Design, Synthesis and Pharmacological Evaluation of Quinazoline Derivatives as Anti-Cancer Agents

Abstract

Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases. CDK activity is increased in proliferative diseases such as cancer, owing to the frequent overexpression of cyclins. CDK2 inhibition essentially restrains uncontrolled cell proliferation. Extensive literature review revealed that compounds containing Quinazoline or Thiophene or both structural features have good anticancer activity. Hence, pharmacophore modeling was performed using 10 structurally diverse molecules with the help of DISCOTech module of Sybyl X1.3. Amongst the generated models, first model was considered as the best having highest score and it was refined with GASP. All generated models were validated by ROC analysis method to determine their ability to identify active molecules from a decoy set. Out of the four models generated, model 3 had the highest score and best ROC-AUC value of 0.806 and was considered as the best model which contained 5 features viz. 2 H-bond donor, 2 H-bond acceptor and 1 hydrophobic region. This model was used as a query for virtual screening in NCI database. A total number of 24988 molecules were obtained after Lipinski filtering. From the results of virtual screening compounds having highest Qfit value and knowledge based structure activity relationship study, various molecules with substituted quinazoline derivatives were designed and docked using Surflex-Dock module and GOLD on co-crystal structure of CDK2 (PDB ID: 2R3I) to predict the binding orientation of drug candidates to their protein target using Indirubin and Flavopiridol as standard drugs. From this, eight derivatives bearing quinazoline moiety having comparable docking score were synthesized and characterized by FT-IR, 1H NMR and Mass spectral data. In-silico ADMET studies were carried out using admetSAR property explorer showing good drug-like properties of designed and synthesized molecules. The designed compounds showed good potential as anticancer agents. Synthesized compounds were evaluated for anti-cancer activity on three cell lines MCF-7 (breast cancer), A-375 (skin cancer) and HCT-15 (colon cancer) using doxorubicin as standard.