Development, synthesis and preclinical evaluation of naringenin and its semi-synthetic derivatives in postmenopausal osteoporosis.

Abstract

In this study, a derivative of Naringenin (NRG-D), a naturally occurring flavonoid was designed by modifying its structure at the 4th carbonyl position, guided by structure-activity relationship analysis. The binding affinity of NRG-D for bone marker proteins was initially assessed through in-silico studies. The therapeutic effects of both NRG and NRG-D were then evaluated in a rat model of postmenopausal osteoporosis induced by vinyl cyclohexene diepoxide (VCD). Female Wistar rats received VCD (160 mg/kg) for 15 days, followed by a 30-day drug-free period. Animals were subsequently divided into seven groups: control, VCD, alendronate, NRG and NRG-D (both at 10 and 25 mg/kg), administered for four weeks. Serum biochemical analyses were conducted to evaluate bone turnover markers, and micro-computed tomography (microCT) and histopathological assessments were performed on femur bones and lumbar vertebrae. The findings revealed that both NRG and NRG-D significantly attenuated osteoporotic changes, evidenced by a reduction in the bone resorption marker RANKL and an increase in the bone formation marker BALP. Additionally, treated animals exhibited improved bone microarchitecture and repaired trabecular bone structures. These results suggest that NRG and its derivative NRG-D exert beneficial bone regenerative effects and may offer a promising phytochemical-based therapeutic approach for the treatment of postmenopausal osteoporosis.Naringenin (NRG), a naturally occurring flavonoid, possesses potent antioxidant and anti-inflammatory properties and has shown potential benefits in managing osteoporosis. In this study, a derivative of NRG (NRG-D) was designed by modifying its structure at the 4th carbonyl position, guided by structure-activity relationship analysis. The binding affinity of NRG-D for bone marker proteins was initially assessed through in-silico studies. The therapeutic effects of both NRG and NRG-D were then evaluated in a rat model of postmenopausal osteoporosis induced by vinyl cyclohexene diepoxide (VCD). Female Wistar rats received VCD (160 mg/kg) for 15 days to simulate postmenopausal conditions, followed by a 30-day drug-free period. Animals were subsequently divided into seven groups: control, VCD, alendronate, NRG (10 and 25 mg/kg), and NRG-D (10 and 25 mg/kg), with treatment administered for four weeks. Serum biochemical analyses were conducted to evaluate bone turnover markers, and micro-computed tomography (microCT) and histopathological assessments were performed on femur bones and lumbar vertebrae. The findings revealed that both NRG and NRG-D significantly attenuated osteoporotic changes, evidenced by a reduction in the bone resorption marker RANKL and an increase in the bone formation marker BALP. Additionally, treated animals exhibited improved bone microarchitecture and repaired trabecular bone structures. These results suggest that NRG and its derivative NRG-D exert beneficial bone regenerative effects and may offer a promising phytochemical-based therapeutic approach for the treatment of postmenopausal osteoporosis.