Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1'H-spiro-pyridine derivatives as a new class of EGFRWt and VEGFR-2 inhibitors with apoptotic inducers.

Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1'H-spiro-pyridine derivatives were designed and synthesized based on an N-(ethyl benzoate) moiety. The structure of the designed derivatives was confirmed by different spectroscopic techniques (FT-IR and NMR) and elemental analysis and then evaluated as antiproliferative against HepG-2 and Caco-2 cell lines compared with Doxorubicin. The spiro-pyridine derivatives 5, 7, and 8 exhibited a remarkably higher activity against Caco-2 cell lines than that of other derivatives. Additionally, these derivatives exhibited activation in the Bax and suppressed Bcl-2 expression with variable degrees. Interestingly, compound 7 showed the lowest cytotoxicity value on Caco-2 cells (IC50 = 7.83 ± 0.50 µM) compared with Doxorubicin (IC50 = 12.49 ± 1.10 µM). Additionally, this compound showed activation of the Bax gene (7.508-fold) and suppressed Bcl-2 (0.194-fold) compared to untreated Caco-2 cells, as revealed by the qRT-PCR technique. Moreover, compound 7 could inhibit EGFR and VEGFR-2 with sub-micromole values of 0.124 µM and 0.221 µM compared with Erlotinib (IC50 = 0.033 µM) and Sorafenib (IC50 = 0.043 µM), respectively. Further, cell cycle and apoptosis analysis demonstrated that compound 7 promoted apoptosis by increasing the apoptosis rate from 1.92 to 42.35% and the S cell accumulation ratio from 31.18 to 42.07% compared to untreated Caco-2 cells. Finally, the most active compound 7 showed good drug-likeness and toxicity profiles. Besides, molecular docking studies were performed to determine the binding mode, which is in agreement with the in vitro results.

Development and radiosterilization of new hydrazono-quinoline hybrids as DNA gyrase and topoisomerase IV inhibitors: Antimicrobial and hemolytic activities against uropathogenic isolates with molecular docking study.

This study aimed to synthesize new potent quinoline derivatives based on hydrazone moieties and evaluate their antimicrobial activity. The newly synthesized hydrazono-quinoline derivatives 2, 5a, 9, and 10b showed the highest antimicrobial activity with MIC values ≤1.0 µg/ml against bacteria and ≤8.0 µg/ml against the fungi. Further, these derivatives exhibited bactericidal and fungicidal effects with MBC/MIC and MFC/MIC ratio ≤4. Surprisingly, the most active compounds displayed good inhibition to biofilm formation with MBEC values ranging between (40.0 ± 10.0 - 230.0 ± 31.0) and (67.0 ± 24.0 - 347.0 ± 15.0) µg/ml against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. The hemolytic assays confirmed that the hydrazono-quinoline derivatives are non-toxic with low % lysis values ranging from 4.62% to 14.4% at a 1.0 mg/ml concentration. Besides, compound 5a exhibited the lowest hemolytic activity value of ~4.62%. Furthermore, the study suggests that the hydrazono-quinoline analogs exert their antibacterial activity as dual inhibitors for DNA gyrase and DNA topoisomerase IV enzymes with IC50 values ranging between (4.56 ± 0.3 - 21.67 ± 0.45) and (6.77 ± 0.4 - 20.41 ± 0.32) µM, respectively. Additionally, the recent work advocated that compound 5a showed the reference SAL at the É£-radiation dose of 10.0 kGy in the sterilization process without affecting its chemical structure. Finally, the in silico drug-likeness, toxicity properties, and molecular docking simulation were performed. Besides, the result exhibited good oral-bioavailability, lower toxicity prediction, and lower binding energy with good binding mode rather than the positive control.

Antimicrobial evaluation of thiadiazino and thiazolo quinoxaline hybrids as potential DNA gyrase inhibitors; design, synthesis, characterization and morphological studies.

A series of thiadiazino[5,6-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives was designed and synthetized from the reaction of 2,3-dichloro-6-(morpholinosulfonyl)quinoxaline (2) with thiosemicarbazide or thiocarbohydrazide and thiourea derivatives to give nineteen quinoxaline derivatives 3-16. All the synthesized compounds were evaluated for in vitro antimicrobial potential against various bacteria and fungi strains that showed considerable antimicrobial activity against tested microorganisms. The most potent compounds 2, 7, 9, 10, 12 and 13c were exhibited bactericidal activity, in addition to fungistatic activity by dead live assay. Moreover, these compounds showed a significant result against all multi-drug resistance (MDRB) used especially compound 13c that displayed the best results with MICs of MDRB (1.95, 3.9, 2.6, 3.9 µg/mL) for stains used in this study, compared with Norfloxacin (1.25, 0.78, 1.57, 3.13 µg/mL). Also, cytotoxicity on normal cell (Vero cells ATCC CCL-81) by MTT assay was performed with lower toxicity results. Additionally, morphological studies, immunostimulatory potency and DNA gyrase inhibition assay of most active compounds was done. A molecular docking study has also been carried out to support the effective binding of the most promising compounds at the active site of the target enzyme S. aureus DNA gyrase (2XCT).