Design, Synthesis and Cytotoxic Studies of Novel 4-anilinoquinazoline Derivatives of Potential Agents for Non-small-cell Lung Cancer

Title:Design, Synthesis and Cytotoxic Studies of Novel 4-anilinoquinazoline Derivatives of Potential Agents for Non-small-cell Lung Cancer

Volume: 21 Issue: 10

Author(s): Deepak K. Dwivedi*, Ram Kishore Agrawal, Sanyog Jain and Kaushik Kuche

Affiliation:

• Department of Pharmaceutical Sciences, Dr. Harisingh Gour Central University, Sagar, (MP), India

Keywords: 4-anilinoquinazoline, molecular docking study, EGFR Kinase 4I22, amino acids, NSCLC, TKIs.

Abstract:

Background: The pre-existing EGFR (Epidermal Growth Factor Receptors) inhibitors (Gefitinib, Afatinib and osimertinib) show significant resistance after one year of EGFR therapy in NSCLC (Non-small cell lung cancer) patients. With the aim of overcoming the resistance problem associated with a current therapeutic regimen, there is an imperative need for the development of novel 4- anilinoquinazoline derivatives that are specifically designed for resistance cases of NSCLC patients.

Objective: We designed and synthesized eighteen 4-anilinoquinazolines derivatives as a novel scaffold and evaluated their anti-cancer potential against different NSCLC cell lines.

Methods: Molecular docking study of designed compounds were performed on Glide v5.8 (Schrodinger, LLC, New York, NY). Synthesis of 4-anilinoquinazoline derivatives were performed, based on the docking score and was characterized by various spectroscopic methods. Further, in vitro anti-cancer activity was performed using MTT assay on different cancer cell lines.

Results: Molecular docking analysis [EGFR^T790M mutant (4I22)] indicated that most of these analogs (6g, 6j, 6l, 6m and 6o) were found to be higher docking scores than gefitinib. Furthermore, spectral analysis revealed that the designed compounds were synthesized successfully. The compounds 6a, 6d, 6g, 6i, 6j and 6m were identified as the potent inhibitors against (A431, H1975, A549) cell lines as compared to reference standard gefitinib. Excitingly, compound 6j (with IC₅₀ values of 4.88 ± 0.13, 4.38 ± 0.08 & 11.97 ± 0.14 μM) was identified as the most potent inhibitor for (A431, H1975, A549) cell lines.

Conclusion: The study suggested that the six derivatives showed significant therapeutic potential against different NSCLC cell lines as compared to reference standard gefitinib.

Cite this article as:

Dwivedi K. Deepak*, Agrawal Kishore Ram, Jain Sanyog and Kuche Kaushik, Design, Synthesis and Cytotoxic Studies of Novel 4-anilinoquinazoline Derivatives of Potential Agents for Non-small-cell Lung Cancer, Letters in Drug Design & Discovery 2024; 21 (10) . https://dx.doi.org/10.2174/1570180820666230505123802