Letters in Drug Design & Discovery - Volume 13, Issue 1, 2016

Serine proteases are involved in the blood coagulation cascade- composed of intrinsic, extrinsic, and common pathways affecting coagulation responses. Among the three pathways of the blood coagulation cascade involving serine proteases, this review focuses on serine protease inhibitors of the understudied extrinsic pathway, which is responsible for bleeding and bleeding complications targeting the (activated factor VII-Tissue Factor) fVIIa-TF complex. In lieu of our search for fVIIa-soluble TF (fVIIa-sTF) inhibitors or scaffolds, we review the serine protease inhibitors present as synthetic and natural products, which are involved in the blood coagulation cascade, and compare them with the serine protease peptide inhibitors found in toxic Microcystis cyanobacteria. Some scaffolds for the extrinsic pathway as inhibitors from the toxic Microcystis cyanobacteria will be identified in the review.

Out of many idiopathic causes, mutation in some genes is linked to Parkinson’s disease (PD). Recent studies showed pathogenic mutation in the kinase domain of the leucine rich repeat kinase (LRRK2) leads to PD, and increasingly gaining attention as a promising therapeutic target. Some of the reported LRRK2 inhibitors have shown undesirable drug properties, primarily the inability to cross the blood-brain barrier. The energy based approach of pharmacophore modeling, which blends ligand- and structure-based methods, has been used to identify new hits of LRRK2 inhibitors. The successful LRRK2 inhibitors in pre-clinical trials, such as GSK2578215A, HG-10-102-01 and GNE-7915 showing high brain penetrability, were selected for developing pharmacophore models. Throughput virtual screening combined with ADMET and molecular docking of molecular databases led to identification of potential LRRK2 inhibitors, substantiated through molecular dynamics and MM-GBSA analyses.

In this study, a nonlinear quantitative structure-activity relationship model for the prediction of the IC50 of trisubstituted thiazoles as Cdc7 kinase inhibitors was developed by the gene expression programming (GEP). This model is based on five descriptors which were selected from the descriptors’ pool by heuristic method (HM). GEP rendered a good correlation between the experimental and predicted log (IC50) values with a correlation coefficient and a mean error of 0.85 and 0.22 for the training set, 0.84 and 0.39 for the testing set, respectively. The results indicate that this QSAR model has good predictive capability and it points to further optimization opportunities for Cdc7 kinase inhibitors.

A group of class I selective HDAC inhibitors were derived previously, with inhibitory preference of HDAC1 and HDAC3 over HDAC2. Molecular docking and molecular dynamic simulation approaches were performed to elucidate the structural basis of inhibitor’s selectivity between HDAC2 and HDAC3. Superimposition of the rigid docked structures showed that residues in the active sites of both receptors are identical, and the inhibitor (D18) has similar binding patterns in both sites. Results of the flexible docking suggested that strong hydrophobic interactions between molecule D18 and Phe199 play significant role in the selectivity. The interactions were verified to be stable by further molecular dynamic simulation processes.

Among anticancer DNA-intercalating agents, medicinally important 1,8-naphthalimide derivatives represent an important class of bioleads possessed substantial cytotoxic activity toward a variety of murine and human cancercells. Amonafide, as the representative of this family, plays an important role due to its potent antitumor properties. Amonafide is a topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptosis by inhibiting the binding of Topo II to the double strand DNA and also preserves anticancer activity even in the presence of multi-drug resistance (MDR), a main contributor to adjuvant therapeutic failure. In this review are summarized recent developments in the synthesis of amonafide derivatives and their bioactivity. In addition, the effect of structural characteristicsof such agents on structure activity relationship (SAR) will be also discussed.

A series of 6,7-disubstituted-3-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}quinazoline- 2,4(1H,3H)-dione derivatives (7-34) were synthesized and their structures were elucidated on the basis of analytical and spectral (UV, IR, 1H-NMR, 13C-NMR and MS) data. These synthesized compounds were evaluated for their in vitro cytotoxicities against a panel of three human cancer cell lines. According to the cytotoxicity screening results, 3-{2-[4-(4-chlorobenzyl)piperazin-1-yl]-2-oxoethyl} quinazoline-2,4(1H,3H)-dione (7) presented the highest activity against HUH-7, MCF-7 and HCT-116 cell line with the IC50 values of 2.5, 6.8 and 4.9 μM, respectively.

In the present study, novel derivatives of 7H-benzo[h]chromeno[2,3-d]pyrimidine were prepared from 4H-benzo[h]chromene-3-carbonitrile and ethyl 4H-benzo[h]chromene-3-carboxylate derivatives and were evaluated as potential cytotoxic agents. The structures of the synthesized compounds were established on the basis of spectral data, IR, 1H NMR, 13C NMR and MS data. The invitro antitumor activity of the synthesized compounds was investigated in comparison with the standard drug Colchicine using MTT colorimetric assay. We explored the Structure-Activity Relationship (SAR) of 4Hbenzo[ h]chromenes with modification at the 2- or 3-positions and 2,3-positions. It was found that some compounds showed good antitumor activity against the cell lines MCF-7, HCT-116 and HepG-2 as compared with Colchicine. The SAR study revealed that the antitumor activity of the synthesized compounds were significantly affected by the lipophilicity (hydrophobic or hydrophilic) of the substituent at 2- or 3-positions and 2,3-positions.

Some new quinoline derivatives were designed and synthesized to evaluate their biological activities as aromatase inhibitors and anti-breast cancer agents. Cytotoxicity of quinolines 8a-g against human breast cancer MCF-7 and T47D cell lines were evaluated. All the compounds 8a-g were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase mRNA less than MCF-7 cells. Their effects on Aromatase activity are also described. Our results showed that compound 8b inhibits aromatase enzyme activity more than reference drug Letrozol.

A series of aminopeptidase N (APN) inhibitors were designed and synthesized. Enzyme inhibitory, docking and antiproliferative studies were performed to evaluate the derived molecules. Molecule D15, with IC50 values of 10.9 μM, showed the best performance in the APN enzymatic inhibition assay. The binding pattern of molecule D9 and D15 in the active site of APN was predicted by docking studies. Hydrophobic and H-bond interactions were discovered to make key roles in the ligand-receptor bindings. Compared with the previous C7, several molecules such as D9, D14 and D15, exhibited significantly improved activities in inhibiting the growth of HL-60, ES-2, A549 and PLC cell lines.

This work describes the synthesis and biological properties of a series of 2- and 4- pyridinylimines and pyridinylhydrazones. All compounds were evaluated in vitro against two species of Leishmania. The antioxidant activity and the toxic effect against murine peritoneal macrophages of the compounds were also performed. The synthesized compounds showed significant antileishmanial and antioxidant activities. For the antileishmanial assay, compounds 1a, 1d and 2a were active against the Leishmania species, and compound 2a was the most effective on promastigotes (IC50 value = 3.38 μM) and amastigotes (IC50 value = 18.96 μM) of L. amazonensis. Only compound 2a exhibited toxicity against murine peritoneal macrophages (CC50 of 54.35 μM). However, this compound was 2.8 times more destructive to the intracellular amastigotes than the host cell. Regarding the antioxidant activity, compounds 1a and 2a exhibited a strong antioxidant effect (IC50 values of 8.79 μM and 19.82 μM), compound 1a being better than the L-ascorbic acid (9.48 μM), used as reference.