New LPA1 receptor modulators: Design, synthesis, in-silico, and anticancer studies of triazole and oxadiazole analogs

•LPA1 receptors are overexpressed in breast cancer and activated by Lysophosphatidic acid (LPA).•Blocking the LPA-LPA1 signaling by small molecules may benefit breast cancer therapy.•New compounds BI-4 and OX-1 inhibited breast carcinoma cells proliferation, migration, and induced apoptosis.•BI-4 and OX-1 inhibit LPA1 and angiogenesis gene expression, making them potential lead compounds for breast carcinoma treatment. Lysophosphatidic acid (LPA) is a bioactive signaling molecule that activates LPA1 receptors, which are over expressed in breast cancer. This signaling cascade promotes cancer cell proliferation, survival, metastasis, and angiogenesis. Small molecules that block LPA1 signaling could benefit breast cancer therapy. Novel 1,2,4-triazoles and 1,3,4-oxadiazoles conjugates of benzimidazole/oxazole/thiazole were designed as LPA1 receptor inhibitors, synthesized, and the in-vitro anticancer activity was examined through breast carcinoma cells (MCF-7) by MTT assay. The compounds that reduced the proliferation of MCF-7 cells were further evaluated for their effects on apoptosis, migration, and angiogenesis at IC50 concentration. Suppression of LPA1 protein and gene expression was analyzed by western blot and qRT-PCR techniques. In addition, ligand interactions towards protein and ligand-receptor stability were predicted by molecular interaction studies and molecular trajectory analysis, respectively. The compounds BI-4 and OX-1 exhibited varying levels of cytotoxicity, with IC50 values of 138 μM and 83.25 μM, respectively. They were able to effectively reduce migration and apoptosis as confirmed by AO/EB staining assay. In addition, these compounds were found to significantly reduce the protein and gene expression of LPA1 and angiogenesis genes (Angiogenin-II and Vegf) in MCF-7 cells. Synthesized ligands also showed interactions with the LPA1 receptor and demonstrated good stability in MD simulation. Overall, BI-4 and OX-1 hold promise as potential lead compounds for further exploration of the role of LPA1 receptors in the management of breast carcinoma. Strategy For Design of Novel LPA1 Receptor Modulators For Breast Cancer Therapy [Display omitted]