New non-hydroxamic ADAMTS-5 inhibitors based on the 1,2,4-triazole-3-thiol scaffold

In this Letter we describe the design, synthesis, screening, and optimization of a new family of ADAMTS-5 inhibitors. These inhibitors display an original 1,2,4-triazole-3-thiol scaffold as a putative zinc binding-group. In vitro results are rationalized by in silico docking of the compounds in ADAMTS-5’s crystal structure.     

Novel interleukin-5 inhibitors based on hydroxyethylaminomethyl-4H-chromen-4-one scaffold

Hydroxyethylaminomethyl-4H-chromenones were previously discovered as fairly strong IL-5 inhibitor. For determination of detail structure activity relationship, N-substituted hydroxyethylaminomethylchromenones 4a–n were prepared and evaluated for their IL-5 inhibitory activity. Shifting the hydrophobic group to nitrogen from 1-position of hydroxyethylamino moiety of hydroxyethylaminomethyl-4H-chromenones enhances the activity. The increment in bulkiness or hydrophobicity of alkyl side chain at amino group increases the activity. The same level of activity of 5-(cyclohexylmethoxy)-3-(N-benzyl-2-hydroxyethylaminomethyl)-4H-chromenone analogs regardless of hydrophobic or hydrophilic substituents at 4th position of phenyl ring might infer the existence of tunnel structure in the putative receptor for accepting these side chains.     

Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors

A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N-benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC₅₀ up to 7.7 nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC₅₀ from 0.19 to 0.71 μM) and c-Met activation-mediated cell metastasis. At a dose of 100 mg/Kg, (R)-10b evidently inhibited tumor growth (45%) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.     

Synthetic hookworm-derived peptides are potent modulators of primary human immune cell function that protect against experimental colitis in vivo

The prevalence of autoimmune diseases is on the rise globally. Currently, autoimmunity presents in over 100 different forms and affects around 9% of the world’s population. Current treatments available for autoimmune diseases are inadequate, expensive, and tend to focus on symptom management rather than cure. Clinical trials have shown that live helminthic therapy can decrease chronic inflammation associated with inflammatory bowel disease and other gastrointestinal autoimmune inflammatory conditions. As an alternative and better controlled approach to live infection, we have identified and characterized two peptides, Acan1 and Nak1, from the excretory/secretory component of parasitic hookworms for their therapeutic activity on experimental colitis. We synthesized Acan1 and Nak1 peptides from the Ancylostoma caninum and Necator americanus hookworms and assessed their structures and protective properties in human cell–based assays and in a mouse model of acute colitis. Acan1 and Nak1 displayed anticolitic properties via significantly reducing weight loss and colon atrophy, edema, ulceration, and necrosis in 2,4,6-trinitrobenzene sulfonic acid–exposed mice. These hookworm peptides prevented mucosal loss of goblet cells and preserved intestinal architecture. Acan1 upregulated genes responsible for the repair and restitution of ulcerated epithelium, whereas Nak1 downregulated genes responsible for epithelial cell migration and apoptotic cell signaling within the colon. These peptides were nontoxic and displayed key immunomodulatory functions in human peripheral blood mononuclear cells by suppressing CD4⁺ T cell proliferation and inhibiting IL-2 and TNF production. We conclude that Acan1 and Nak1 warrant further development as therapeutics for the treatment of autoimmunity, particularly gastrointestinal inflammatory conditions.     

Over-expression of CXCR4 on mesenchymal stem cells protect against experimental colitis via immunomodulatory functions in impaired tissue

Bone marrow-derived mesenchymal stem cells (BMSCs) are attractive candidates for tissue regeneration and immunoregulation in inflammatory bowel disease. However, their in vivo reparative capability is limited owing to barren efficiency of BMSCs to injury region. Stromal cell-derived factor (SDF-1) plays an important role in chemotaxis and stem cell homing through interaction with its specific receptor CXC chemokine receptor 4 (CXCR4). The present study was designed to investigate the role of SDF-1α/CXCR4 axis in the therapeutic effects of lentivirus-preconditioned BMSCs for 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis rats. BMSCs were isolated from female Sprague–Dawley rats and identified by flow cytometry. Lentiviral transduction was applied to over-express CXCR4/GFP (Ad-CXCR4-BMSCs) or null/GFP (Ad-GFP-BMSCs). Efficacy of engraftment was determined by the presence of enhanced green fluorescent protein (GFP) positive cells. One week after intravenous administration, Ad-GFP-BMSCs failed to colonize in the inflamed colon and had no beneficial effect in TNBS-induced colitis. Instead, Ad-CXCR4-BMSCs signally ameliorated both clinical and microanatomical severity of colitis. Immunofluorescence and western blotting showed that Ad-CXCR4-BMSCs migrated toward inflamed colon was more efficient than Ad-GFP-BMSCs. The therapeutic effect of Ad-CXCR4-BMSCs was mediated by the suppression of pro-inflammatory cytokines and STAT3 phosphorylation in injured colon. Collectively, our data indicated that over-expression CXCR4 led to enhance in vivo mobilization and engraftment of BMSCs into inflamed colon where these cells can function as an anti-inflammatory and immunomodulatory component of the immune system in TNBS-induced colitis.     

3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold

With annual death tolls in the millions and emerging resistance to existing drugs, novel therapies are needed against malaria. Wiesner et al. recently developed a novel class of antimalarials derived from farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold. The compounds displayed a wide range of activity, including submicromolar, against the multi-drug resistant Plasmodium falciparum strain Dd2. In order to investigate quantitatively the local physicochemical properties involved in the interaction between drug and biotarget, we used the 3D-QSAR methods CoMFA and CoMSIA to study some of the series, including the screened lead compound 2,5-bis-acylaminobenzophenone, 28 cinnamic acid derivatives, 29 N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides, and 34 N-(4-substituted-amino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides. We found that steric, electrostatic, and hydrophobic properties of substituent groups play key roles in the bioactivity of the series of compounds, while hydrogen bonding interactions show no obvious impact. We built several highly predictive 3D-QSAR models, including a CoMSIA one composed of steric, electrostatic, and hydrophobic fields, with r(2)=0.94, q(2)=0.63, and r(pred)(2)=0.63. The results provide insight for optimization of this class of antimalarials for better activity and may prove helpful for further lead optimization.     

The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold

Imidazole-based structures of p38 inhibitors served as a starting point for the design of JNK3 inhibitors. Construction of a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold led to the synthesis of the (S)-enantiomers, which exhibited p38/JNK3 IC50 ratio of up to 10 and were up to 20 times more potent inhibitors of JNK3 than the relevant (R)-enantiomers. The JNK3 inhibitory potency correlated well with inhibition of c-Jun phosphorylation and neuroprotective properties of the compounds in low K+-induced cell death of rat cerebellar granule neurones.     

Potent norovirus inhibitors based on the acyclic sulfamide scaffold

The development of small molecule therapeutics to combat norovirus infection is of considerable interest from a public health perspective because of the highly contagious nature of noroviruses. A series of amino acid-derived acyclic sulfamide-based norovirus inhibitors has been synthesized and evaluated using a cell-based replicon system. Several compounds were found to display potent anti-norovirus activity, low toxicity, and good aqueous solubility. These compounds are suitable for further optimization of pharmacological and ADMET properties.     

Human chymase inhibitors based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold.

A series of compounds that utilize the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold was synthesized and shown to be highly effective inhibitors of recombinant human skin chymase.     

Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold

Poly(ADP-ribose)polymerase-I (PARP-1) enzyme is involved in maintaining DNA integrity and programmed cell death. A virtual screening of commercial libraries led to the identification of five novel scaffolds with inhibitory profile in the low nanomolar range. A hit-to-lead optimization led to the identification of a group of new potent PARP-1 inhibitors, acyl-piperazinylamides of 3-(4-oxo-3,4-dihydro-quinazolin-2-yl)-propionic acid. Molecular modeling studies highlighted the preponderant role of the propanoyl side chain.     

New inhibitors of fungal 17beta-hydroxysteroid dehydrogenase based on the [1,5]-benzodiazepine scaffold

The synthesis and activity of a new series of non-steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase that are based on a 1,5-benzodiazepine scaffold are presented. Their inhibitory potential was screened against 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17beta-HSDcl), a model enzyme of the short-chain dehydrogenase/reductase superfamily. Some of these compounds are potent inhibitors of 17beta-HSDcl activity, with IC50 values in the low micromolar range and represent promising lead compounds that should be further developed and investigated as inhibitors of human 17beta-HSD isoforms, which are the enzymes associated with the development of many hormone-dependent and neuronal diseases.     

Synthesis of alpha amylase inhibitors based on privileged indole scaffold

Twenty five derivatives of indole carbohydrazide (1–25) had been synthesized. These compounds were characterized using ¹H NMR and EI-MS, and further evaluated for their α-amylase inhibitory potential. The analogs (1–25) showed varying degree of α-amylase inhibitory potential.ranging between 9.28 and 599.0 µM when compared with standard acarbose having IC₅₀ value 8.78 ± 0.16 µM. Six analogs, 25 (IC₅₀ = 9.28 ± 0.153 µM), 22 (IC₅₀ = 9.79 ± 0.43 µM), 4 (IC₅₀ = 11.08 ± 0.357 µM), 1 (IC₅₀ = 12.65 ± 0.169 µM), 8 (IC₅₀ = 21.37 ± 0.07 µM) and 14 (IC₅₀ = 43.21 ± 0.14 µM) showed potent α-amylase inhibition as compared to the standard acarbose (IC₅₀ = 8.78 ± 0.16 µM). All other analogs displayed good to moderate inhibitory potential. Structure-activity relationship was established through the interaction of the active compounds with enzyme active site with the help of docking studies.     

The effect of angiotensin-converting enzyme inhibitors on experimental colitis in rats

The present study was aimed to investigate the effect of ACE inhibition on trinitrobenzene sulphonic acid (TNBS)-induced colonic inflammation in rats by using captopril and lisinopril. In treatment groups, the rats were treated with ACE inhibitors, captopril or lisinopril (0.1 and 1 mg/kg/day; intraperitoneally). The drugs were given 5 min after induction of colitis and the treatment was continued for 3 days. Three days after the induction of colitis, all rats were decapitated. The distal colon was weighed and the mucosal lesions were scored at both macroscopical at microscopic levels. Malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were assessed in tissue samples. Formation of reactive oxygen species in colonic samples was monitored by using chemiluminescence technique. Serum TNF-alphalevel was assessed in trunk blood. Captopril treatment was found to be beneficial in all parameters, except colonic glutathione content. On the other hand, although stimulation of lipid peroxidation and increase in serum TNF-alpha level were successfully prevented by lisinopril, the morphology of the lesions remained unchanged. In conclusion, sulphydryl and non-sulphydryl ACE inhibitors, captopril and lisinopril do not seem to be similarly effective in TNBS-induced colitis model at least at the doses tested in our study.     

Synthesis and biological evaluation of histone deacetylase inhibitors that are based on FR235222: a cyclic tetrapeptide scaffold

We outline the synthesis of six novel derivatives that are based on a recently discovered HDAC inhibitor FR235222. Our work is the first report utilizing a novel binding element, guanidine, as metal coordinators in HDAC inhibitors. Further, we demonstrate that these compounds show cytotoxicity that parallels their ability to inhibit deacetylase activity, and that the most potent compounds maintain an L-Phe at position 1, and a D-Pro at position 4. Both inhibition of HDAC activity and cytotoxicity against the pancreatic cancer cell line BxPC3 are exhibited by these compounds, establishing that a guanidine unit can be utilized successfully to inhibit HDAC activity.     

New artificial siderophores based on a monosaccharide scaffold

New artificial catecholate siderophores with methyl -d-glucopyranoside as scaffold were synthesized. The dihydroxy- or di(acetoxy)benzoyl moieties were attached either directly or via aminopropyl spacer groups, to the carbohydrate scaffold. The siderophore activity of the prepared siderophore analogs was examined by a growth promotion assay using various Gram-negative bacteria and mycobacteria and by the CAS-assay.     

Straightforward synthesis of novel Akt inhibitors based on a glucose scaffold

Glucose-based analogues of phosphatidylinositol 3-phosphate were straightforwardly synthesised from 2,3,4,6-tetra-O-acetyl-d-glucosyl bromide as protein kinase B (PKB/Akt) inhibitors. β-d-Glucuronyl diethyl phosphoramidate was identified as a promising hit through biological screening in two different cellular systems. In addition, RNA interference experiments (siRNA) provide evidence of the ability of the compound to exert biological effects specifically through Akt signalling.     

Synthesis of novel brassinosteroid biosynthesis inhibitors based on the ketoconazole scaffold

Brassinosteroids (BRs) are steroidal plant hormones that control several important agronomic traits such as plant architecture, seed yield, and stress tolerance. Inhibitors that target BR biosynthesis are candidate plant growth regulators. We synthesized novel triazole derivatives, based on the ketoconazole scaffold, that function as inhibitors of BR biosynthesis. The biological activity of the test compounds was evaluated by determining their ability to induce dwarfism in Arabidopsis seedlings grown in the dark. The chemically induced dwarfism of Arabidopsis seedlings was further evaluated by a rescue experiment using the co-application of brassinolide and/or gibberellins (GA). The structure-activity relationship studies revealed a potent BR biosynthesis inhibitor, 2RS, 4RS-1-{2-(4-chlorophenyl)-4-[2-(2-ethoxyphenyl)-ethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole (7m), with an IC(50) value of 0.10±0.03 μM for retardation of Arabidopsis seedling stem elongation. The compound-induced hypocotyl dwarfism was counteracted by the co-application of 10nM brassinolide, but not 1 μM GA(3), which produced seedlings that resembled BR-deficient mutants. This result suggests that 7m is a potent and specific inhibitor of BR biosynthesis.     

FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity

Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.     

Noncovalent inhibitors of human leukocyte elastase based on the 4-imidazolidinone scaffold

A central problem associated with the design of enzyme inhibitors in general, and serine protease inhibitors in particular, is the identification of templates capable of binding to the active site of an enzyme in a predictable and substrate-like fashion, orienting appended recognition elements in a correct spatial relationship so that favorable binding interactions with multiple sites are achieved. Described herein for the first time is the design of noncovalent inhibitors of human leukocyte elastase that employs a functionalized 4-imidazolidinone scaffold.     

Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold

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