Design, synthesis and biological evaluation of novel triazoloquinazolinone and imidazoquinazolinone derivatives as allosteric inhibitors of SHP2 phosphatase.

ABSTRCTA series of novel triazoloquinolinone and imidazoquinazolinone derivatives were designed and synthesised, and their biological activities against SHP2 protein and melanoma A357 cell line were evaluated in vitro. The results show that some target compounds have moderate to excellent inhibitory activity on SHP2 protein and melanoma A357 cell line. Structure-activity relationships (SARs) showed that both imidazoquinazolinone and triazoloquinazolinone derivatives have good SHP2 protein kinase and melanoma cell line A357 inhibitory activity. The results of molecular docking also showed that the cores of imidazoquinazolinone and triazoloquinazolinone have a certain affinity for SHP2 protein at the same time. Compared with SHP244, the target compounds have quite good liver microsomal stability and has more drug potential. The most promising compound B1 has a strong inhibitory effect on the melanoma cell line A357 at 100 µM (76.15% inhibition).

Design, synthesis, and biological evaluation of novel triazoloquinazolinone derivatives as SHP2 protein inhibitors.

A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their in vitro biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds 12f, 12l, 12j, 17e, and 17f have strong antiproliferative activity on A375 cells. The compound 12l showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with SHP244. The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound 12l displayed improved physicochemical properties as well as metabolic stability compared to SHP244. Our efforts identified 12l as a promising SHP2 protein inhibitor, warranting its further investigation.

Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain inhibitors via structure-based virtual screening.

Bromodomain PHD finger transcription factor (BPTF), a bromodomain-containing protein, plays a crucial role in the regulation of downstream gene expression through the specific recognition of lysine acetylation on bulk histones. The dysfunction of BPTF is closely involved with the development and progression of many human diseases, especially cancer. Therefore, BPTF bromodomain has become a promising drug target for epigenetic cancer therapy. However, unlike BET family inhibitors, few BPTF bromodomain inhibitors have been reported. In this study, by integrating docking-based virtual screening with biochemical analysis, we identified a novel selective BPTF bromodomain inhibitor DCB29 with the IC50 value of 13.2 ±â€¯1.6 µM by homogenous time-resolved fluorescence resonance energy transfer (HTRF) assays. The binding between DCB29 and BPTF was confirmed by NMR and SPR. Molecular docking disclosed that DCB29 occupied the pocket of acetylated H4 peptide substrate and provided detailed SAR explanations for its derivatives. Collectively, DCB29 presented great potential as a powerful tool for BPTF-related biological research and further medicinal chemistry optimization.

Identification of novel 5-hydroxy-1H-indole-3-carboxylates with anti-HBV activities based on 3D QSAR studies.

Infection with hepatitis B virus (HBV) is a major cause of liver diseases such as cirrhosis and hepatocellular carcinoma. In our previous studies, we identified indole derivatives that have anti-HBV activities. In this study, we optimize a series of 5-hydroxy-1H-indole-3-carboxylates, which exhibited potent anti-HBV activities, using three-dimensional quantitative structure-activity relationship (3D QSAR) studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The lowest energy conformation of compound 3, which exhibited the most potent anti-HBV activity, obtained from systematic search was used as the template for alignment. The best predictions were obtained with the CoMFA standard model (q (2) = 0.689, r (2) = 0.965, SEE = 0.082, F = 148.751) and with CoMSIA combined steric, electrostatic, hydrophobic and H-bond acceptor fields (q (2) = 0.578, r (2) = 0.973, SEE = 0.078, F = 100.342). Both models were validated by an external test set of six compounds giving satisfactory prediction. Based on the clues derived from CoMFA and CoMSIA models and their contour maps, another three compounds were designed and synthesized. Pharmacological assay demonstrated that the newly synthesized compounds possessed more potent anti-HBV activities than before (IC(50): compound 35a is 3.1 µmol/l, compound 3 is 4.1 µmol/l). Combining the clues derived from the 3D QSAR studies and from further validation of the 3D QSAR models, the activities of the newly synthesized indole derivatives were well accounted for. Furthermore, this showed that the CoMFA and CoMSIA models proved to have good predictive ability.

Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 5-hydroxy-1H-indole-3-carboxylates.

A series of ethyl 5-hydroxy-1H-indole-3-carboxylates 6A-10T were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The IC50 and selective index of inhibition on replication of HBV DNA of compounds 10(L) (1.52 microg/ml, 9.38) and 10(P) (2.00 microg/ml, 8.85) were higher than those of the other evaluated compounds including lamivudine (7.02). Compounds 7E and 10J exhibited significant anti-HBV activities, and the IC50 values on replication of HBV DNA of these compounds were 24.90 and 15.41 microg/ml, respectively, which were far more potent than the positive control lamivudine 228.00 microg/ml.

Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates.

A series of ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates, 8a-11v, were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The selective indexes of inhibition on replication of HBV DNA of compounds 11s (>8.7) and 11t (10.8), which were introduced halogen on the phenyl ring at position 2, were greater than those of the other evaluated compounds including lamivudine (7.0). Compounds 9e, 9h, 9l, and 11v exhibited significant anti-HBV activities, and the IC(50) values on replication of HBV DNA of these compounds were 3.6, 6.37, 5.2, and 5.4 microg/ml, respectively, which were far more potent than the positive control lamivudine 228 microg/ml.