2-Thioxo-3,4-dihydropyrimidine and thiourea endowed with sulfonamide moieties as dual EGFRT790M and VEGFR-2 inhibitors: Design, synthesis, docking, and anticancer evaluations.

The effectiveness of a new series of thiopyrimidine and thiourea containing sulfonamides moieties was tested on HCT-116, MCF-7, HepG2, and A549. HepG2 cell line was the one that all the new derivatives affected the most. The greatest potent compounds against the four HepG2, HCT116, MCF-7, and A549 cell lines were 8f and 8g with IC50 = 4.13, 6.64, 5.74, 6.85 µM and 4.09, 4.36, 4.22, 7.25 µM correspondingly. Compound 8g exhibited higher activity than sorafenib against HCT116 and MCF-7 but exhibited lower activity against HepG2 and A549. Moreover, compounds 8f and 8g exhibited higher activities than erlotinib on HepG2, HCT116, and MCF-7 but demonstrated lower activity on A549. The most potent cytotoxic derivatives 6f, 6g, 8c, 8d, 8e, 8f, and 8g were examined on normal VERO cell lines. Our derivatives have low toxicity on VERO cells with IC50 values ranging from 32.05 to 53.15 µM. Additionally, all compounds were assessed for dual VEGFR-2 and EGFRT790M inhibition effects. Compounds 8f and 8g were the most potent derivatives inhibited VEGFR-2 at IC50 value of 0.88 and 0.90 µM, correspondingly. As well, derivatives 8f and 8g could inhibit EGFRT790M demonstrating strongest effects with IC50 = 0.32 and 0.33 µM sequentially. Additionally, the greatest active derivatives ADMET profile was evaluated in relationship with sorafenib and erlotinib as reference agents. The data attained from docking were greatly related to that achieved from the biological testing.

New 1,3-diphenyl-1H-pyrazol-5-ols as anti-methicillin resistant Staphylococcus aureus agents: Synthesis, antimicrobial evaluation and in silico studies.

In the present work, two hybrid series of pyrazole-clubbed pyrimidine and pyrazole-clubbed thiazole compounds 3-21 from 4-acetyl-1,3-diphenyl-1H-pyrazole-5(4H)-ole 1 were synthesized as novel antimicrobial agents. Their chemical structures were thoroughly elucidated in terms of spectral analyses such as IR, 1H NMR, 13C NMR and mass spectra. The compounds were in vitro evaluated for their antimicrobial efficiency against various standard pathogen strains, gram -ive bacteria (Pseudomonas aeruginosa, Klebsiella pneumonia), gram + ive bacteria (MRSA, Bacillus subtilis), and Unicellular fungi (Candida albicans) microorganisms. The ZOI results exhibited that most of the tested molecules exhibited inhibition potency from moderate to high. Where compounds 7, 8, 12, 13 and 19 represented the highest inhibition potency against most of the tested pathogenic microbes comparing with the standard drugs. In addition, the MIC results showed that the most potent molecules 7, 8, 12, 13 and 19 showed inhibition effect against most of the tested microbes at low concentration. Moreover, the docking approach of the newly synthesized compounds against DNA gyrase enzyme was performed to go deeper into their molecular mechanism of antimicrobial efficacy. Further, computational investigations to calculate the pharmacokinetics parameters of the compounds were performed. Among them 7, 8, 12, 13 and 19 are the most potent compounds revealed the highest inhibition efficacy against most of the tested pathogenic microbes comparing with the standard drugs.