthesized and tested for their antitumor activities in vitro against a panel of four human cancer cell lines and for their DNA-binding affinity. Among the synthesized compounds, 4c and 5b with 4-substitution at the phenyl ring were found to have the highest inhibitory effects against breast adenocarcinoma (MCF-7), colon cancer (HCT-116), hepatocellular carcinoma (HePG-2), and human skin cancer (HFB4). Further investigation revealed that compounds 4a and 5d exhibited better affinity to bind with DNA than other tested compounds. 1. Introduction Although the development of novel targeted antitumor drugs has made important progress in recent years, cancer remains the major leading cause of death in the world due to drug resistance or undesirable toxic effects [1]. erefore, continued commitment to the laborious task of discovering new anticancer agents remains critically important [2]. In the course of finding new bioactive molecules that may serve as potent antitumor agents, quinazoline deriva- tives are of particular interest [3]. ese quinazolines have been identified as a new class of cancer chemotherapeutic agents against solid tumors and exert their antitumor ac- tivity through the inhibition of the receptor tyrosine kinases (RTKs) [4], specifically epidermal growth factor receptor (EGFR), such as PD153035 [5], and gefitinib [6], or dihy- drofolate reductase, such as trimetrexate (TMQ) [7] (Fig- ure 1). Moreover, the anticancer activity of quinazoline- based drugs is related to their DNA-binding affinity to show inhibition of topoisomerases, such as Luotonin A [8], or inhibition of telomerase such as 05 9 (Figure 1), leading to cell death by inhibition of replicative enzymes and DNA repair systems. In the current study, we have synthesized a series of 2,4- disubstituted quinazolines 4a-d and 5a-d (Figure 1), each of which contains a simple alkyl amino side chain at position 4 instead of the diaminopropyl moiety of 05 [9]. In addition, an aryl amino moiety was introduced at position 2 of the quinazoline ring instead of the substituted aryl fragment. is can significantly increase the binding ability of these compounds with the relevant desired receptors, such as EGFR tyrosine kinase or DNA, through the formation of hydrogen bonding. An evaluation of their antiproliferative activity was carried out using four human tumor cell lines, in addition to their DNA-binding affinity. 2. Results and Discussion 2-Arylamino-4-alkylaminoquinazoline derivatives 4a-d and 5a-d were prepared as shown in Figure 2. e starting material 2-aminobenzoic acid was condensed with potas- sium cyanate conveniently cyclized to quinazoline-2,4-dione as described in the literature. Compound 1 was refluxed with phosphorous oxychloride to corresponding diclor- oquinazoline (2) [10] Compoun3d 1 yielded the corre- sponding 2,4-dichloroquinazoline (2) upon refluxing with Hindawi Journal of Chemistry Volume 2022, Article ID 7763545, 6 pages https://doi.org/10.1155/2022/7763545