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A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7-43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure-activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC 50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC 50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization., (Copyright © 2018 Elsevier Inc. All rights reserved.)

• The present work describes the synthesis of 26 novel pyrimidine analogs. • All derivatives were tested against K-562, MV4–11, G361, and HCC827 cell lines. • Most of the compounds displayed low micromolar potency against leukemia cell lines. • The most active compounds arrested the cell cycle in G2/M and induced caspase-independent death in K562 cells. Pyrimidine is a privileged scaffold and part of many anti-cancer drugs, whereas cinnamamides are present in many natural products. The present work reports the rational design and synthesis of 26 novel pyrimidine and cinnamamide hybrid analogs with further optimization in the core structure. The synthesized derivatives were tested against K-562 (chronic myeloid leukemia), MV4–11 (acute myeloid leukemia), G361 (malignant melanoma), and HCC827 (lung adenocarcinoma) cell lines. Compounds 10j, 10m, 10r, and 10t displayed low micromolar potency against leukemia cell lines. 10 m and 10r were the most potent analogs against G361 and HCC827 cell lines. Subsequently, structure-activity relationship study was carried out and revealed the nitro substitution was unfavorable for the activity. Cellular effects of compounds 10j and 10t were studied in the most sensitive cell line K562. The compounds arrested the cell cycle in G2/M phases and induced caspase-independent cell death. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract The cyclin-dependent kinases (CDKs) play a crucial role in cell cycle progression and are validated targets of cancer therapy. Pyrazolopyrimidines are versatile scaffolds, which have been exploited for developing potential anticancer agents. We herein report the synthesis and in vitro CDK2/cyclin E kinase inhibitory activity of 34 novel 4,6-disubstituted pyrazolo [3,4- d ]pyrimidines (9a-9s, 13a-13h, 14a-14d, 15a-15c). The structure-activity relationship (SAR) studies revealed that compounds with thiopentane/thiophenethyl group at C-6 and heteroatom-containing bicyclic moiety (benzofuran) at C-4 exhibited good CDK2 inhibitory activity. Further, the binding energies obtained for the active compounds from in silico molecular docking studies with CDK2 were found to be in consonance with the observed SAR and experimental results. In addition, some of the synthesized compounds showed anti-proliferative activity against K-562 (chronic myelogenous leukaemia) and MCF-7 (breast adenocarcinoma) cell lines in micromolar ranges. Further, the cytotoxicity studies on CHO cell line revealed that all the compounds are non-toxic to normal cells and are safe. Thus, the research findings revealed the anticancer potential of 4,6-disubstituted pyrazolo [3,4- d ]pyrimidine derivatives which could be further considered for lead optimization. Graphical abstract Image 1 Highlights • A novel series of mono and di-substituted pyrazolo [3,4- d ]pyrimidine analogues. • All compounds were screened for their anticancer (CDK2 & Abl) and anti-proliferative (K-562 & MCF-7) activity. • Compounds 13a , 13c , 14c , 15a and 15b displayed significant CDK2 inhibitory activity. • The structure-activity relationship was discussed. [ABSTRACT FROM AUTHOR]

• 25 novel 1,2,4-triazolo[4,3- b ] pyridazine derivatives were prepared. • Anti-proliferative activity against K562, MV4-11, G361 and HCC827 cancer cell lines was evaluated. • Almost all the synthesised compounds were active against MV4-11. • Compound 8l induces apoptotic cell death in MV4-11. Novel 1,2,4-triazolo[4,3- b ]pyridazine derivatives (7a–d, 8a–m and 9a–i) were designed and synthesized in good to moderate yields. The synthesized compounds were characterized by spectroscopic studies (NMR and IR) and the fluorine coupled 13C NMR data for each synthesized series have also been explained. The compounds were evaluated for their in-vitro anti-proliferative activity against K562, MV4-11, G361 and HCC827 human cancer cell lines. Almost all the synthesised compounds were active against MV4-11 below 25 µM, especially 8l which showed activity with IC 50 of 1.5 µM. Furthermore, compound 8l displayed anticancer activity against all four cancer cell lines tested with IC 50 values ranging from 1.5 to 7.6 µM. In general, most of the compounds did not show any significant anti-proliferative activity against K562, G361 and HCC827 cells. Preliminary investigation of their effect on proliferation and viability of MV4-11 cells was carried out with 8l and the results indicate that the cells undergo a cell death with biochemical signs of apoptosis. [Display omitted] [ABSTRACT FROM AUTHOR]