Small size silver nanoparticles loaded with glycoside rich portion of Boerhavia Diffusa Linn. promotes wound healing: in-silico and in-vivo studies.

Silver nanoparticles (Ag-NPs) are increasingly used in various fields, including medicine, owing to their unique physicochemical properties. Due to their smaller size, the contact with biological components is increased, and consequently, it performs better as an antibacterial and antimicrobial. In this study, the authors have focused on the synthesis of small-sized spherical silver nanoparticles (Ag-NPs) by a chemical reduction method using two different capping agents and concentrations of AgNO3 as a precursor. Additionally, various amounts of Glycoside Rich Portion (GRP) isolated from the roots of Boerhaavia diffusa L. were loaded onto synthesised Ag-NPs. Punarnavoside, a glycoside found in GRP, has been reported to have antifibrinolytic properties. The docking study of punarnavoside present in GRP has shown good binding affinity with various antifibrinolytic targets. The surface plasmon resonance band, particle size, polydispersity index, and zeta potential values have been used to analyse the interaction and kind of bonding between GRP and Ag-NPs. A batch of trisodium citrate (TSC)-capped Ag-NPs loaded with 0.1 ml of 1% GRP solution showed particle size smaller than 50 nm with a stable zeta potential value of - 55.3 mV. Fourier transform infrared spectroscopic results showed CO and C-O bonds in GRP interacted with Ag-NPs. A batch of TSC-capped GRP-loaded Ag-NPs (1%)-based gel was developed using carbopol as a polymer. The TSC-capped GRP-loaded silver nanogel had greater wound closure in rats, as observed during the histopathological studies in the excision wound model. The antifibrinolytic activity of GRP, when coupled with the antibacterial and bactericidal properties of silver, demonstrated an increased wound healing effect.

Alleviating CYP and hERG liabilities by structure optimization of dihydrofuran-fused tricyclic benzo[d]imidazole series - Potent, selective and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-2.

In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106 mg/kg).

Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1.

This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3 mg/kg in guinea pig.