Synthesis and evaluation of larvicidal efficacy against C. pipiens of some new heterocyclic compounds emanated from 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide.

Several infectious diseases are transmitted and spread by mosquitoes, and millions of people die annually from them. The mosquito, Culex pipiens is a responsible for the emergence of various Virus in Egypt. So, we devote our work to evaluate the larvicidal efficacy against C. pipiens of some new heterocyclic compounds containing chlorine motifs. The implementation was emanated from using 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide (3) as scaffold to synthesize some new heterocyclic compounds. The structures of the synthesized compounds were interpreted scrupulously by spectroscopic and elemental analyses. Thereafter, the larvicidal activity against C. pipiens of thirteen synthesized compounds was estimated. Noteworthy, cyanoacetohydrazide derivative 3 and 3-iminobenzochromene derivative 12 showed a fabulous potent efficacy with LC50 equal to 3.2 and 3.5 ppm against C. pipiens, respectively, and are worth being further evaluated in the field of pest control.

New pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors: design, green synthesis, potential anti-proliferative activity and P-glycoprotein inhibition.

In this study, four series of new pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized with both green and conventional methods. All the synthesized candidates were chemically confirmed using spectroscopic methods, and the DFT of the reaction mechanism was illustrated. The anti-proliferative activity of the synthesized compounds was evaluated against NCI 60 cancer cell lines. Two compounds (15 & 16) exhibited excellent broad-spectrum cytotoxic activity in NCI 5-log dose assays against the full 60-cell panel with GI50 values ranging from 0.018 to 9.98 µM. Moreover, the enzymatic assessment of the most active derivatives 4, 15, and 16 against EGFR tyrosine kinase showed significant inhibitory activities with IC50 of 0.054, 0.135, and 0.034 µM, respectively. The quantitative real-time PCR for the P-glycoprotein effect of compounds 15 and 16 was examined and illustrated the ability to inhibit the P-glycoprotein by 0.301 and 0.449 fold in comparison to the control. Mechanistic study using reversal activity in MDA-MB-468 cell line revealed the effect of both compounds 15 and 16 cytotoxicity against DOX/MDA-MB-468 with IC50 = 0.267 and 0.844 µM, respectively. Additionally, compound 16 was found to induce cell cycle arrest at the S phase with a subsequent increase in pre-G cell population in MDA-MB-468 cell line. It also increased the percentage of apoptotic cells in a time-dependent manner. Moreover, a molecular docking study was carried out to explain the target compounds' potent inhibitory activity within the EGFR binding site.

Rational design and eco-friendly one-pot multicomponent synthesis of novel ethylidenehydrazineylthiazol-4(5H)-ones as potential apoptotic inducers targeting wild and mutant EGFR-TK in triple negative breast cancer.

A novel series of ethylidenehydrazineylthiazol-4(5H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a, having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes.

New 1,3,4-thiadiazoles as potential anticancer agents: pro-apoptotic, cell cycle arrest, molecular modelling, and ADMET profile.

A series of novel 1,3,4-thiadiazoles was synthesized via the reaction of N-(5-(2-cyanoacetamido)-1,3,4-thiadiazol-2-yl)benzamide (3) with different carbon electrophiles and evaluated as potential anticancer agents. The chemical structures of these derivatives were fully elucidated using various spectral and elemental analyses. Out of 24 new thiadiazoles, derivatives 4, 6b, 7a, 7d, and 19 have significant antiproliferative activity. However, derivatives 4, 7a, and 7d were toxic to the normal fibroblasts, and therefore were excluded from further investigations. Derivatives 6b and 19 with IC50 at less than 10 µM and with high selectivity were selected for further studies in breast cells (MCF-7). Derivative 19 arrested the breast cells at G2/M probably through inhibition of CDK1, while 6b significantly increased the sub-G1 percent of cells probably through induction of necrosis. These results were confirmed by the annexin V-PI assay where 6b did not induce apoptosis and increased the necrotic cells to 12.5%, and compound 19 significantly increased the early apoptosis to 15% and increased the necrotic cells to 15%. Molecular docking showed that compound 19 was like FB8, an inhibitor of CDK1, in binding the CDK1 pocket. Therefore, compound 19 could be a potential CDK1 inhibitor. Derivatives 6b and 19 did not violate Lipinski's rule of five. In silico studies showed that these derivatives have a low blood-brain barrier penetration capability and high intestinal absorption. Taken together, derivatives 6b and 19 could serve as potential anticancer agents and merit further investigations.

Annulated pyrazole derivatives as a novel class of urokinase (uPA) inhibitors: Green synthesis, anticancer activity, DNA-damage evaluation, and molecular modelling study.

Different series of annulated pyrazole derivatives were designed, synthesized via both green and traditional methods, and structurally characterized. In vitro uPA evaluation, antiproliferative activities and DNA binding damage was studied in this work. Thus, all the synthesized compounds were evaluated against three types of cancer cell lines; HepG-2, HCT-116, and MCF-7 cancer cell lines in addition to normal cell line WI38. Compounds 11, 20, 21, 23 and 24 displayed the most significant antiproliferative activity with IC50 ranging between 4.42 ± 0.59 µM to 11.05 ± 0.95 µM against HepG-2, HCT-116, and MCF-7 cancer cell lines compared to the reference drug, doxorubicin. Thus compound 11 exhibited cytotoxic activity with IC50 8.58 µM, 9.22 µM and 7.53 µM, compound 20 showed IC50 9.99 µM, 6.72 µM and 6.87 µM, analogue 21 displayed IC50 10.80 µM, 7.90 µM and 9.16 µM, compound 23 showed IC50 4.82 µM, 11.05 µM and 4.42 µM and derivative 24 exhibited potent cytotoxic activity with IC50 7.44 µM, 5.18 µM and 8.22 µM against HepG-2, HCT-116, and MCF-7 cancer cell lines, respectively. Additionally, compounds 11, 21, 23 and 24 showed significant uPA inhibitory activity with IC50 27.28 µM, 29.36 µM, 11.73 µM, and 7.96 µM respectively. Moreover, HCT-116 cell lines were treated with both compounds 23 and 24 that remarkably showed a high score of DNA binding damage. Mechanistic studies demonstrated the apoptotic activity of the most active tricyclic heteroaromatic analogue 24 on HCT-116 cancer cells by inducing a strong S phase cell cycle arrest suggesting that the mechanism of its antiproliferative activity may be through uPA inhibition. Finally, deeper insight illustrated that the hit compounds exhibited characteristic binding interactions in the active site of uPA that are required in the S pocket, which are important for activity Arg 217, Gly 219, and Ser 190.

The Reformatsky analogous reaction for the synthesis of novel ß-thioxoesters via using aroyl isothiocyanates under solvent-free ball milling and conventional conditions.

The classical Reformatsky reaction, initially described in 1887, is considered one of the most useful ways of forming C-C bonds. The target of this work includes improving the Reformatsky reaction between aroyl isothiocyanates and α-haloesters using metallic zinc to form ß-thioxoesters (3-11). In this procedure, a new metal-mediated carbon-carbon linkage is formed with the formation of an organozinc halide and decomposition due to the presence of dilute acid, affording a good yield of the desired product via conventional techniques and ball milling. The Reformatsky reaction requires no solvent and no inert gases.