Discovery of (S)-flurbiprofen-based novel azine derivatives as prostaglandin endoperoxide synthase-II inhibitors: Synthesis, in-vivo analgesic, anti-inflammatory activities, and their molecular docking.

The anti-inflammatory and analgesic drugs currently used are associated with several adverse effects and found to be highly unsafe for long-term use. Currently, nineteen novel bis-Schiff base derivatives (1-19) of flurbiprofen have been designed, prepared and assessed for in-vivo analgesic, anti-inflammatory and in vivo acute toxicity evaluation. The structures of the acquired compounds were deduced through modern spectroscopic techniques including HR-ESI-MS, 13C-, and 1H NMR. Amongst the series, compounds 7, 9, and 10 attributed potent activities with 93.89, 92.50, and 90.47% decreased edema, respectively compared to flurbiprofen (90.01%), however, compounds 11 and 15 exhibited significant activity of 90.00% decrease. Out of them, fourteen compounds (1-6, 8, 12-14, and 16-19) displayed good activity in the range of 68.96-86.95%. In case of an analgesic study, all the derivatives significantly (p 0.001) increased the pain threshold time particularly compound 7 had the best analgesic effect (24 ± 2.08 s) in comparison with flurbiprofen (21.66 ± 2.02 s) using hot plate test. Similarly, in the acetic acid-induced writhing test, compound 7 determined a potent inhibitory effect (60.47 %) close to flurbiprofen (59.28%). All the synthesized derivatives were found safe up to the dose of 30 mg/kg, in acute toxicity study. On a molecular scale, the synthesized compounds were modeled through a ligand-based pharmacophore study and molecular docking to have insight into the different possible interactions leading to high inhibition levels against the COX-2 enzyme.

Onosma hispidum L. extract reverses hyperlipidemia, hypertension, and associated vascular dysfunction in rats.

Onosma hispidum.L (O. hispidum) belongs to the family Boregineacea. A preliminary study and its medicinal use suggested its role in the management of hyperlipidemia. The present study aimed to assess the effect of methanolic root extract of O. hispidum in hyperlipidemia and associated vascular dysfunction. Oral administration of O. hispidum crude extract (Oh. Cr) to tyloxopol and high fat diet-induced hyperlipidemic Sprague-Dawley rats for 10 and 28 days significantly reduced total triglycerides and cholesterol (p < 0.001), compared to hyperlipidemic rats. Oh. Cr 250 mg/kg orally treated rats significantly (p < 0.001) reduced both the total body weight and atherogenic index in tylaxopol and HFD rats. In HMG-CoA assay, the inhibition of the enzyme was significant in Oh.Cr (250 mg/kg) treated group. Histopathological studies indicated that the group treated with Oh.Cr 250 mg/kg/day showed regular morphology of aortic intima, media and adventitia, and improved the endothelial damage. To investigate the vascular dysfunction, isolated rat aorta rings from all groups were pre-contracted with 1 µM phenylephrine (PE), and the effect of acetylcholine (Ach) was monitored. In the aorta isolated from Oh.Cr (50 mg/kg) treated group, Ach completely relaxed the PE-induced contraction with EC50 value of 0.05 µg/mL 0.015 (0.01-0.2) compared to the hyperlipidemic control group (<30% relaxation). In atorvastatin (10 mg/kg) treated rat aorta, Ach showed 50% relaxation. The Oh.Cr extract also reduced (105.92 ± 1.14 to 66.63 ± 0.85 mmHg) mean arterial pressure in hyperlipidemic hypertensive rats. These findings suggest that extract of O. hispidum is an effective remedy for hypercholesterolemia, and hypertriglyceridemia, which acts through inhibition of HMG-CoA and improving vascular dysfunction.

Novel Polyhydroquinoline-Hydrazide-Linked Schiff's Base Derivatives: Multistep Synthesis, Antimicrobial, and Calcium-Channel-Blocking Activities.

Polyhydroquinoline (PHQ) are the unsymmetrical Hantzsch derivatives of 1,4-dihydropyridines with several biological applications. In this work, twenty-five (3-27) new Schiff's base derivatives of polyhydroquinoline hydrazide were synthesized in excellent to good yields by a multi-component reaction. The structures of the synthesized products (1-27) were deduced with the help of spectroscopic techniques, such as 1H-, 13C -NMR, and HR-ESI-MS. The synthesized products (1-27) were tested for their antibacterial and in vitro calcium -channel-blocking (CCB) potentials using the agar-well diffusion method, and isolated rat aortic ring preparations, respectively. Among the series, sixteen compounds were found to inhibit the growth of Escherichia coli and Enterococcus faecalis. Among them, compound 17 was observed to be the most potent one at a dose 2 µg/mL, with an 18 mm zone of inhibition against both bacteria when it was compared with the standard drug amoxicillin. Eight compounds showed CCB activity of variable potency; in particular, compound 27 was more potent, with an EC50 value of 0.7 (0.3-1.1) µg/mL, indicating their CCB effect.