Synthesis of highly functionalized 2,4-diaminoquinazolines as anticancer and anti-HIV agents

• Published in: Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (15), p.4432-4435
• Main Authors: Yan, Sheng-Jiao, Zheng, Han, Huang, Chao, Yan, Yu-Yun, Lin, Jun
• Format: Article
• Language: English
• Subjects: Anti-HIV activity; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Anticancer activity; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Antiviral agents; Biological and medical sciences; Cell Line, Tumor; Crystallography, X-Ray; Drug Screening Assays, Antitumor; General aspects; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Medical sciences; Molecular Conformation; Neoplasms - drug therapy; Pharmacology. Drug treatments; Polyhalo 2,4-diaminoquinazoline; Polyhaloisophthalonitrile; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - therapeutic use; Solvent-free synthesis; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.056

The novel 2,4-diaminoquinazolines 3–5 were easily prepared based on the reaction of polyhaloisophthalonitriles with guanidine carbonate. The anticancer and anti-HIV activities of 3–5 were evaluated in vitro. Compound 5a was the most potent derivative against the five tumor cell lines with an IC50 value lower than 2.5μg/mL, and 3c showed the most potent anti-HIV-1 activity with EC50 values of 0.6 and 1.6μg/mL, and TI values of >59.6 and 66.6, respectively. Novel polyhalo 2,4-diaminoquinazolines 3a–3d were prepared by reacting polyhaloisophthalonitriles with guanidine carbonate under solvent-free conditions and in the absence of a catalyst with good yields (74–95%). A series of highly functionalized 2,4-diaminoquinazolines 4–5 were then synthesized based on 3a–3c. The anticancer activities of compounds 3–5 were evaluated in vitro against human cell lines such as Skov-3, HL-60, A431, A549, and HepG-2. Some of the compounds showed excellent cytotoxic activity and 5a was found to be the most potent derivative, with an IC50 value lower than 2.5μg/mL against the five tumor cell lines, making it more active than cisplatin. Representative compounds were also preliminarily evaluated as HIV-1 inhibitors in vitro, and 3c showed the most potent anti-HIV-1 activity with EC50 values of 0.6 and 1.6μg/mL, and TI values of >59.6 and 66.6, respectively.