New orally active PDE4 inhibitors with therapeutic potential

The design, synthesis, and biological evaluation of a series of pyrazolopyridines was carried out. Structural optimization of the aniline moiety of 4-anilinopyrazolopyridine derivative 3a, which is one of the newly discovered chemical leads for PDE4 inhibitors from our in-house library, was performed successfully. The details of the discovery of new orally active PDE4 inhibitors, which are expected to show therapeutic potential, are presented and their structure-activity relationships are discussed. Pharmacological evaluation and pharmacokinetic data for representative compounds are also presented.     

Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes

Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.     

Synthesis and biological evaluation of novel small non-peptidic HIV-1 PIs: the benzothiophene ring as an effective moiety

Synthesis and biological evaluation of a new series of potential HIV-1 protease inhibitors incorporating different heterocycles are described. The variation of heteroatom in such molecules has displayed totally different biological activities and a benzothiophene containing inhibitor has shown high potency against wild type HIV-1 protease with IC(50)=60 nM, thanks to the lower desolvation penalty to be payed by such hydrophobic moiety.     

Discovery of novel and potent aryl diamines as leukotriene A4 hydrolase inhibitors

The synthesis and biological evaluation of a series of aryl diamines as inhibitors of LTA₄-h inhibitors are described. The optimization which led to the identification of the optimal para-substitution on the diphenyl ether moiety and diamine spacer is discussed. The resulting compounds such as 3l have excellent enzyme and cellular potency as well as desirable pharmacokinetic properties.     

Structure,function and selective inhibition of bacterial acetyl-coa carboxylase

Acetyl-CoA carboxylase (ACC) catalyses the first committed step in fatty acid biosynthesis: a metabolic pathway required for several important biological processes including the synthesis and maintenance of cellular membranes. ACC employs a covalently attached biotin moiety to bind a carboxyl anion and then transfer it to acetyl-CoA, yielding malonyl-CoA. These activities occur at two different subsites: the biotin carboxylase (BC) and carboxyltransferase (CT). Structural biology, together with small molecule inhibitor studies, has provided new insights into the molecular mechanisms that govern ACC catalysis, specifically the BC and CT subunits. Here, we review these recent findings and highlight key differences between the bacterial and eukaryotic isozymes with a view to establish those features that provide an opportunity for selective inhibition. Especially important are examples of highly selective small molecule inhibitors capable of differentiating between ACCs from different phyla. The implications for early stage antibiotic discovery projects, stemming from these studies, are discussed.     

Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors

We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.     

C7N氨基环醇家族的天然α-糖苷酶/淀粉酶抑制剂研究进展

C7N氨基环醇家族化合物是一类由放线菌产生的天然化合物,化学结构相对较新颖。其核心基团井岗胺赋予该家族化合物多种生物活性,其中最主要的是α-糖苷酶/淀粉酶抑制剂活性。该家族化合物在生物医学和农业领域中具有较大的应用价值。本文将结合作者的研究方向,综述已被报道的C7N家族α-糖苷酶/淀粉酶抑制剂的化学结构与生物活性。     

Novel β-dicarbonyl derivatives as inhibitors of aminopeptidase N (APN)

Most zinc metalloproteases are over-expressed in tumor cells and play a critical role in the genesis, development, and metastasis of tumors. Novel zinc binding groups (ZBGs) represent a novel strategy to obtain optimal potency and selectivity for zinc metalloproteases inhibitors. Here we described the design, synthesis, and biological studies of novel β-dicarbonyl derivatives as aminopeptidase N (APN/CD13) inhibitors. The results demonstrated that some compounds exhibited moderate to good inhibitory activities against APN with compound 5c being the most potent, suggesting that 5c could serve as new lead for the future APN inhibitor development. The results further confirm our design rationale of β-dicarbonyl moiety as a new ZBG, which may provide a new direction for the design and discovery of zinc metalloproteases inhibitors as new anti-tumor agents.     

Design and synthesis of sulfoximine based inhibitors for HIV-1 protease

A new class of potent sulfoximine inhibitors for HIV-1 protease has been designed and synthesized. Substitution of the sulfoximine moiety into different parent compounds yields different inhibition effects. While our previously studied sulfoximine-based inhibitors display potency of 2.5 nM (IC(50)) against HIV-1 protease, introduction of the sulfoximine moiety into the asymmetric Indinavir yielded only micromolar inhibition. Docking studies showed structural variations in their modes of binding which explains this unexpected observation. The implication of these observations in the development of other sulfoximine inhibitors is discussed.     

Design, synthesis, and biological evaluation of novel tricyclic HIV-1 integrase inhibitors by modification of its pyridine ring

This communication details both the syntheses and biological evaluation of a novel class of HIV-1 integrase inhibitors. When the quinoline moiety is replaced with the quinoxoline moiety, the antiviral activity is significantly compromised. Similarly, introduction of imidazole to replace the pyridine ring is deleterious to the potency of the compound against the enzyme. Substitution at the 3-position of the pyridine has been investigated. The presence of the pyridine ring in the tricyclic core is preferred for antiviral activity against HIV integrase.     

Crystal structures of eosinophil-derived neurotoxin (EDN) in complex with the inhibitors 5'-ATP, Ap3A, Ap4A, and Ap5A

Eosinophil-derived neurotoxin (EDN) is a catalytically proficient member of the pancreatic ribonuclease superfamily secreted along with other eosinophil granule proteins during innate host defense responses and various eosinophil-related inflammatory and allergic diseases. The ribonucleolytic activity of EDN is central to its antiviral and neurotoxic activities and possibly to other facets of its biological activity. To probe the importance of this enzymatic activity further, specific inhibitors will be of great aid. Derivatives of 5'-ADP are among the most potent inhibitors currently known. Here, we use X-ray crystallography to investigate the binding of four natural nucleotides containing this moiety. 5'-ATP binds in two alternative orientations, one occupying the B2 subsite in a conventional manner and one being a retro orientation with no ordered adenosine moiety. Diadenosine triphosphate (Ap3A) and diadenosine tetraphosphate (Ap4A) bind with one adenine positioned at the B2 subsite, the polyphosphate chain extending across the P1 subsite in an ill-defined conformation, and a disordered second adenosine moiety. Diadenosine pentaphosphate (Ap5A), the most avid inhibitor of this series, binds in a completely ordered fashion with one adenine positioned conventionally at the B2 subsite, the polyphosphate chain occupying the P1 and putative P(-1) subsites, and the other adenine bound in a retro-like manner at the edge of the B1 subsite. The binding mode of each of these inhibitors has features seen in previously determined structures of adenosine diphosphates. We examine the structure-affinity relationships of these inhibitors and discuss the implications for the design of improved inhibitors.     

Heterocyclic zinc-binding groups for use in next-generation matrix metalloproteinase inhibitors: potency, toxicity, and reactivity

In an effort to improve the zinc-chelating portion of matrix metalloproteinase (MMP) inhibitors, we have developed a family of heterocyclic zinc-binding groups (ZBGs) as alternatives to the widely used hydroxamic acid moiety. Elaborating on findings from an earlier report, we performed in vitro inhibition assays with recombinant MMP-1, MMP-2, and in a cell culture assay using neonatal rat cardiac fibroblast cells. In both recombinant and cell culture assays, the new ZBGs were found to be effective inhibitors, typically 10–100-fold more potent than acetohydroxamic acid. The toxicity of these chelators was examined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt cytotoxicity assays, which demonstrate that most of these compounds are nontoxic at concentrations of almost 100 μM. To address the possible interaction of sulfur-containing ZBGs with biological reductants, the reactivity of these chelators with 5,5′-dithiobis(2-nitrobenzoic acid) was examined. Finally, thione ZBGs were shown to be effective inhibitors of cell invasion through an extracellular matrix membrane. The data presented herein suggest these heterocyclic ZBGs are potent, nontoxic, and biocompatible compounds that show promise for incorporation into a new family of MMP inhibitors.     

Design, synthesis, biological evaluation and molecular modeling of 1,3,4-oxadiazoline analogs of combretastatin-A4 as novel antitubulin agents

A total of 20 novel 1,3,4-oxadiazoline analogs (6a-6t) of combretastatin A-4 with naphthalene ring were designed, synthesized, and evaluated for biological activities as potential tubulin polymerization inhibitors. Among these compounds, 6n showed the most potent antiproliferative activities against multiple cancer cell lines and retained the microtubule disrupting effects. Docking simulation was performed to insert compound 6n into the crystal structure of tubulin to determine the probable binding model. These results indicated oxadiazoline compounds bearing the naphthyl moiety are promising tubulin inhibitors.     

Carbonic anhydrase inhibitors: inhibition of isozymes I, II and IV by sulfamide and sulfamic acid derivatives

Sulfamide and sulfamic acid are the simplest compounds containing the SO2NH2 moiety, responsible for binding to the Zn(II) ion within carbonic anhydrase (CA, EC 4.2.1.1) active site, and thus acting as inhibitors of the many CA isozymes presently known. Here we describe two novel classes of CA inhibitors obtained by derivatizations of the lead molecules mentioned above. The new compounds, possessing the general formula RSO2NH-SO2X (X = OH, NH2), were obtained by reaction of sulfamide or sulfamic acid with alkyl/arylsulfonyl halides or arylsulfonyl isocyanates. A smaller series of derivatives has been obtained by reaction of aromatic aldehydes with sulfamide, leading to Schiff bases of the type ArCH = NSO2NH2. All the new compounds act as strong inhibitors of isozymes I, II and IV of carbonic anhydrase. Their mechanism of CA inhibition is also discussed based on electronic spectroscopic measurements on adducts with the Co(II)-substituted enzyme. These experiments led to the conclusion that the new inhibitors are directly coordinated (in a monodentate manner) to the metal ion within the enzyme active site, similarly to the classical inhibitors, the aromatic/heterocyclic sulfonamides.     

Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model

Botulinum neurotoxins (BoNTs) are the most poisonous biological substance known to humans. They cause flaccid paralysis by blocking the release of acetylcholine at the neuromuscular junction. Here, we report a number of small molecule non-peptide inhibitors of BoNT serotype E. The structure–activity relationship and a pharmacophore model are presented. Although non-peptidic in nature, these inhibitors mimic key features of the uncleavable substrate peptide Arg-Ile-Met-Glu (RIME) of the SNAP-25 protein. Among the compounds tested, most of the potent inhibitors bear a zinc-chelating moiety connected to a hydrophobic and aromatic moiety through a carboxyl or amide linker. All of them show low micromolar IC₅₀ values.     

Peptide derivatives as inhibitors of NS2B-NS3 protease from Dengue,West Nile,and Zika flaviviruses

Currently, more than 70 flaviviruses were identified and reported in the literature, whose Dengue (DENV), Zika (ZIKV), and West Nile (WNV) viruses have been responsible for millions of cases of infections worldwide, mainly in developing countries. These viruses are transmitted by the bite of mosquitoes from genus Aedes, or Culex and, in some cases, Stegomyia. Despite numerous efforts to identify a selective, safe, and effective antiviral agent, there is no currently approved drug for the treatment of flaviviral infections. Then, current pharmacological therapy has the objective to treat the clinical symptoms. Various peptidomimetics and peptide-derivatives have been synthesized and evaluated against several biological targets from flaviviruses with different applications, such as diagnosis, E protein inhibitors, entry inhibitors, virucidal inhibitors, and also viral replication inhibitors. Flaviviral replication depends on the NS3^pro that is completely activated when it is complexed to its cofactor, NS2B; forming a viral enzymatic complex. The development of NS2B-NS3^pro inhibitors is considered a challenging work due to its active site is shallow and open-pocket. In this work, we report all advances involving peptidomimetics, peptide-derived, and peptide-hybrids found in the literature. In sense, we discuss the influence of different functional groups in the activity and selectivity. Moreover, the first inhibitors reported in the literature as covalent ligands, comprising two basic residues followed by an electrophilic moiety that binds to the catalytic serine (Ser¹³⁵–O^?) are also discussed in details, such as trifluoromethyl ketones, aldehydes, and boronic acids. Furthermore, it is presented the influence of introducing transition metals, providing metallopeptide inhibitors; and cyclization of linear peptides, generating cyclic and macrocyclic peptide inhibitors. Finally, we provide the most accurate state of the art found in the literature, which can be utilized to design new and effective antiviral agents.     

Aryl tetrahydropyridine inhibitors of farnesyltransferase: glycine,phenylalanine and histidine derivatives

Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered a series of aryl tetrahydropyridines that incorporate substituted glycine, phenylalanine and histidine residues. The design, synthesis, SAR and biological properties of these compounds will be discussed.     

True interaction mode of porcine pancreatic elastase with FR136706, a potent peptidyl inhibitor

The crystal structure of porcine pancreatic elastase (PPE) complexed with a potent peptidyl inhibitor, FR136706, was solved at 2.2A resolution. FR136706 fits snugly into the extended active site pocket. The benzene moiety of FR136706 induced dramatic movement of the side chain moiety of Arg217 and both moieties formed a pi-pi interaction, which has never been found previously in structures of PPE complexed with inhibitors. This novel interaction mode may lead to design of new types of inhibitors.     

Cinnamoyl nitrogen mustard derivatives of pyrazole analogues of tallimustine modified at the amidino moiety: design, synthesis, molecular modeling and antitumor activity studies

The design, synthesis and in vitro activities of a series of cinnamoyl nitrogen mustard pyrazole analogues of tallimustine 8-13, in which the amidino moiety has been replaced by moieties of different physico-chemical features are described, and the structure-activity relationships are discussed. In spite of the relevance of these modifications on the amidino moiety, these derivatives showed significant growth inhibitory activity against mouse leukemia L1210 cells. A selected series of compounds have been evaluated for their sequence selective alkylating properties and cytotoxicity against human K562 leukemia cells. Therefore, the presence of the amidino moiety, and in general of a basic moiety, is not an absolute requirement for biological activity. Our preliminary results indicated that the compounds of this series have a pattern of alkylation similar to that of tallimustine, but they seem to be less reactive overall in alkylating naked DNA.     

Submicromolar phosphinic inhibitors of Escherichia coli aspartate transcarbamoylase

The design, syntheses, and enzymatic activity of two submicromolar competitive inhibitors of aspartate transcarbamoylase (ATCase) are described. The phosphinate inhibitors are analogs of N-phosphonacetyl-l-aspartate (PALA) but have a reduced charge at the phosphorus moiety. The mechanistic implications are discussed in terms of a possible cyclic transition-state during enzymatic catalysis.