Therapeutic potential of natural products in inflammation: underlying molecular mechanisms, clinical outcomes, technological advances, and future perspectives.

Chronic inflammation is a common underlying factor in many major diseases, including heart disease, diabetes, cancer, and autoimmune disorders, and is responsible for up to 60% of all deaths worldwide. Metformin, statins, and corticosteroids, and NSAIDs (non-steroidal anti-inflammatory drugs) are often given as anti-inflammatory pharmaceuticals, however, often have even more debilitating side effects than the illness itself. The natural product-based therapy of inflammation-related diseases has no adverse effects and good beneficial results compared to substitute conventional anti-inflammatory medications. In this review article, we provide a concise overview of present pharmacological treatments, the pathophysiology of inflammation, and the signaling pathways that underlie it. In addition, we focus on the most promising natural products identified as potential anti-inflammatory therapeutic agents. Moreover, preclinical studies and clinical trials evaluating the efficacy of natural products as anti-inflammatory therapeutic agents and their pragmatic applications with promising outcomes are reviewed. In addition, the safety, side effects and technical barriers of natural products are discussed. Furthermore, we also summarized the latest technological advances in the discovery and scientific development of natural products-based medicine.

Design and synthesis of new spirooxindole candidates and their selenium nanoparticles as potential dual Topo I/II inhibitors, DNA intercalators, and apoptotic inducers.

A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines. In situ selenium nanoparticles (SeNPs) for some derivatives were synthesised. The targets and the SeNP derivatives were examined for their cytotoxicity towards five cancer cell lines. The inhibitory potencies of the best members against Topo I and Topo II were also assayed besides their DNA intercalation abilities. Compound 7d NPs exhibited the best inhibition against Topo I and Topo II enzymes with IC50 of 0.042 and 1.172 µM, respectively. The ability of compound 7d NPs to arrest the cell cycle and induce apoptosis was investigated. It arrested the cell cycle in the A549 cell at the S phase and prompted apoptosis by 41.02% vs. 23.81% in the control. In silico studies were then performed to study the possible binding interactions between the designed members and the target proteins.

A new wave of dual Topo I/II inhibitors was designed and synthesised via the hybridisation of spirooxindoles and pyrimidines.In situ selenium nanoparticles (SeNPs) for some derivatives were synthesised.Cytotoxicity, Topo I and Topo II inhibitory assays, and DNA intercalation abilities were evaluated.Compound 7d NPs showed the best Topo I and Topo II inhibition.Cell cycle arrest, apoptosis induction, and molecular docking studies were performed.

Scaffold Repurposing of In-House Small Molecule Candidates Leads to Discovery of First-in-Class CDK-1/HER-2 Dual Inhibitors: In Vitro and In Silico Screening.

Recently, multitargeted drugs are considered a potential approach in treating cancer. In this study, twelve in-house indole-based derivatives were preliminary evaluated for their inhibitory activities over VEGFR-2, CDK-1/cyclin B and HER-2. Compound 15l showed the most inhibitory activities among the tested derivatives over CDK-1/cyclin B and HER-2. Compound 15l was tested for its selectivity in a small kinase panel. It showed dual selectivity for CDK-1/cyclin B and HER-2. Moreover, in vitro cytotoxicity assay was assessed for the selected series against nine NCI cell lines. Compound 15l showed the most potent inhibitory activities among the tested compounds. A deep in silico molecular docking study was conducted for compound 15l to identify the possible binding modes into CDK-1/cyclin B and HER-2. The docking results revealed that compound 15l displayed interesting binding modes with the key amino acids in the binding sites of both kinases. In vitro and in silico studies demonstrate the indole-based derivative 15l as a selective dual CDK-1 and HER-2 inhibitor. This emphasizes a new challenge in drug development strategies and signals a significant milestone for further structural and molecular optimization of these indole-based derivatives in order to achieve a drug-like property.

Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents.

Repositioning of the antipsychotic drug trifluoperazine for treatment of glioblastoma, an aggressive brain tumor, has been previously suggested. However, trifluoperazine did not increase the survival time in mice models of glioblastoma. In attempt to identify an effective trifluoperazine analog, fourteen compounds have been synthesized and biologically in vitro and in vivo assessed. Using MTT assay, compounds 3dc and 3dd elicited 4-5 times more potent inhibitory activity than trifluoperazine with IC50 = 2.3 and 2.2 µM against U87MG glioblastoma cells, as well as, IC50 = 2.2 and 2.1 µM against GBL28 human glioblastoma patient derived primary cells, respectively. Furthermore, they have shown a reasonable selectivity for glioblastoma cells over NSC normal neural cell. In vivo evaluation of analog 3dc confirmed its advantageous effect on reduction of tumor size and increasing the survival time in brain xenograft mouse model of glioblastoma. Molecular modeling simulation provided a reasonable explanation for the observed variation in the capability of the synthesized analogs to increase the intracellular Ca2+ levels. In summary, this study presents compound 3dc as a proposed new tool for the adjuvant chemotherapy of glioblastoma.

Hit discovery of 4-amino-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide: A novel EGFR inhibitor from a designed small library.

Searching for hit compounds within the huge chemical space resembles the attempt to find a needle in a haystack. Cheminformatics-guided selection of few representative molecules of a rationally designed virtual combinatorial library is a powerful tool to confront this challenge, speed up hit identification and cut off costs. Herein, this approach has been applied to identify hit compounds with novel scaffolds able to inhibit EGFR kinase. From a generated virtual library, six 4-aryloxy-5-aminopyrimidine scaffold-derived compounds were selected, synthesized and evaluated as hit EGFR inhibitors. 4-Aryloxy-5-benzamidopyrimidines inhibited EGFR with IC50 1.05-5.37 µM. Cell-based assay of the most potent EGFR inhibitor hit (10ac) confirmed its cytotoxicity against different cancerous cells. In spite of no EGFR, HER2 or VEGFR1 inhibition was elicited by 4-aryloxy-5-(thio)ureidopyrimidine derivatives, cell-based evaluation suggested them as antiproliferative hits acting by other mechanism(s). Molecular docking study provided a plausible explanation of incapability of 4-aryloxy-5-(thio)ureidopyrimidines to inhibit EGFR and suggested a reasonable binding mode of 4-aryloxy-5-benzamidopyrimidines which provides a basis to develop more optimized ligands.