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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 IC 50 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., Competing Interests: Authors declare that they have no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Three thienylpicolinamidine derivatives 4a-c were prepared from their corresponding picolinonitriles 3a-c on treatment with lithium trimethylsilylamide, LiN(TMS) 2 , followed by a de-protection step using ethanol/HCl (gas). DFT calculations were used to optimize the geometric structure of the newly synthesized picolinamidines. The comparison of DFT calculated spectral data with the experimental data ( 1 H-NMR and 13 C-NMR) showed a good agreement. The in vitro antiproliferative activity of the cationic compounds 4a-c was determined against 60 cancer cell lines representing nine types of cancer. The tested picolinamidines were highly active with compounds 4a and 4b eliciting mainly cytotoxic activity with GI values ranging from -7.17 to -86.03. Leukemia (SR and K-562), colon (SW-620 and HT29), and non-small cell lung cancer (NCI-H460) cell lines were the most responsive to the investigated picolinamidines. In particular, 4-methoxyphenyl derivative 4a showed a profound growth deterring power with GI 50 of 0.34 μM against SR, 0.43 μM against SW-620, and 0.52 μM against NCI-H460. The three tested picolinamidines elicited potent GI 50 values against all tested cell lines at low micromolar to sub-micromolar level. The new picolinamidines were selective and did not affect normal human fibroblasts. The selectivity index ranged from 13-21 μM. The novel picolinamidines downregulated the expression of key genes in the cell cycle, cdk1 and topoII , but did not affect p53 or txnrd1 . Compounds 4b and 4c caused a significant reduction in the concentrations of TopoII and MAPK proteins but were devoid of any effect on the activity of caspase 3. Taken together, these promising anticancer candidates are effective at very low concentrations and safe to normal cells, and most probably work through arresting the cell cycle, and therefore, they deserve further investigations., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

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(2 H )-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., Competing Interests: The authors declare no conflict of interest, financial or otherwise., (This journal is © The Royal Society of Chemistry.)