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The biological activities of deoxy sugars (deoxy monosaccharides) have remained largely unstudied until recently. We compared the growth inhibition by all 1-deoxyketohexoses using the animal model Caenorhabditis elegans. Among the eight stereoisomers, 1-deoxy- d -allulose (1d- d -Alu) showed particularly strong growth inhibition. The 50% inhibition of growth (GI 50) concentration by 1d- d -Alu was estimated to be 5.4 mM, which is approximately 10 times lower than that of d -allulose (52.7 mM), and even lower than that of the potent glycolytic inhibitor, 2-deoxy- d -glucose (19.5 mM), implying that 1d- d -Alu has a strong growth inhibition. In contrast, 5-deoxy- and 6-deoxy- d -allulose showed no growth inhibition of C. elegans. The inhibition by 1d- d -Alu was alleviated by the addition of d -ribose or d -fructose. Our findings suggest that 1d- d -Alu-mediated growth inhibition could be induced by the imbalance in d -ribose metabolism. To our knowledge, this is the first report of biological activity of 1d- d -Alu which may be considered as an antimetabolite drug candidate. [ABSTRACT FROM AUTHOR]

A high-throughput screening (HTS) campaign was carried out for Trypanosoma cruzi glucokinase (Tc GlcK), a potential drug-target of the pathogenic protozoan parasite. Glycolysis and the pentose phosphate pathway (PPP) are important metabolic pathways for T. cruzi and the inhibition of the glucose kinases (i.e. glucokinase and hexokinase) may be a strategic approach for drug discovery. Glucose kinases phosphorylate d -glucose with co-substrate ATP to yield G6P, and moreover, the produced G6P enters both pathways for catabolism. The Tc GlcK – HTS campaign revealed 25 novel enzyme inhibitors that were distributed in nine chemical classes and were discovered from a primary screen of 13,040 compounds. Thirteen of these compounds were found to have low micromolar IC 50 enzyme – inhibition values; strikingly, four of those compounds exhibited low toxicity towards NIH-3T3 murine host cells and notable in vitro trypanocidal activity. These compounds were of three chemical classes: (a) the 3-nitro-2-phenyl-2 H -chromene scaffold, (b) the N -phenyl-benzenesulfonamide scaffold, and (c) the gossypol scaffold. Two compounds from the 3-nitro-2-phenyl-2 H -chromene scaffold were determined to be hit-to-lead candidates that can proceed further down the early-stage drug discovery process. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Discovery and SAR of a first-in-class series of selective PPARα/δ dual antagonists. • Identification of a robust lead molecule, compound 11 , fit for proof-of-concept studies. • Demonstration of target engagement with PPAR-associated genes (ACOT2 and CPT1a) • Preliminary evidence for efficacy in fatty-acid metabolizing cancer models. Abstract We previously published on the design and synthesis of novel, potent and selective PPARα antagonists suitable for either i.p. or oral in vivo administration for the potential treatment of cancer. Described herein is SAR for a subsequent program, where we set out to identify selective and potent PPARα/δ dual antagonist molecules. Emerging literature indicates that both PPARα and PPARδ antagonism may be helpful in curbing the proliferation of certain types of cancer. This dual antagonism could also be used to study PPARs in other settings. After testing for selective and dual potency, off-target counter screening, metabolic stability, oral bioavailability and associated toxicity, compound 11 , the first reported PPARα/δ dual antagonist was chosen for more advanced preclinical evaluation. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Two first examples of potent (low μM) inhibitors against the tRNA-activated human SIRT7 deacetylase activity were found. • The two inhibitors are cyclic tripeptides each harboring a catalytic mechanism-based sirtuin inhibitory warhead. • The two inhibitors also exhibited potent (low μM) inhibition against the deacylase activities of human SIRT1/2/3/6. • Our finding could facilitate the future development of more potent and selective human SIRT7 inhibitors. Abstract In the current study, two cyclic tripeptides respectively harboring a thiourea-type and a carboxamide-type of catalytic mechanism-based sirtuin inhibitory warheads as the central residue were found to behave as potent (low μM level) inhibitors against the tRNA-activated human SIRT7 deacetylase activity. Despite exhibiting a potent pan-inhibition against the deacylase activities of the five tested human sirtuins (i.e. SIRT1/2/3/6/7), these two compounds represent the first examples of potent SIRT7 inhibitors ever identified thus far, and their identification could facilitate the future development of more potent and selective SIRT7 inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders. Herein, based on the existing PDE2 inhibitors and their binding modes, a series of purin-6-one derivatives were designed, synthesized and evaluated for PDE2 inhibitory activities, which led to the discovery of the best compounds 6p and 6s with significant inhibitory potency (IC 50 : 72 and 81 nM, respectively). Docking simulation was performed to insert compound 6s into the crystal structure of PDE2 at the active site to determine the binding mode. Furthermore, compound 6s significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cAMP and cGMP levels. It also produced anxiolytic-like effect in the elevated plus-maze test and exhibited favorable pharmacokinetic properties in vivo. These results might bring significant instruction for further development of potent PDE2 inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • New class of Wnt/β-catenin inhibitors discovered from SAR studies of Niclosamide. • The amide SAR of Niclosamide clarified. • Replacement of Niclosamide's amide with a triazole provides Wnt inhibitors. Abstract Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Virtual docking of 1648 covalent fragments is performed. • Covalent inhibitor of Cathepsin L is identified. • Cathepsin L inhibitor did not inhibit USP8, Calpain I, Cathepsin B. Abstract Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of covalent fragments as an approach to discover covalent enzyme inhibitors. [ABSTRACT FROM AUTHOR]

Piperlongumine (PL), isolated from Piper longum L., is receiving intense interest due to its selectively ability to kill cancer cells but not normal cells. We synthesized a number of analogues by replacing the cyclic amide of PL with aliphatic amides to explore structural diversity. Compound CG-06 had the strongest cytotoxic profile of this series, showing potent effects in human prostate cancer DU-145 cells, in which signal transducer and activator of transcription 3 (STAT3) is constitutively active. CG-06 inhibited STAT3 phosphorylation at tyrosine 705 in a dose- and time dependent manner in DU-145 cells and suppressed IL-6-induced STAT3 phosphorylation at Tyr-705 in DU-145 and LNCaP cell lines. CG-06 decreased the expression levels of STAT3 target genes, such as cyclin A, Bcl-2, and survivin. Notably, we used drug affinity responsive target stability (DARTS) to show that CG-06 binds directly to STAT3, and the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) rescued the CG-06 -induced suppression p-STAT3. Our results suggest that CG-06 is a novel inhibitor of STAT3 and may be a useful lead molecule for the development of a therapeutic STAT3 inhibitor. [ABSTRACT FROM AUTHOR]

The P2X3 receptor is primarily expressed in the peripheral sensory nerves, and therefore, antagonists of this receptor may be useful for the treatment of chronic pain. Pyrrolinone derivatives have been identified as a novel class of P2X3 receptor antagonists. A lead structure with moderate activity was discovered through a high-throughput screening assay. A structure-activity study led to the discovery of several P2X3 receptor antagonists. Compound 34 showed potent and specific antagonistic activity and analgesic efficacy. [ABSTRACT FROM AUTHOR]

A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3- syn -diol and 1,3- anti -diol chemophoric moieties, e.g. 4a – d and 5a – c respectively, have been designed and synthesized starting from d -glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve™ as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca 2+ ] i release assay, 4a and 5a , when tested at 30 μM, inhibited the trypsin agonist induced protease-activated receptor-2 (PAR2) activity by 80% and 70% respectively. IC 50 of 4a (SB70) has been determined as 6 μM which is in the same range of current benchmarks for PAR2 antagonists. [ABSTRACT FROM AUTHOR]

In order to replace thiourea group with the more drug-like moiety for 1,3-dibenzylthioureas having TRPV1 antagonist activity, we introduced a set of functional groups between the two aromatic rings based on bioisosteric replacement. The synthesized bioisosteres of 1,3-dibenzylthioureas were tested for their antagonist activities on TRPV1 by 45 Ca 2+ -influx assay using neonatal rat cultured spinal sensory neurons. Among the tested 14 kinds of bioisosters, 2-methylacrylamide group was the best candidate to replace thiourea group. Compound 7c , 2-methylacrylamide analog of ATC-120, showed as potent as ATC-120 in its antagonist activity. In addition, 2-methylacrylamide analog 7e having vinyl moiety showed the most potent activity with 0.022 μM of IC 50 value, indicating that thiourea group of 1,3-dibenzylthioureas could be replaced to 2-methylacrylamide without loss of their potencies. [ABSTRACT FROM AUTHOR]

The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 α-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The condensation of α-pyridinium methyl ketone salts and α,β-unsaturated carbonyl compounds in the presence of a source of ammonia, or the Kröhnke pyridine synthesis, is a simple approach to afford highly functionalized pyridines. We adapted this chemistry to rapidly generate low-micromolar inhibitors of Mcl-1 wherein the 2,4,6-substituents were predicted to mimic the i , i  + 2 and i  + 7 side chains of the BH3 α-helix. [ABSTRACT FROM AUTHOR]

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1 H -pyrrolo[2,3- c ]pyridin-7(6 H )-ones (A) and the 1-methyl-1 H -pyrrolo[2,3- c ]pyridin-7(6 H )-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models. [ABSTRACT FROM AUTHOR]

A hit to lead process to identify reversible, orally available ADP receptor (P2Y 12 ) antagonists lead compounds is described. High throughput screening afforded 1 . Optimization of 1 , using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23 . Compound 23 is an orally available, competitive reversible antagonist (K B  = 94 nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low, reasonable levels were achieved to merit extensive lead optimization of this structural class. [ABSTRACT FROM AUTHOR]

The mechanism of an antioxidant action of water-soluble polyol – methanofullerenes C 60 [ C 9 H 10 O 4 ( OH ) 4 ] 6 and C 60 [ C 13 H 18 O 4 ( OH ) 4 ] 6 as the mild uncouplers of an oxidative phosphorylation and respiration is postulated. According to this mechanism, hydroxyl group of methanofullerenols can be protonated under excess of protons in the intermembrane space of hyperpolarized mitochondria. Protonation of fullerene derivatives is confirmed by the decrease in their negative Zeta potential in the pH below 5.4. Heavily protonated methanofullerenols become positively charged and move into the mitochondrial matrix. As a consequence, the proton gradient is dissipated, which causes a decrease in mitochondrial transmembrane potential (ΔΨ m ) and reduction in ROS production. [ABSTRACT FROM AUTHOR]

Sesquiterpene compounds are widely known for their numerous pharmacological activities. Herein the focus of the authors was on α-Santonin, a sesquiterpene lactone from the Artemisia genus: the aim was to determine whether α-Santonin could be considered in the treatment of inflammation and pain. To this purpose, a small series of derivatives was designed and screened in silico against the enzyme COX-2 along with the parent compound. Drug-likeness parameters were also assessed. The compounds were eventually synthesized, and few were tested to determine their efficacy in the inhibition of COX-2 activity and expression. Overall, compound A2 was the only one with a detectable inhibitory potential of COX-2 activity whilst two of its ether derivatives demonstrated improved ability in the inhibition of COX-2 expression. [ABSTRACT FROM AUTHOR]

An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4 , improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity. [ABSTRACT FROM AUTHOR]

Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability. [ABSTRACT FROM AUTHOR]

A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC 50  = 52.0 ± 0.09 µg/ml), 4h (IC 50  = 56.0 ± 0.71 µg/ml) and 4l (IC 50  = 59.3 ± 0.55 µg/ml) were shown significant antileishmanial when compared with standard sodium stibogluconate (IC 50  = 490.0 ± 1.5 µg/ml). Antioxidant study revealed that compounds 4i (IC 50  = 2.44 ± 0.47 µg/ml) and 4l (IC 50  = 3.69 ± 0.44 µg/ml) have shown potent comparable activity when compared with standard ascorbic acid (IC 50  = 3.31 ± 0.34 µg/ml). Molecular docking study was carried out which replicating results of biological activity in case of initial hits 4f and 4h suggesting that these compounds have a potential to become lead molecules in drug discovery process. In silico ADME study was performed for predicting pharmacokinetic profile of the synthesised antileishmanial agents and expressed good oral drug like behaviour. [ABSTRACT FROM AUTHOR]

Novel 2-aryl-cyclic-1,3-diones containing a 5-methoxy-[1,2,5]triazepane unit were explored towards an effective and wheat safe control of grass weeds. Their preparation builds on the ease of synthetic access to 7-membered heterocyclic [1,2,5]triazepane building blocks. Substitution and pattern hopping in the phenyl moiety revealed structure–activity relationships in good agreement with previously disclosed observations amongst the pinoxaden family of acetyl-CoA carboxylase inhibitors. In light of basic physicochemical, enzyme inhibitory and binding site properties, the N- methoxy functionality effectively acts as a bioisostere of the ether group in the seven-membered hydrazine ring. [ABSTRACT FROM AUTHOR]

Prostaglandin E 2 (PGE 2 ) is a lipid mediator of inflammation and its inhibition has become a popular drug target due to its harmful physiological roles. Diarylheptanoids are one class of compounds that have shown successful inhibition of PGE 2 . This paper reports the synthesis and PGE 2 inhibitory activity of a series of analogues of a naturally occurring diarylheptanoid. The most efficacious compounds were examined for dose-dependent PGE 2 inhibition. Among several promising compounds, the lead candidate exhibited an IC 50 value of 0.56 ng/µL or 1.7 µM with no detectable toxicity at the highest dose of 10 ng/µL. [ABSTRACT FROM AUTHOR]

The viral protein HIVgp41 is an attractive and validated drug target that proceeds through a sequence of conformational changes crucial for membrane fusion, which facilitates viral entry. Prior work has identified inhibitors that interfere with the formation of a required six-helix bundle, composed of trimeric C-heptad (CHR) and N -heptad (NHR) repeat elements, through blocking association of an outer CHR helix or obstructing formation of the inner NHR trimer itself. In this work, we employed similarity-based scoring to identify and experimentally characterize 113 compounds, related to 2 small-molecule inhibitors recently reported by Allen et al. ( Bioorg. Med. Chem Lett. 2015 , 25 2853–59), proposed to act via the NHR trimer obstruction mechanism. The compounds were first tested in an HIV cell-cell fusion assay with the most promising evaluated in a second, more biologically relevant viral entry assay. Of the candidates, compound #11 emerged as the most promising hit (IC 50 = 37.81 µM), as a result of exhibiting activity in both assays with low cytotoxicity, as was similarly seen with the known control peptide inhibitor C34. The compound also showed no inhibition of VSV-G pseudotyped HIV entry compared to a control inhibitor suggesting it was specific for HIVgp41. Molecular dynamics simulations showed the predicted DOCK pose of #11 interacts with HIVgp41 in an energetic fashion (per-residue footprints) similar to the four native NHR residues (IQLT) which candidate inhibitors were intended to mimic. [ABSTRACT FROM AUTHOR]

Pyrroloquinazoline is a privileged chemical scaffold with diverse biological activities. We recently described a series of N -3 acylated 1,3-diaminopyrroloquinazolines with potent anticancer activities. The N -1 primary amino group in 1,3-diaminopyrroloquinazoline is critical for its inhibitory activity against dihydrofolate reductase (DHFR). In order to design out this unnecessary DHFR inhibition activity and further expand the chemical space associated with pyrroloquinazoline, we removed the N -1 primary amino group. In this report, we describe our design and synthesis of a series of N -3 acylated monoaminopyrroloquinazolines. Biological evaluation of these compounds identified a naphthamide 4a as a potent anticancer agent (GI 50 = 88–200 nM), suggesting that removing the N -1 primary amino group in 1,3-diaminopyrroloquinazoline is a useful chemical modification that can be introduced to improve the anticancer activity. [ABSTRACT FROM AUTHOR]

A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excellent potency but were limited by high in vitro clearance in rat and human microsomes. Using a scaffold morphing strategy, these analogs were transformed into a related pyrazolo[4,3- b ]pyridine series with improved ADME properties. [ABSTRACT FROM AUTHOR]

This letter presents synthesis and structure-activity relationship study of sulfonamide derivatives as inhibitors of Human Uric Acid Transporter 1 (hURAT1). Among all tested sulfonamide derivatives, compounds 9b , 16i and 19b exhibited excellent inhibition activity with IC 50 value of 10, 2, and 83 nM, respectively. In addition, compounds 9b and 19b demonstrated moderate PK profile in rats. [ABSTRACT FROM AUTHOR]

Snakebites represent an important public health problem, with a great number of victims with permanent sequelae or fatal outcomes, particularly in rural, agriculturally active areas. The snake venom metalloproteases (SVMPs) are the principal proteins responsible for some clinically-relevant effects, such as local and systemic hemorrhage, dermonecrosis, and myonecrosis. Because of the difficulties in neutralizing them rapidly and locally by antivenoms, the search and design of small molecules as inhibitors of SVMPs are proposed. The Bothrops asper metalloprotease P 1 (BaP1) is hereby used as a target protein and by High Throughput Virtual Screening (HTVS) approach, the free access virtual libraries: ZINC, PubChem and ChEMBL, were searched for potent small molecule inhibitors. Results from the aforementioned approaches provided strong evidences on the structural requirements for the efficient BaP1 inhibition such as the presence of the pyrimidine-2,4,6-trione moiety. The two proposed compounds have also shown excellent results in performed in vitro interaction studies against BaP1. [ABSTRACT FROM AUTHOR]

2,2,2-Trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-yl}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol 1 was identified as a novel potent aldosterone synthase inhibitor. Despite large species differences, compound 1 inhibits both human and rodent CYP11B2 in a nano-molar range. [ABSTRACT FROM AUTHOR]

In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC 50 values of 9.3 nM and 9.7 nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme. These results suggest that compound 13h possessed nanomolar PI3Kδ inhibitory activity and distinctive chemical structure, deserving further structural optimization. [ABSTRACT FROM AUTHOR]

According to WHO, leishmaniasis is a major tropical disease, ranking second after malaria. Significant efforts have been therefore invested into finding potent inhibitors for the treatment. In this work, eighteen novel 1,2,3-triazoles appended with l -amino acid (Phe/Pro/Trp) tail were synthesized via azide-alkyne click chemistry with moderate to good yield, and evaluated for their anti-leishmanial activity against promastigote form of Leishmania donovani (Dd8 strain). Among all, compounds 40 , 43 , and 53 were identified with promising anti-leishmanial activity with IC 50 = 88.83 ± 2.93, 96.88 ± 12.88 and 94.45 ± 6.51 μM respectively and displayed no cytotoxicity towards macrophage cells. Moreover, compound 43 showed highest selectivity index (SI = 8.05) among all the tested compounds. Supported by docking studies, the lead inhibitors ( 40 , 43 and 53 ) showed interactions with key residues in the catalytic site of trypanothione reductase. The results of pharmacokinetic parameters suggest that these selected inhibitors can be carried forward for further structural optimization and pharmacological investigation. [ABSTRACT FROM AUTHOR]

A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo . [ABSTRACT FROM AUTHOR]

Previously, 4-tosylanthra[1,2- c ][1,2,5]thiadiazole-6,11-dione ( 1 ) was identified as a novel non-camptothecin topoisomerase I (Top1) inhibitor by structure-based virtual screening. Herein, a series of 4-substituted derivatives were designed and synthesized. Most of them showed potent Top1 inhibitory activity. Their in vitro antiproliferative activity was also evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines. Compound 8s showed good antiproliferative activity with IC 50 of 0.52 μM and 0.42 μM against HCT-116 and ZR-75-30 cell line, respectively. Top1 unwinding assay and molecular modeling studies rationalized the mode of action of this new class of inhibitors. [ABSTRACT FROM AUTHOR]

Starting from acylsufonamide HTS hit 2 , a novel series of para-N -acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 ( 4j ), which exhibited significantly improved pharmacological profiles over grapiprant ( 1 ). [ABSTRACT FROM AUTHOR]

To enhance aldose reductase (ALR2) inhibition and add antioxidant ability, phenolic hydroxyl was introduced both to the quinoxalinone core and C3 side chain, resulting in a series of derivatives as ALR2 inhibitors. Biological activity tests suggested that most of the derivatives were potent and selective inhibitors with IC 50 values ranging from 0.059 to 6.825 μM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2 H )-yl)acetic acid ( 6b ) was the most active. Particularly, it was encouraging to find that some derivatives endowed with obvious antioxidant activity, and among them the phenolic 3,4-dihydroxyl compound 6f with 7-hydroxyl in the quinoxalinone core showed the most potent activity, even comparable with the well-known antioxidant Trolox. Structure-activity relationship and docking studies highlighted the importance of phenolic hydroxyl both in C3 side chain and the core structure for constructing potent ALR2 inhibitors with antioxidant activity. [ABSTRACT FROM AUTHOR]

Proanthocyanidin, an oligomer of catechin, is a natural antioxidant and a potent inhibitor of lectin-like oxidized LDL receptor-1, which is involved in the pathogenesis of arteriosclerosis. We synthesized proanthocyanidin analogue 1 , in which the geometry of one catechin molecule in procyanidin B3, a dimer of (+)-catechin, is constrained to be planar. The antioxidant activities of the compounds were evaluated in terms of their capacities to scavenge galvinoxyl radicals, and results demonstrate that while procyanidin was 3.8 times more potent than (+)-catechin, the radical scavenging activity of proanthocyanidin analogue 1 was further increased to 1.9 times that of procyanidin B3. This newly designed proanthocyanidin analogue 1 may be a promising lead compound for the treatment of arteriosclerosis and related cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Our initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC 50 values ⩽1 μM and 11 effective at ⩽2 μM in an ex vivo assay. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a clonal disorder of hematopoietic progenitor cell. In AML, a mutation in FLT3 is commonly occurs and is associated with poor prognosis. We have previously reported that thieno[2,3 -d ]pyrimidine derivative compound 1 exhibited better antiproliferative activity against MV4-11 cells which harbor mutant FLT3 than AC220 , which is a well-known FLT3 inhibitor, and has good microsomal stability. However, compound 1 had poor solubility. We then carried out further structural modification at the C 2 and the C 6 positions of thieno[2,3 -d ]pyrimidine scaffold. Compound 13b , which possesses a thiazole moiety at the C 2 position, exhibited better antiproliferative activity than compound 1 and showed increased solubility and moderate microsomal stability. These results indicate that compound 13b could be a promising potential FLT inhibitor for AML chemotherapy. [ABSTRACT FROM AUTHOR]

Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC 50 for KLK1 The most active compound ( 10 ) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects. [ABSTRACT FROM AUTHOR]

Structure based virtual screening attempts to discover DUSP1 inhibitors have yielded a scaffold featuring benzoxazole and acylthiourea pharmacophore. A series of its analogues were synthesized to explore structure activity relationship (SAR) of DUSP1 inhibition. [ABSTRACT FROM AUTHOR]

This letter describes the development of a series of potent and selective small molecule Legumain inhibitors suitable as chemical probes for in vitro experiments. Our previous research had identified a dipeptide inhibitor utilizing a semi-reversible cyano warhead that generated 2 , a cell active inhibitor. This work explores an alternative P2-P3 linker and further SAR exploration of the P3 group which led to the identification of 16i , a highly potent inhibitor with excellent physiochemical properties. [ABSTRACT FROM AUTHOR]

Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core. [ABSTRACT FROM AUTHOR]

Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45 – 47 , 54 , 56 , and 65 , which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition. [ABSTRACT FROM AUTHOR]

We synthesized (+)-decursin derivatives substituted with cinnamoyl- and phenyl propionyl groups originating from (+)-CGK062 and screened them using a cell-based assay to detect relative luciferase reporter activity. Of this series, compound 8b , in which a 3-acetoxy cinnamoyl group was introduced, most potently inhibited (97.0%) the Wnt/β-catenin pathway. Specifically, compound 8b dose-dependently inhibited Wnt3a-induced expression of the β-catenin response transcription (CRT) and increased β-catenin degradation in HEK293 reporter cells. Furthermore, compound 8b suppressed expression of the downstream β-catenin target genes cyclin D1 and c-myc and suppressed PC3 cell growth in a concentration-dependent manner. [ABSTRACT FROM AUTHOR]

The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor’s extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying antibiotics resistance. Further synthetic modification was undertaken to optimize the potency of amide compounds. To lower metabolic susceptibility and in turn reduce unwanted metabolic toxicity that was observed clinically, while retaining desired antibacterial activity, the use of azoles as amide bioisosteres had also been investigated. After the completion of chemical synthesis, all the compounds were evaluated through in vitro antibacterial activity assay, some of which were further subject to in vivo rat pharmacokinetic assessment. Those findings in this letter showed that spiro cyclopropyl proline N -formyl hydroxylamines, and especially the bioisosteric azoles, can represent a promising class of PDF inhibitors. [ABSTRACT FROM AUTHOR]

A series of homologous analogues of prototype antagonist 1 and its urea surrogate were investigated as h TRPV1 ligands. Through one-carbon elongation in the respective pharmacophoric regions, N -(3-fluoro-4-methylsulfonamidomethylphenyl)urea was identified as a novel and potent TRPV1 antagonistic template. Its representative compound 27 showed a potency comparable to that of lead compound 1 . Docking analysis of compound 27 in our h TRPV1 homology model indicated that its binding mode was similar with that of 1 S . [ABSTRACT FROM AUTHOR]

The serine protease matriptase-2 has attracted much attention as a potential target for the treatment of iron overload diseases. In this study, a series of 27 symmetric, achiral bisbenzamidines was evaluated for inhibitory activity against human matriptase-2, against the closely related enzyme human matriptase, as well as against human thrombin, bovine factor Xa and human trypsin. The conformationally restricted piperazine derivative 19 and the oxamide-derived bisbenzamidine 1 were identified as the most potent inhibitors of this series for matriptase-2 and matriptase, respectively. [ABSTRACT FROM AUTHOR]

A series of pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF α release. Meanwhile, the activity of compounds containing 1,2,4-triazole (series II ) was higher than that of pyrazole-attached derivatives (series I ). The primary structure–activity relationship study and docking results showed that the 1,2,4-triazole moiety of compound IIk played a key role to form integral hydrogen bonds and π–π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound IIk would be great promise as a hit compound for further study based on the preliminary structure–activity relationship and molecular modeling studies. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis and structure–activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of ( S )-2-(((6-chloropyridin-2-yl)oxy)methyl)-4-((6-fluoro-1 H -indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1 μM against D 1 , D 2L , D 2S , D 3 , and D 5 ). [ABSTRACT FROM AUTHOR]

The compound class of 1 H -pyrazolo[3,4- d ]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure–activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho -methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging. [ABSTRACT FROM AUTHOR]

A facile and highly efficient one-pot synthesis of phthalazine–quinoline derivatives is reported via four component reaction of phthalic anhydride, hydrazine hydrate, 5,5-dimethyl 1,3 cyclohexanedione and various quinoline aldehydes using Pr x CoFe 2− x O 4 ( x = 0.1) nanoparticles as a catalyst. The synthesized compounds have been evaluated for anti-biofilm activity against Pseudomonas aeruginosa and Candida albicans . The compounds 12a (IC 50 = 30.0 μM) and 12f (IC 50 = 34.5 μM) had shown promising anti-biofilm activity against P. aeruginosa and C. albicans , respectively, when compared with standards without affecting the growth of cells (and thus behave as anti-quorum sensing agents). Compounds 12a (MIC = 45.0 μg/mL) and 12f (MIC = 57.5 μg/mL) showed significant potent antimicrobial activity against P. aeruginosa and C. albicans , respectively. Thus, the active derivatives were not only potent biofilm inhibitors but also efficient antimicrobial agents. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antimicrobial drug discovery initiatives. [ABSTRACT FROM AUTHOR]