Eco-sustainable Synthesis and Potential Efficiency of Some Novel N-containing Heterocyclic Derivatives as Insecticidal and Photosensitizing Agents Against Musca domestica L.

The rising application of conventional synthetic insecticides develops resistant populations of houseflies; therefore, using new chemical agents with different modes of action is essential to overcome this problem. The mechanical grinding technique was used as a green method, to synthesize the tested compounds because it is a more facile work-up and high-yield economy, simplicity and solvent-free than conventional thermal technique. Various methods were employed to synthesize new heterocycles containing anthracene (a photosensitizing agent) from chalcone 3, a building block material such as the preparation of the pyrazole derivatives 4-7, isoxazole derivative 8, pyrimidines 9-11, and oxirane derivative 12. The novel synthesized compounds were analyzed by FT-IR, 1H-NMR, 13C-NMR spectra, and elemental analysis. Herein, the toxicity of the anthracene derivatives was assessed against Musca domestica larvae and adults in different conditions to demonstrate the effect of various inserted moieties on the efficiency of tested compounds. Furthermore, the influence of sunlight on the toxicity of anthracene was studied in dark and sunlight tests against adult houseflies. Moreover, these compounds diminished the total protein and lipids contents while significantly influencing the antioxidant enzymes activities of M. domestica adults. Structure-activity relationships demonstrated the role of each moiety on the toxicity of compounds.

Design, synthesis, and SAR studies of novel 4-methoxyphenyl pyrazole and pyrimidine derivatives as potential dual tyrosine kinase inhibitors targeting both EGFR and VEGFR-2.

Guided by the pharmacophoric features of both EGFR and VEGFR-2 antagonists, two novel series of 4-methoxyphenyl pyrazole and pyrimidine derivatives [(4a-c) and (5a-c, 6, 7a-c, 8, 9, 10, 11a,c, 12, 13a-c, 14a-c, and 15a,b)], respectively, were designed and synthesized as dual EGFR/VEGFR-2 inhibitors. Interestingly, compound 12 showed very strong antiproliferative effects towards all the five studied cell lines (HepG-2, MCF-7, MDA-231, HCT-116, and Caco-2) with IC50 values of 3.74, 7.81, 4.85, 2.96, and 9.27 µM, respectively. Also, it achieved the highest inhibitory activities against both EGFR and VEGFR-2 as well (IC50 = 0.071 and 0.098 µM) compared to the two reference drugs, erlotinib (IC50 = 0.063 µM) and sorafenib (IC50 = 0.041 µM), respectively. Moreover, four compounds (4a, 7a, 7c, and 12) were selected for further evaluation through cell cycle analysis and Annexin V-based flow cytometry assay in the HepG-2 cell line. In addition, deep computational studies including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions were performed for the designed compounds to evaluate the prospective drug candidates. Finally, analyzing the structure-activity relationship (SAR) of the new derivatives gives us a lot of interesting promising results which could help medicinal chemists to design more potent drug candidates soon as well.