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.

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.

Diversity oriented synthesis and SAR studies of new quinazolinones and related compounds as insecticidal agents against Culex pipiens L. Larvae and associated predator.

The ongoing study reports the synthesis, spectroscopic analyses and larvicidal efficacy of novel series of quinazolinone derivatives and related compounds. The structures of the products were confirmed relied on their analytical and spectral data (IR, 1H NMR, and 13C NMR). The spectral documentation promoted the successful isolation of the desirable compounds. The insecticidal activities of the synthesized compounds were assessed against laboratory and field strains of Culex pipiens larvae and a predator from the same ecological niche, Cybister tripunctatus. The results revealed that most of the tested compounds showed high potencies against lab strain of C. pipiens larvae with low resistance ratios in filed strain. In particular, compounds 15, 6 and 16 showed low LC50 values, 0.094, 0.106, 0.129 (µg/mL), respectively against lab strain of C. pipiens larvae. The present study also explored the toxicity of tested compounds against field strain of non-target C. tripunctatus. Most of tested compounds were safer than temephos, especially 15 and 6 with SI/PSF values 96.746 and 83.167, respectively. Structure-activity relationship (SAR) was discussed the effect of substituents insertion on the derivatives activities. Quinazolinone derivatives and related compounds are promising compounds in the mosquito control programs and further studies are recommended to develop more effective derivatives and reveal their mode of action.

New N-(1,3,4-thiadiazol-2-yl)furan-2-carboxamide derivatives as potential inhibitors of the VEGFR-2.

The present study reports the synthesis and biological evaluation of a new series of novel N-(1,3,4-thiadiazol-2-yl)furan-2-carboxamide derivatives. The reactions were executed under both conventional and microwave irradiation conditions. An enhancement in the synthetic yields and rates was observed when the reactions were carried out under the microwave compared with the classical conditions. The structures of the products were ascertained by different analytical and spectral analyses. The antiproliferative activities were evaluated against three human epithelial cell lines; breast (MCF-7), colon (HCT-116), and prostate (PC-3) using MTT assay technique and doxorubicin was utilized as a reference drug. Besides, molecular docking studies were also performed and the vascular endothelial growth factor recptor-2 (VEGFR-2) was identified as a potential molecular target. Compounds 6, 7, 11a, 11b, 12, 14, and 16 showed promising antiproliferative activity against the three cancer cell lines investigated. Compounds 2 and 15b had significant antiproliferative activities against only colon and breast cells but not against the prostate cells. All the active antiproliferative compounds were highly selective. All the active antiproliferative compounds were good inhibitors of the VEGFR-2 at 7.4-11.5 nM compared with Pazopanib. Compound 7 with the most favorable orientation to the VEGFR-2 from the docking studies, was also the best inhibitor of the receptor. The antiproliferative activity of these compounds is in partial caused by their ability to inhibit the VEGFR-2 and since other molecular targets were not examined, other possibilities cannot be ruled out.

Synthesis of new oxadiazol-phthalazinone derivatives with anti-proliferative activity; molecular docking, pro-apoptotic, and enzyme inhibition profile.

Background and aim: The current study reports the synthesis and biological evaluation of two novel series of 4-(5-mercapto-1,3,4-oxadiazol-2-yl)phthalazin-1(2H)-one derivatives. Methods: The synthetic reactions were carried out under both conventional and ultrasonic irradiation conditions. The anti-proliferative activity of the newly synthesized compounds against two human epithelial cell lines; liver (HepG2) and breast (MCF-7) in addition to normal fibroblasts (WI-38) was investigated. In addition to molecular docking studies, the possible mechanism(s) of action were also explored. Results: In general, an improvement in synthetic rates and yields was observed when reactions were carried out under sonication compared with classical conditions. The structures of the products were established based on analytical and spectral data. Derivatives 2e and 7d, in addition to compound 1, had significant and selective anti-proliferative activity against liver and breast cancer cell lines without harming normal fibroblasts. These derivatives arrested the cell cycle progression and/or induced apoptosis. This has been manifested by the elevation in the expression of p53 and caspase 3, down-regulation of cdk1, and a reduction in the concentrations of MAPK and Topo II at submicromolar concentrations. The latter results confirmed the molecular docking study. Conclusions: Compound 1 had the best profile on the gene and protein levels (arresting cell cycle and inducing apoptosis). The ability of compounds 1 and 2e to inhibit both MAPK and Topo II nominates these derivatives as potential candidates for further anticancer and antitumor studies.