Design, synthesis and biological evaluation of new quinazolinone-benzopyran-indole hybrid compounds promoting osteogenesis through BMP2 upregulation

• Published in: European journal of medicinal chemistry Vol. 244; p. 114813
• Main Authors: Sardar, Anirban, Ansari, Alisha, Gupta, Sampa, Sinha, Shradha, Pandey, Shubham, Rai, Divya, Kumar, Mukesh, Bhatta, Rabi Sankar, Trivedi, Ritu, Sashidhara, Koneni V.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.12.2022; Elsevier
• Subjects: Benzopyran; Bone anabolism; Bone morphogenetic protein; Chemistry, Medicinal; Life Sciences & Biomedicine; Molecular hybridization; Osteoblast; Pharmacology & Pharmacy; Science & Technology; Osteoblast; Molecular hybridization; Benzopyran; Bone morphogenetic protein; Bone anabolism; ACTIVATED PROTEIN-KINASE; OSTEOBLAST DIFFERENTIATION; ALKALINE-PHOSPHATASE; NATURAL-PRODUCTS; OSTEOPOROSIS; DISCOVERY; ROMOSOZUMAB; POSTMENOPAUSAL WOMEN; BONE MASS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114813

In search of novel osteogenic entities, a series of twenty-seven quinazolinone-benzopyran-indole hybrids were designed and synthesized using molecular hybridization approach. All the compounds were scrutinized for their osteogenic potential, primarily based on alkaline phosphatase assay as one of the major anabolic markers. From the primary screening, four osteogenic compounds were sorted from the series and were found nontoxic to the osteoblasts. Further, increased osteoblast differentiation and osteogenic mRNA upregulations suggest compound 47 as the most potent osteoanabolic agent. Immunoblot and ELISA analysis demonstrated that compound 47 promotes osteogenesis via RUNX2 and BMP2 mediated non-canonical p38 pathway. In vivo studies in BALB/c mice inferred that compound 47 stimulates bone anabolism as evident from histological and gene expression studies at 5 mg. kg−1. day−1 dose. Furthermore, structural activity relationship (SAR) and pharmacokinetic studies suggest compound 47 as a BMP2 upregulator and a potential bone anabolic lead for combating future bone metabolic disorders. [Display omitted] •Novel Quinazolinone-Benzopyran-Indole Hybrids were synthesized.•Compounds 26, 42, 45 and 47 exhibited significant bone anabolic activity.•Mechanistically 47, exerting its bioactivity through BMP2 upregulation.•Compound 47, showed increase in osteogenic markers and rate of bone formation.