A series of novel 3-cyanopyridone/pyrazoline hybrids (21–30) exhibiting dual inhibition against EGFR and BRAF^V600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI₅₀ values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAF^V600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAF^V600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAF^V600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.

Osteoarthritis (OA) is a degenerative joint disease, characterized by infiltration of monocytes into the synovial joint which promotes inflammation, stiffness, joint swelling, cartilage degradation and further bone destruction. The leaves of Ocimum forskolei have been used for inflammation-related disease management in traditional medicine. Additionally, the downregulation of NF-κB and the MMP/TIMP-1 ratio has been shown to protect against OA. The LC-HR-MS metabolic analysis of Ocimum yielded 19 putative compounds, among which ursolic acid (UA) was detected. Ursolic acid possesses significant anti-inflammatory effects and has been reported to downregulate oxidative stress and inflammatory biomarkers. It was tested on rats in a model of intra-articular carrageenan injection to investigate its efficacy on osteoarthritis progression. The UA emulgel exerted chondroprotective, analgesic and local anaesthetic efficacies confirmed via histopathological investigation and radiographical imaging. A network pharmacology followed by molecular docking highlighted TNF-α, TGF-β and NF-κB as the top filtered genes. Quantitative real-time PCR analysis showed that UA significantly attenuated serum levels of TNF-α, IL-1β, NF-κB, MMP-9/TIMP-1 and elevated levels of TGF-β. Taken together, these results suggest that UA could serve as a functional food-derived phytochemical with a multi-targeted efficacy on progression of OA, regulating the immune and inflammatory responses, particularly, attenuating chondrocytes degeneration via suppression of NF-κB and MMP-9/TIMP-1. Accordingly, UA might be a promising alternative to conventional therapy for safe, easily applicable and effective management of OA.

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAF^V600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI₅₀ values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI₅₀ = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAF^V600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAF^V600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects.

Many studies have been carried out to find synthetic pathways to nicotinonitriles (3-cyanopyridines) and their analogs, which has resulted in a substantial amount of knowledge on their biological, therapeutic, and medical characteristics. That possess diverse important biological activities such as anti oxidant anti inflammatory and anti cancer. Some of nicotinonitrile derivatives have emerged as marketed drugs such as bosutinib, milrinone, neratinib, and olprinone. So this ring has attracted alloy of attention in the last decade. Many researchers tried to to focus on the development of this ring to improve its biological activities and to discover other new activities. In this review, we discuss the recently synthesized nicotinonitrile-based hybrids that possess important biological activity and will be useful for drug discovery and development.