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Targeting Pim-1 kinase recently proved to be profitable for conquering cancer proliferation. In the current study, we report the design, synthesis and biological evaluation of two novel series of 2-amino cyanopyridine series ( 5a-g ) and 2-oxocyanopyridine series ( 6a-g ) targeting Pim-1 kinase. All of the newly synthesized compounds were evaluated for their in vitro anticancer activity against a panel of three cell lines, namely, the liver cancer cell line (HepG2), the colon cancer cell line (HCT-116) and the breast cancer cell line (MCF-7). Most of the compounds showed good to moderate anti-proliferative activity against HepG2 and HCT-116 cell lines while only few compounds showed significant cytotoxic activity against MCF-7 cell line. Further, the Pim-1 kinase inhibitory activity for the two series was evaluated where most of the tested compounds showed marked Pim-1 kinase inhibitory activity (26%–89%). Moreover, determination of the IC 50 values unraveled very potent molecules in the submicromolar range where compound 6c possessed an IC 50 value of 0.94 μM . Moreover, apoptosis studies were conducted on the most potent compound 6c to evaluate the proapoptotic potential of our compounds. Interestingly, it induced the level of active caspase 3 and boosted the Bax/Bcl2 ratio 22704 folds in comparison to the control. Finally, a molecular docking study was conducted to reveal the probable interaction with the Pim-1 kinase active site. [ABSTRACT FROM AUTHOR]

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Two series of indazole-based derivatives were synthesized. • Compds 11b , 11c , and 11e had VEGFR-2 IC 50 = 5.4 nM, 5.6 nM, and7 nM, respectively. • Compds 11a and 11c showed the most potent anticancer activity. • Molecular dynamics simulation was utilized to study their binding mode. Abstract VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b , 11c and 11e exhibited the most potent action, with IC 50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 μM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI 50) and safety (LC 50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action. [ABSTRACT FROM AUTHOR]

Gram-negative bacteria pose a distinctive risk worldwide, especially with the evolution of major resistance to carbapenems, fluoroquinolones and colistin. Therefore, development of new antibacterial agents to target Gram-negative infections is of utmost importance. Using phenotypic screening, we synthesized and tested thirty-one benzimidazole derivatives against E. coli JW55031 (TolC mutant strain). Compound 6c showed potent activity with MIC value of 2 μg/ml, however, it lacked activity against several Gram-negative microbes with intact efflux systems, including E. coli BW25113 (wild-type strain). Combination of 6c with colistin partially restored its antibacterial activity against wild strains (MIC range, 8–16 μg/ml against E. coli , K. pneumoniae , A. baumannii , and P. aeruginosa). 6c exhibited no cytotoxicity against two mammalian cell lines. Therefore, compound 6c represents a promising lead for further optimization to overcome Gram-negative resistance alone or in combination therapy. Image 1 • Benzimidazole derivative, 6c is a promising lead to target Gram-negative bacteria. • Compound 6c shows potent activity against TolC mutant E. coli. • 6c and colistin manifest synergistic activity against Gram-negative bacteria. • Compound 6c shows no cytotoxicity on mammalian cell lines. [ABSTRACT FROM AUTHOR]

Pyrazolopyrimidines 11f , 16b and 11i showed potent antiproliferative activity towards Huh-7, HeLa and MCF-7 cell lines with IC 50 = 6.3, 7.8 and 3.0 µM, whereas 11i and 16b exhibited IC 50 = 4.32 µM and 5.74 µM, against MDA-MB231 cell lines. 11i induced a reduction in G1 phase with arrest in S phase and G2/M phase of MCF-7 cells. 16b induced a reduction in G1 phase and arrest in G2/M phase of Hela cells. 11i induced arrest in G1 phase and reduction in S phase of MDA-MB-231 cells. 11i induced an arrest in G1 phase with reduction in S phase of MDA-MB-231. • A series of pyrazolo[1,5- a ]pyrimidines 11a–j , 16a–c and 22 were synthesized. • 11f , 16b and 11i emerged as the most active compounds against 4 tested cells. • 11i and 16b showed potent activity against MDA-MB231 cell lines. • 11i induced a reduction in G1 phase with arrest in S and G2/M phase of MCF-7 cells. • 16b induced a reduction in G1 phase with arrest in G2/M phase of Hela cells. A series of 2-phenyl-7-(aryl)pyrazolo[1,5- a ]pyrimidine-3-carbonitriles 11a–j and 2-phenyl-7-(aryl)pyrazolo[1,5- a ]pyrimidine-3,6-dicarbonitriles 16a–c was synthesized by the reaction of 5-amino-3-phenyl-1 H -pyrazole-4-carbonitrile (5) with 3-(dimethylamino)-1-arylprop-2-en-1-ones 6a–j or 2-aryl-3-(dimethylamino)acrylonitriles 12a–c , respectively. In addition, 7-amino-5-oxo-2-phenyl-4,5-dihydropyrazolo[1,5- a ]pyrimidine-3-carbonitrile (22) was prepared from the reaction of compound 5 with ethyl cyanoacetate. The anticancer activity of the newly synthesized compounds against Huh-7, HeLa, MCF-7 and MDA-MB231 cell lines showed moderate activity of compound 11f as anti-proliferative agent against Huh-7 cell line with IC 50 = 6.3 µM when compared with doxorubicin (IC 50 = 3.2 µM). On the other hand, compound 16b revealed potent anti-proliferative activity against HeLa cell line with IC 50 = 7.8 µM when compared with doxorubicin (IC 50 = 8.1 µM). Also compound 11i exhibited a promising anti-proliferative activity against MCF-7 cell line (IC 50 = 3.0 µM) whereas IC 50 of doxorubicin = 5.9 µM, finally compounds 11i and 16b have potent activity as anti-proliferative agents against MDA-MB231 cell line with IC 50 = 4.32 and 5.74 µM, respectively when compared with doxorubicin (IC 50 = 6.0 µM). [ABSTRACT FROM AUTHOR]

• Series of thieno[2,3- d ]pyrimidines as Amuvatinib analogues were designed and synthesized. • Most of the newly synthesized compounds displayed a remarkable activity against (PANC-1) cell line. • 3D-QSAR model was built up with five-featured pharmacophore (AAHHR). • ADME study was carried out to predict the pharmacokinetic properties. Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs) , this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3- d ]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2- d ]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC 50 value of 5.4 µM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC 50 value 0.155 µM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy. [ABSTRACT FROM AUTHOR]

• Pyrazolo[1,5- a ][1,3,5]triazine derivatives were designed and synthesized. • The pyrazolotriazine derivatives 9f showed best CDK2 inhibition 82.38% and IC 50 of 1.85 µM. • Antiproliferative activity on 60 NCI cell lines was assessed. • Binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme was studied. Cyclin Dependent Kinases CDKs unpredictable activity has been accounted for a wide assortment of human malignancies, so it might be conceivable to design pharmacologically relevant ligands that go about as specific and potent inhibitors of CDK2 action. In this respect, a series of novel pyrazolo[1,5- a ][1,3,5]triazine derivatives were designed, synthesized and evaluated for CDK2 enzyme inhibitory and anticancer activity. Compounds 9f and 10c showed best CDK2 inhibition among the newly synthesized compounds, with percent inhibition at 82.38%, and 81.96% against CDK2 and IC 50 of 1.85 and 2.09 µM, respectively. Additionally, the newly synthesized compounds were tested for their antiproliferative activity against 60 NCI cell lines. Molecular docking revealed the binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme (PDB code: 3ddq). Conclusively, pyrazolotriazine derivatives represent a talented starting point for further study as anticancer drug. [ABSTRACT FROM AUTHOR]