Identification of Benzothiazoles Bearing 1,3,4-Thiadiazole as Antiproliferative Hybrids Targeting VEGFR-2 and BRAF Kinase: Design, Synthesis, BIO Evaluation and In Silico Study

• Published in: Molecules (Basel, Switzerland) Switzerland), 2024-07, Vol.29 (13), p.3186
• Main Authors: Ewes, Wafaa A, Tawfik, Samar S, Almatary, Aya M, Ahmad Bhat, Mashooq, El-Shafey, Hamed W, Mohamed, Ahmed A B, Haikal, Abdullah, El-Magd, Mohammed A, Elgazar, Abdullah A, Balaha, Marwa, Hamdi, Abdelrahman
• Format: Article
• Language: English
• Subjects: Angiogenesis; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor activity; apoptosis; benzothiazoles; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; BRAF inhibition; Cancer; cell cycle analysis; Cell Line, Tumor; Cell Proliferation - drug effects; Computer Simulation; Cytotoxicity; Drug Design; Drug Screening Assays, Antitumor; Enzymes; Humans; Hydrogen bonds; Kinases; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - metabolism; Signal transduction; Sorafenib - chemistry; Sorafenib - pharmacology; Structure-Activity Relationship; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR-2 inhibition
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29133186

Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds- , , , and -demonstrated remarkable cytotoxicity, with IC values ranging from 3.58 to 15.36 μM, against three cancer cell lines. Furthermore, these compounds showed IC values of 38.77-66.22 μM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC values similar to sorafenib (0.071 and 0.194 μM, respectively). Moreover, compound caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.