1.Design, synthesis and biological evaluation of pyrazol-furan carboxamide analogues as novel Akt kinase inhibitors.
Zhan W1, Xu L2, Dong X1, Dong J1, Yi X1, Ma X1, Qiu N1, Li J2, Yang B1, Zhou Y3, Hu Y4. Eur J Med Chem. 2016 Apr 5;117:47-58. doi: 10.1016/j.ejmech.2016.03.074. [Epub ahead of print]
A series of novel pyrazol-furan carboxamide analogues were designed, synthesized and biologically evaluated for their Akt1 inhibitory activities, as well as anti-proliferative efficacies against HCT116 and OVCAR-8 cell lines. Most compounds exhibited moderate to excellent Akt1 inhibitory activities, together with favorable cytotoxicities. Further kinase selectivity assay of the most promising compound 25e illustrated that it was also potent against the structurally related AGC kinases, including Akt2, Akt3, ROCK1 and PKA, but was specific over kinases from other subfamilies. In addition, the Western blot analysis indicated that 25e could significantly suppress the phosphorylation level of Akt substrate GSK3β in PC-3 cell. Moreover, 25e demonstrated a concentration-dependent inhibition of phosphorylation of PRAS40 in LNCaP cell, with IC50 value of 30.4 nM.
2.Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors.
Sweidan K1, Sabbah DA2, Bardaweel S3, Dush KA4, Sheikha GA5, Mubarak MS4. Bioorg Med Chem Lett. 2016 Jun 1;26(11):2685-90. doi: 10.1016/j.bmcl.2016.04.011. Epub 2016 Apr 6.
Structure-based drug design and molecular modeling were employed to identify a new series of indole-2-carboxamides as potential anticancer agents. These compounds were synthesized and characterized with the aid of several spectroscopic techniques, such as FT-IR, NMR, and mass spectrometry as well as by elemental analysis. Molecular docking studies confirmed that the newly synthesized compounds accommodate PI3Kα and EGFR kinase catalytic sites and form H-bonding with the key binding residues. The antitumor activity of these new compounds against an array of cancer cell lines (human colon carcinoma (HCT116), leukemia (K562), and breast cancer (MDA231) was evaluated. Results revealed that these compounds were selective against the kinase domain, and none of them showed any inhibitory activity against K562. In addition, results showed that compound 13 exhibited high potency in HCT116 and MDA231 with IC50 values of 19 and 15μM, respectively. Our findings recommend that further optimization of this series would be beneficial for colon and breast cancer treatment.
3.Syntheses, biological activities and SAR studies of novel carboxamide compounds containing piperazine and arylsulfonyl moieties.
Wang BL1, Shi YX2, Zhang SJ1, Ma Y1, Wang HX1, Zhang LY1, Wei W1, Liu XH1, Li YH1, Li ZM3, Li BJ4. Eur J Med Chem. 2016 Apr 5;117:167-178. doi: 10.1016/j.ejmech.2016.04.005. [Epub ahead of print]
A series of novel carboxamide compounds 19a-19j, 20a-20j and 22a-22d containing piperazine and arylsulfonyl moieties have been synthesized. The bioassay results showed that some compounds exhibited favorable herbicidal activities against dicotyledonous plants and many of them possessed excellent antifungal activities. Among 24 novel compounds, some showed superiority over the commercial fungicides Chlorothalonil, Dimethomorph, Thiophanate-methyl, Iprodione, and Zhongshengmycin at 500 mg/L concentration. Some compounds also exhibited high KARI inhibitory activity at 100 μg/mL concentration and could be used as new KARI lead inhibitors for further studies. Moreover, SAR of these new compounds were comprehensively investigated using different computational methods in which 3D-QSAR model obtained provided useful information for further structural optimization for the discovery of new fungicides. The results of this research will contribute to explore comprehensive biological activities of piperazine-containing compounds in different areas of chemistry.
4.Immuno-modulatory Properties of a Quinolin-2-(1H)-on-3-carboxamide Derivative: Relevance in Multiple Sclerosis.
Malfitano AM1, Laezza C, Pisanti S, Manera C, Bifulco M2. Recent Pat CNS Drug Discov. 2016 Apr 21. [Epub ahead of print]
BACKGROUND: We have recently released the structure of a class of quinolin-2-(1H)-on-3-carboxamide derivatives and among them; the drug A2 has the highest CB2 receptor affinity and selectivity.