Synthesis and evaluation of novel N1-acylated 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors.

Protein kinase dysregulation was strongly linked to cancer pathogenesis. Moreover, histone alterations were found to be among the most important post-translational modifications that could contribute to cancer growth and development. In this context, haspin, an atypical serine/threonine kinase, phosphorylates histone H3 at threonine-3 and is notably overexpressed in various common cancer types. Herein, we report novel 5-(4-pyridinyl)indazole derivatives as potent and selective haspin inhibitors. Amide coupling at N1 of the indazole ring with m-hydroxyphenyl acetic acid yielded compound 21 with an IC50 value of 78 nM against haspin. This compound showed a meaningful selectivity over 15 of the most common off-targets, including Clk 1-3 and Dyrk1A, 1B, and 2. The most potent haspin inhibitors 5 and 21 effectively inhibited the growth of the NCI-60 cancer cell lines, further emphasizing the success of our scaffold as a new selective lead for the development of anti-cancer therapeutic agents.

N1-Benzoylated 5-(4-pyridinyl)indazole-based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents.

Haspin and Clk4 are both understudied protein kinases (PKs), offering potential targets for the development of new anticancer agents. Thus, the identification of new inhibitors targeting these PKs is of high interest. However, the inhibitors targeting haspin or Clk4 developed to date show a poor selectivity profile over other closely related PKs, increasing the risk of side effects. Herein, we present two newly developed N1-benzyolated 5-(4-pyridinyl)indazole-based inhibitors (18 and 19), derived from a newly identified indazole hit. These inhibitors exhibit an exceptional inhibitory profile toward haspin and/or Clk4. Compound 18 (2-acetyl benzoyl) showed a preference to inhibit Clk4 and haspin over a panel of closely related kinases, with sixfold selectivity for Clk4 (IC50 = 0.088 and 0.542 µM, respectively). Compound 19 (4-acetyl benzoyl) showed high selectivity against haspin over the common off-target kinases (Dyrks and Clks) with an IC50 of 0.155 µM for haspin. Molecular docking studies explained the remarkable selectivity of 18 and 19, elucidating how the new scaffold can be modified to toggle between inhibition of haspin or Clk4, despite the high homology of the ATP-binding sites. Their distinguished profile allows these compounds to be marked as interesting chemical probes to assess the selective inhibition of haspin and/or Clk4.

Development and evaluation of 2,4-disubstituted-5-aryl pyrimidine derivatives as antibacterial agents.

Designing novel candidates as potential antibacterial scaffolds has become crucial due to the lack of new antibiotics entering the market and the persistent rise in multidrug resistance. Here, we describe a new class of potent antibacterial agents based on a 5-aryl-N2,N4-dibutylpyrimidine-2,4-diamine scaffold. Structural optimization focused on the 5-aryl moiety and the bioisosteric replacement of the side chain linker atom. Screening of the synthesized compounds focused on a panel of bacterial strains, including gram-positive Staphylococcus aureus strains (Newman MSSA, methicillin- and vancomycin-resistant), and the gram-negative Escherichia coli (ΔAcrB strain). Several compounds showed broad-spectrum antibacterial activity with compound 12, bearing a 4-chlorophenyl substituent, being the most potent among this series of compounds. This frontrunner compound revealed a minimum inhibitory concentration (MIC) value of 1 µg/mL against the S. aureus strain (Mu50 methicillin-resistant S. aureus/vancomycin-intermediate S. aureus) and an MIC of 2 µg/mL against other tested strains. The most potent derivatives were further tested against a wider panel of bacteria and evaluated for their cytotoxicity, revealing further potent activities toward Streptococcus pneumoniae, Enterococcus faecium, and Enterococcus faecalis. To explore the mode of action, compound 12 was tested in a macromolecule inhibition assay. The obtained data were supported by the safety profile of compound 12, which possessed an IC50 of 12.3 µg/mL against HepG2 cells. The current results hold good potential for a new class of extended-spectrum antibacterial agents.

An overview of cdc2-like kinase 1 (Clk1) inhibitors and their therapeutic indications.

Over the past decade, Clk1 has been identified as a promising target for the treatment of various diseases, in which deregulated alternative splicing plays a role. First small molecules targeting Clk1 are in clinical trials for the treatment of solid cancer, where variants of oncogenic proteins derived from alternative splicing promote tumor progression. Since many infectious pathogens hi-jack the host cell's splicing machinery to ensure efficient replication, further indications in this area are under investigation, such as Influenza A, HIV-1 virus, and Trypanosoma infections, and more will likely be discovered in the future. In addition, Clk1 was found to contribute to the progression of Alzheimer's disease through causing an imbalance of tau splicing products. Interestingly, homozygous Clk1 knockout mice showed a rather mild phenotype, opposed to what might be expected in view of the profound role of Clk1 in alternative splicing. A major drawback of most Clk1 inhibitors is their insufficient selectivity; in particular, Dyrk kinases and haspin were frequently identified as off-targets, besides the other Clk isoforms. Only few inhibitors were shown to be selective over Dyrk1A and haspin, whereas no Clk1 inhibitor so far achieved selectivity over the Clk4 isoform. In this review, we carefully compiled all Clk1 inhibitors from the scientific literature and summarized their structure-activity relationships (SAR). In addition, we critically discuss the available selectivity data and describe the inhibitor's efficacy in cellular models, if reported. Thus, we provide a comprehensive overview on the current state of Clk1 drug discovery and highlight the most promising chemotypes.

Design, synthesis, and metabolite identification of Tamoxifen esterase-activatable prodrugs.

Tamoxifen (TAM) is used in treatment of hormonal dependent breast cancer, both in premenopausal and postmenopausal women. TAM is intrinsically metabolized by CYP450 enzymes to more active metabolites. Recent reports identified CYP2D6, an enzyme involved in the conversion of TAM to the more potent 4-OH-TAM, is encoded by theCYP2D6gene, which is highly polymorphic. Women with inactive alleles are poor metabolizers; in many cases they suffer acquired TAM resistance. Herein we report synthesis and biological evaluation of novel TAM analogues. The novel analogues are designed to elude CYP2D6 metabolism. Hydrolysis of the carbamate moiety on ring C is mediated via carboxylesterases. Compound 3d [E/Z Benzyl-carbamic acid4-{2-benzyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-but-1-enyl}-phenyl ester] showed GI50 = 0.09 µM on MCF-7 and GI50 = 1.84 µM on MDA-MB231 cell lines. To further validate our hypothesis, metabolites of selected novel analogues were determined in vitro under different incubation conditions. The hydroxylated analogues were obtained under non CYP2D6 dependent conditions. Compound 8d, a benzyl carbamate derivative, was the least-stable analog and showed the highest rate of metabolism among all tested analogues. Our in silico model showed the novel flexible analogues can still adopt an antiestrogenic binding profile occupying the same pocket as 4-OH-TAM.

Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer's disease.

Neurodegenerative diseases such as Alzheimer's disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional "one-target, one-molecule" approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 µM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 µM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.

Novel 9-Benzylaminoacridine Derivatives as Dual Inhibitors of Phosphodiesterase 5 and Topoisomerase II for the Treatment of Colon Cancer.

It has been shown that phosphodiesterase 5 (PDE5) inhibitors have anticancer effects in a variety of malignancies in both in vivo and in vitro experiments. The role of cGMP elevation in colorectal carcinoma (CRC) has been extensively studied. Additionally, DNA topoisomerase II (Topo II) inhibition is a well-established mechanism of action that mediates the effects of several approved anticancer drugs such as doxorubicin and mitoxantrone. Herein, we present 9-benzylaminoacridine derivatives as dual inhibitors of the PDE5 and Topo II enzymes. We synthesized 31 derivatives and evaluated them against PDE5, whereby 22 compounds showed micromolar or sub-micromolar inhibition. The anticancer activity of the compounds was evaluated with the NCI 60-cell line testing. Moreover, the effects of the compounds on HCT-116 colorectal carcinoma (CRC) were extensively studied, and potent compounds against HCT-116 cells were studied for their effects on Topo II, cell cycle progression, and apoptosis. In addition to exhibiting significant growth inhibition against HCT116 cells, compounds 11, 12, and 28 also exhibited the most superior Topo II inhibitory activity and low micromolar PDE5 inhibition and affected cell cycle progression. Knowing that compounds that combat cancer through multiple mechanisms are among the best candidates for effective therapy, we believe that the current class of compounds merits further optimization and investigation to unleash their full therapeutic potential.

Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Modification of the benzenoid part.

Bacterial resistance to currently used antibiotics demands the development of novel antibacterial agents with good safety margins and sufficient efficacy against multi-drug resistant isolates. We have previously described the synthesis of N-butyl-2-(butylthio)quinazolin-4-amine (I) as an optimized hit with broad-spectrum antibacterial activity and low cytotoxicity. In addition, we have identified a potential growing vector for this series of compounds. Herein, we describe further hit optimization which includes systematic diversifications of both the benzenoid part and the substituents at position 6 and 7 of compound I. Growing of the molecule beside the core modifications yielded several compounds with remarkable anti(myco)bacterial activity against a panel of pathogenic bacteria, including drug-resistant strains. Compound 12 showed a 2-4 fold improvement in activity than I against S. aureus Newman, S. pneumoniae DSM-20566 and E. faecalis DSM-20478. The compounds also showed a good safety profile towards human HepG2 cells.

From EGFR kinase inhibitors to anti-inflammatory drugs: Optimization and biological evaluation of (4-(phenylamino)quinazolinyl)-phenylthiourea derivatives as novel NF-κB inhibitors.

The transcription factor NF-κB is a pivotal mediator of chronic inflammatory and autoimmune diseases. Based on our previously published dual EGFR/NF-κB inhibitors, we designed and synthesized new thiourea quinazoline derivatives that retained only the NF-κB inhibitory activity. Several congeners displayed a strong suppression of NF-κB activity in a reporter gene assay, yet low cytotoxicity, and were further evaluated in differentiated macrophage-like THP-1 cells. The compounds exhibited a strong inhibition of IL-6 and, less potently, of TNFα release, which was accompanied by a selective induction of macrophage cell death. The mode of action was investigated with a selected inhibitor, 18, revealing that the translocation of p65/RelA to the nucleus but not its release from the IκB complex was inhibited. Eventually, 18 was identified as the first small molecule inhibitor affecting only the phosphorylation of p65-Ser468 but not of Ser536, which may be causally related to the retention of NF-κB in the cytoplasm. Altogether, our novel NF-κB inhibitors seem applicable for the suppression of cytokine release and the additional selective depletion of activated macrophages in various inflammatory diseases.

Development of fluorinated and methoxylated benzothiazole derivatives as highly potent and selective cannabinoid CB2 receptor ligands.

The upregulation of the CB2 receptors in neuroinflammation and cancer and their potential visualization with PET (positron emission tomography) could provide a valuable diagnostic and therapy-monitoring tool in such disorders. However, the availability of reliable CB2-selective imaging probes is still lacking in clinical practice. We have recently identified a benzothiazole-2-ylidine amide hit (6a) as a highly potent CB2 ligand. With the aim of enhancing its CB2 over CB1 selectivity and introducing structural sites suitable for radiolabeling, we herein describe the development of fluorinated and methoxylated benzothiazole derivatives endowed with extremely high CB2 binding affinity and an exclusive selectivity to the CB2 receptor. Compounds 14, 15, 18, 19, 21, 24 and 25 displayed subnanomolar CB2Ki values (ranging from 0.16 nM to 0.68 nM) and interestingly, all of the synthesized compounds completely lacked affinity at the CB1 receptor (Ki > 10,000 nM for all compounds), indicating their remarkably high CB2 over CB1 selectivity factors. The fluorinated analogs, 15 and 21, were evaluated for their in vitro metabolic stability in mouse and human liver microsomes (MLM and HLM). Both 15 and 21 displayed an exceptionally high stability (98% and 91% intact compounds, respectively) after 60 min incubation with MLM. Contrastingly, a 5- and 2.8-fold lower stability was demonstrated for compounds 15 and 21, respectively, upon incubation with HLM for 60 min. Taken together, our data present extremely potent and selective CB2 ligands as credible leads that can be further exploited for 18F- or 11C-radiolabeling and utilization as PET tracers.

Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Optimization of the 2,4-substituents.

The emergence of bacterial resistance has triggered a multitude of efforts to develop new antibacterial agents. There are many compounds in literature that were reported as potent antibacterial agents, however, they lacked the required safety to mammalian cells or no clear picture about their toxicity profile was presented. Inspired by discovered hit from our in-house library and by previously reported 2,4-diaminosubstituted quinazolines, we describe the design and synthesis of novel 2,4-disubstituted-thioquinazolines (3-13 and 36), 2-thio-4-amino substituted quinazolines (14-33) and 6-substituted 2,4-diamonsubstituted quinazolines (37-39). The synthesized compounds showed potent antibacterial activity against a panel of Gram-positive, efflux deficient E.coli and Mycobacterium smegmatis. The panel also involved resistant strains including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium, in addition to Mycobacterium smegmatis. The newly synthesized compounds revealed MIC values against the tested strains ranging from 1 to 64 µg/mL with a good safety profile. Most of the 2-thio-4-amino substituted-quinazolines showed significant antimycobacterial activity with the variations at position 2 and 4 offering additional antibacterial activity against the different strains. Compared to previously reported 2,4-diaminosubstituted quinazolines, the bioisosteric replacement of the 2-amino with sulfur offered a successful approach to keep the high antibacterial potency while substantially improving safety profile as indicated by the reduced activity on different cell lines and a lack of hemolytic activity.

Novel thiazolidine derivatives as potent selective pro-apoptotic agents.

A series of 2-arylthiazolidine-4-carboxylic acid amide derivatives were synthesized and their cytotoxic activity against three cancer cell lines (PC-3, SKOV3 and MDA-MB231) was evaluated. Various structural modifications were tried including modifications of the length of the amide chain and modifications of the 2-aryl part using disubstituted phenyl and thiophene derivatives. The structure activity relationship was evaluated based on the in vitro biological evaluation against the above mentioned three cancer cell lines. The most selective compounds towards cancer cells were further evaluated against DLD-1, NCI-H520, Du145, MCF-7 and NCI-N87 cancer cells. The dodecyl amide having the 4-bromothienyl as the 2-aryl, compound 2e, exhibited the highest selectivity for cancer cells vs non-tumor cells. Mechanistic studies of the anticancer effect of compound 2e in prostate cancer PC-3 and colorectal cancer DLD-1 cells revealed that 2e could prevent the cell cycle in the G0/G1 phase by up-regulating the expression of p21 and reducing the expression of CDK2 and cyclin E. It increased the pro-apoptotic protein Bax and cleaved caspase 3, and down-regulated the expression of anti-apoptotic protein Bcl-2 to induce apoptosis. In addition, 2e also downregulated AKT, N-cadherin, and vimentin proteins expression giving indication that 2e inhibit the PI3K/AKT pathway to regulate cell cycle arrest and induce apoptosis, and can regulate the expression of epithelial-mesenchymal transition-related proteins.

Manipulating Estrogenic/Anti-Estrogenic Activity of Triphenylethylenes towards Development of Novel Anti-Neoplastic SERMs.

Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ERα) agonists or antagonists depending on the target issue. Tamoxifen (TAM) (a non-steroidal triphenylethylene derivative) was the first SERM approved as anti-estrogen for the treatment of metastatic breast cancer. On the hunt for novel SERMs with potential growth inhibitory activity on breast cancer cell lines yet no potential to induce endometrial carcinoma, we designed and synthesized 28 novel TAM analogs. The novel analogs bear a triphenylethylene scaffold. Modifications on rings A, B, and C aim to attenuate estrogenic/anti-estrogenic activities of the novel compounds so they can potentially inhibit breast cancer and provide positive, beneficial estrogenic effects on other tissues with no risk of developing endometrial hyperplasia. Compound 12 (E/Z-1-(2-{4-[1-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-propenyl]-phenoxy}-ethyl)-piperidine) showed an appreciable relative ERα agonistic activity in a yeast estrogen screen (YES) assay. It successfully inhibited the growth of the MCF-7 cell line with GI50 = 0.6 µM, and it was approximately three times more potent than TAM. It showed no potential estrogenicity on Ishikawa endometrial adenocarcinoma cell line via assaying alkaline phosphatase (AlkP) activity. Compound 12 was tested in vivo to assess its estrogenic properties in an uterotrophic assay in an ovariectomized rat model. Compared to TAM, it induced less increase in wet uterine wet weight and showed no uterotrophic effect. Compound 12 is a promising candidate for further development due to its inhibition activity on MCF-7 proliferation with moderate AlkP activity and no potential uterotrophic effects. The in vitro estrogenic activity encourages further investigations toward potential beneficial properties in cardiovascular, bone, and brain tissues.

5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency.

Clks have been shown by recent studies to be promising targets for cancer therapy, as they are considered key regulators in the process of pre-mRNA splicing, which in turn affects every aspect of tumor biology. In particular, Clk1 and -4 are overexpressed in several human tumors. Most of the potent Clk1 inhibitors reported in the literature are non-selective, mainly showing off-target activity towards Clk2, Dyrk1A and Dyrk1B. Herein, we present new 5-methoxybenzothiophene-2-carboxamide derivatives with unprecedented selectivity. In particular, the introduction of a 3,5-difluoro benzyl extension to the methylated amide led to the discovery of compound 10b (cell-free IC50 = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound 1b. Moreover, 10b showed an improved growth inhibitory activity with T24 cells (GI50 = 0.43 µM). Furthermore, a new binding model in the ATP pocket of Clk1 was developed based on the structure-activity relationships derived from new rigidified analogues.

Synthesis of novel 1,2-diarylpyrazolidin-3-one-based compounds and their evaluation as broad spectrum antibacterial agents.

There is a continuous need to develop new antibacterial agents with non-traditional mechanisms to combat the nonstop emerging resistance to most of the antibiotics used in clinical settings. We identified novel pyrazolidinone derivatives as antibacterial hits in an in-house library screening and synthesized several derivatives in order to improve the potency and increase the polarity of the discovered hit compounds. The oxime derivative 24 exhibited promising antibacterial activity against E. coli TolC, B. subtilis and S. aureus with MIC values of 4, 10 and 20 µg/mL, respectively. The new lead compound 24 was found to exhibit a weak dual inhibitory activity against both the E. coli MurA and MurB enzymes with IC50 values of 88.1 and 79.5 µM, respectively, which could partially explain its antibacterial effect. A comparison with the previously reported, structurally related pyrazolidinediones suggested that the oxime functionality at position 4 enhanced the activity against MurA and recovered the activity against the MurB enzyme. Compound 24 can serve as a lead for further development of novel and safe antibiotics with potential broad spectrum activity.

Symmetric benzidine derivatives as anti-HCV agents: Insight into the nature, stereochemistry of the capping amino acid and the size of the terminal capping carbamates.

Novel symmetric molecules, bearing a benzidine prolinamide core, two terminal carbamate caps of variable sizes and nature, including natural and unnatural amino acids were developed. Several terminal N-carbamate substituents of the core structure, ranging from linear methyl, ethyl and butyl groups to branching isobutyl group; and an aromatic substituent were also synthesized. Series 1 has hydrophobic AA residues, namely S and R phenylglycine and a terminal carbamate capping group, whereas Series 2 bears sulphur containing amino acids, specifically S and R methionine and the natural R methylcysteine. The novel compounds were tested for their inhibitory activity (EC50) and their cytotoxicity (CC50), using an HCV 1b (Con1) reporter replicon cell line. Compound 4 with the unnatural capping residue, bearing d-Phenylglycine amino acid residue and N-isobutyloxycarbonyl capping group, was the most active within the two series, with EC50 = 0.0067 nM. Moreover, it showed high SI50 > 14788524 and was not cytotoxic at the highest tested concentration (100 µΜ), indicating its safety profile. Compound 4 also inhibited HCV genotypes 2a, 3a and 4a. Compared to the clinically approved NS5A inhibitor Daclatasvir, compound 4 shows higher activity against genotypes 1b and 3a, as well as improved safety profile.

Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors.

Celecoxib, is a selective cyclooxygenase-2 (COX2) inhibitor with a 1,5-diaryl pyrazole scaffold. Celecoxib has a better safety profile compared to other COX2 inhibitors having side effects of systemic hypertension and thromboembolic complications. This may be partly attributed to an off-target activity involving phosphodiesterase 5 (PDE5) inhibition and the potentiation of NO/cGMP signalling allowing coronary vasodilation and aortic relaxation. Inspired by the structure of celecoxib, we synthesized a chemically diverse series of compounds containing a 1,3,5-trisubstituted pyrazoline scaffold to improve PDE5 inhibitory potency, while eliminating COX2 inhibitory activity. SAR studies for PDE5 inhibition revealed an essential role for a carboxylic acid functionality at the 1-phenyl and the importance of the non-planar pyrazoline core over the planar pyrazole with the 5-phenyl moiety tolerating a range of substituents. These modifications led to new PDE5 inhibitors with approximately 20-fold improved potency to inhibit PDE5 and no COX-2 inhibitory activity compared with celecoxib. PDE isozyme profiling of compound 11 revealed a favorable selectivity profile. These results suggest that trisubstituted pyrazolines provide a promising scaffold for further chemical optimization to identify novel PDE5 inhibitors with potential for less side effects compared with available PDE5 inhibitors used for the treatment of penile erectile dysfunction and pulmonary hypertension.

Extending the use of tadalafil scaffold: Development of novel selective phosphodiesterase 5 inhibitors and histone deacetylase inhibitors.

Herein we present the synthesis and characterization of a novel chemical series of tadalafil analogues that display different pharmacological profiles. Compounds that have the 6R, 12aR configuration and terminal carboxylic acid group at the side chain arising from the piperazinedione nitrogen were potent PDE5 inhibitors, with compound 11 having almost equal potency to tadalafil and superior selectivity over PDE11, the most common off-target for tadalafil. Modifying the stereochemistry into 6S, 12aS configuration and adopting the hydroxamic acid moiety as a terminal group gave rise to compounds that only inhibited HDAC. Dual PDE5/HDAC inhibition could be achieved with compounds having 6R, 12aR configuration and hydroxamic acid moiety as a terminal group. The anticancer activity of the synthesized compounds was evaluated against a diverse number of cell lines of different origin. The compounds elicited anticancer activity against cell lines belonging to lymphoproliferative cancer as well as solid tumors. Despite the previous reports suggesting anticancer activity of PDE5 inhibitors, the growth inhibitory activity of the compounds seemed to be solely dependent on HDAC inhibition. Compound 26 (pan HDAC IC50 = 14 nM, PDE5 IC50 = 46 nM) displayed the most potent anticancer activity in the present series and was shown to induce apoptosis in Molt-4 cells. HDAC isoform selectivity testing for compound 26 showed that it is more selective for HDAC6 and 8 over HDAC1 by more than 20-fold.

Expanding the chemical space of anti-HCV NS5A inhibitors by stereochemical exchange and peptidomimetic approaches.

Here we report a series of potent anti-HCV agents bearing a symmetrical benzidine l-prolinamide backbone with different capping groups including alkyl/aryl carbamates of natural and unnatural valine and leucine amino acids. All compounds were investigated for their inhibitory activity in an HCV replicon assay on genotype 1b. The novel compounds share some chemical and clinical attributes of commercially available NS5A inhibitors. Compounds 5 and 6 with unnatural capping residue and ethyl and isobutyl carbamates showed EC50 values in the picomolar range with a low toxicity profile and selectivity indices of several orders of magnitude. These findings enlarge the chemical space from which NS5A inhibitors may be discovered by adopting unnatural amino acids, amino acids other than valine and carbamates other than methyl as the capping groups.

Design and synthesis of novel annulated thienopyrimidines as phosphodiesterase 5 (PDE5) inhibitors.

Novel cycloalkene-fused thienopyrimidine analogues with enhanced phosphodiesterase 5 (PDE5) inhibitory properties are presented. The structure of the reported scaffold was modulated through variation of the terminal cycloalkene ring size, as well as by varying the substituents at position 4 through the attachment of different groups including aniline, benzylamine, cyclohexylethylamine, methyl/acetyl/aryl piperazines, and aryl hydrazones. Compound 15Y with a benzylamine substituent and cycloheptene as terminal ring showed the highest PDE5 inhibitory activity with an IC50 value as low as 190 nM and with good selectivity versus PDE7 and PDE9.