Benzofuran-dihydropyridine hybrids: A new class of potential bone anabolic agents. Issue 24 (15th December 2017)

• Record Type: Journal Article
• Authors: Modukuri, Ram K.; Choudhary, Dharmendra; Gupta, Sampa; Rao, K. Bhaskara; Adhikary, Sulekha; Sharma, Tanuj; Siddiqi, Mohammad Imran; Trivedi, Ritu; Sashidhara, Koneni V.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 24(2017)
• Page Start: 6450
• Page End: 6466
• Publication Date: 2017-12-15
• Subjects: BMP2 bone morphogenic protein-2 -- ALP alkaline phosphatase -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- qRT-PCR Quantitative Real-Time Polymerase Chain Reaction -- RUNX2 Runt-related transcription factor 2 -- ALP alkaline phosphatase -- COL1 collagen type-I -- Osx osterix -- BV/TV trabecular bone volume/tissue volume -- Tb.N trabecular number; Benzofuran-dihydropyridine hybrids -- Alkaline phosphatase -- Bone morphogenic protein-2 -- Molecular hybridization; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.10.018
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of novel benzofuran-dihydropyridine hybrids were designed by molecular hybridization approach and evaluated for bone anabolic activities. Among the screened library, ethyl 4-(7-( sec -butyl)-2-(4-methylbenzoyl)benzofuran-5-yl)-2-methyl-5-oxo-1, 4, 5, 6, 7, 8-hexahydroquinoline-3-carboxylate (compound21 ) significantly enhanced the ALP production and mineralized nodule formation, which are primary requisites in the process of in vitro osteogenesis. Oral administration of compound21 at 10 mg.kg −1 day −1 for two weeks led to restoration of trabecular bone microarchitecture in drill hole fracture model by significantly increasing BV/TV and Tb.N. Furthermore, histological and molecular studies showed compound21 triggering the new bone regeneration in a drill hole defect site by increasing BMP expression. Furthermore, molecular modeling studies were performed to gain insight into the binding approach, which revealed that both benzofuran and dihydropyridine moieties are essential to show similar binding interactions to fit into the active site of BMP2 receptor, an important target of the osteogenic agents. Our results suggest that compound21 stimulates BMP2 synthesis in osteoblast cells that promotes new bone formation (∼40%) at the fracture site which helps in shorten the healing period.