Synthesis, ADMET predictions, molecular docking studies, and in-vitro anticancer activity of some benzoxazines against A549 human lung cancer cells

• DOI: 10.1515/jbcpp-2020-0433
• Publication Date: 2021-07-02T16:45:59Z
• Authors: Melanny Ika Sulis...; Retno Widyowati; Galih Satrio Putra; Tutuk Budiati; Katsuyoshi Matsunami
• Keywords: 0303 health sciences; Lung Neoplasms; Molecular Structure; RS1-441 Pharmacy and materia medica; RS200-201 Pharmaceutical dosage forms; 610; Antineoplastic Agents; R Medicine; Benzoxazines; 3. Good health; ErbB Receptors; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; 615; Cell Line, Tumor; Spectroscopy, Fourier Transform Infrared; Humans; Drug Screening Assays, Antitumor; RS Pharmacy and materia medica; Cell Proliferation

Abstract

Objectives This study aims to synthesize a series of benzoxazines (1–5) to be examined as an epidermal growth factor receptor (EGFR) inhibitor by in-silico study. The overexpression of EGFR causes the growth of normal lung cells to become uncontrollable, which may lead to cancer formation. We also conducted the absorption, distribution, metabolism, excretions and toxicity (ADMET) properties evaluation and also examined in vitro anticancer assay on human lung cancer cells line, which is A549.

Methods Benzoxazines (1–5) were synthesized by reacting anthranilic acid and benzoyl chlorides. The structures of the compounds were determined with 1H, 13C-NMR, HRMS, UV and FT-IR spectrometric methods. Prediction of ADMET was using online pkCSM, and the molecular docking studies were using MVD with EGFR-TKIs as the target (PDB ID: 1M17). In vitro assay of anticancer activity was performed by MTT assay.

Results Compounds 1–5 were successfully synthesized in good yields (71–84%). The ADMET prediction showed that benzoxazines are able to be absorbed through GIT, metabolized by CYP 450, and not hepatotoxic. The title compounds have a greater Moldock Score than Erlotinib, and 3 has the highest activity against A549 compared with other benzoxazines, IC50=36.6 μg/mL.

Conclusions Compound (3) more active as anticancer against Human cancer cells line compared with other benzoxazines.