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Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound 3e (IC 50 = 0.081 ± 0.003 µM), 6a (IC 50 = 0.0022 ± 0.0002 µM), 9e (IC 50 = 0.0250 ± 0.0007 µM) and 12d (IC 50 = 0.0266 ± 0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC 50 = 17.814 ± 0.096 µM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds 3e , 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a , 12b , 12d , 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C., Competing Interests: The authors declare no conflict of interest.

A visible light‐induced reductive addition of 1°, 2° and 3° alkyl iodides to ethenesulfonyl fluoride, employing Hantzsch ester as a hydrogen source at room temperature was developed. This method featured a wide substrate scope and great functional group compatibility, providing facile and robust process to alkyl sulfonyl fluorides including enzyme inhibitors, natural products and drugs derivatives in up to 99% yield. Further derivatization of resultant aliphatic sulfonyl fluorides was also achieved through sulfur fluoride exchange (SuFEx) reactions to deliver sulfonates and sulfonamides as privileged motifs for medicinal chemistry. [ABSTRACT FROM AUTHOR]

Lysine specific demethylase 1 (LSD1) and Histone deacetylases (HDACs) are promising drug targets for cancers. Recent studies reveal an important functional interplay between LSD1 and HDACs, and there is evidence for the synergistic effect of combined LSD1 and HDAC inhibitors on cancers. Therefore, development of inhibitors targeting both LSD1 and HDACs might be a promising strategy for epigenetic therapy of cancers. We report herein the synthesis of a series of tranylcypromine derivatives as LSD1/HDACs dual inhibitors. Most compounds showed potent LSD1 and HDACs inhibitory activity, especially compound 7 displayed the most potent inhibitory activity against HDAC1 and HDAC2 with IC 50 of 15 nM and 23 nM, as well as potent inhibition against LSD1 with IC 50 of 1.20 μM. Compound 7 demonstrated stronger anti-proliferative activities than SAHA with IC 50 values ranging from 0.81 to 4.28 μM against MGC-803, MCF-7, SW-620 and A-549 human cancer cell lines. Further mechanistic studies showed that compound 7 treatment in MGC-803 cells dose-dependently increased cellular H3K4 and H3K9 methylation, as well as H3 acetylation, decreased the mitochondrial membrane potential and induced remarkable apoptosis. Docking studies showed that compound 7 can be well docked into the active binding sites of LSD1 and HDAC2. This finding highlights the potential for the development of LSD1/HDACs dual inhibitors as novel anticancer drugs. [ABSTRACT FROM AUTHOR]

A series of novel di- or trisubstituted isatin derivatives were designed and synthesized in 5–6 steps in 25–45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of the fourty-three new isatin derivatives against human T lymphocyte cells Jurkat was evaluated by MTT assay in vitro . SAR study suggested that the combination of 1-benzyl and 5-[ trans -2-(methoxycarbonyl)ethen-1-yl] substitution greatly enhanced their cytotoxic activity. Among them, compound 2h was shown to have a significant cytotoxic activity with an IC50 value of 0.03 μM, more than 330-fold higher than that of it's mother molecule isatin. Investigation of the cell morphology changes and annexin-V/PI staining study demonstrated that compound 2h inhibited the proliferation of Jurkat cells by inducing apoptosis. Since compound 2h induced the dissipation of mitochondrial membrane potential and the activation of caspase-3, it was obvious that compound 2h inhibited the proliferation of Jurkat cells through the mitochondrial apoptotic pathway. Other than this, compound 2h exerted inhibition effect to many other tumor cells and only showed weak cytotoxic to human normal cells suggesting that compound 2h possessed a broad range of anticancer spectrum and high safety to normal cells. [ABSTRACT FROM AUTHOR]

VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty-one 4-alkoxyquinazoline-based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 ( VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 n m (for VEGFR2) and 0.25 μ m (for MCF-7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4 ASE active site, and the result showed that compound 3h could bind well at the 4 ASE active site. [ABSTRACT FROM AUTHOR]

A series of phenylpiperazine derivatives ( 3a – 3q ) were designed and synthesized. In vitro assays indicated that several phenylpiperazine derivatives had excellent antiproliferative properties against four cancer cell lines including multidrug-resistant cancer cell lines, with IC 50 values in the low micromolar range. The average IC 50 of the most active compound 3b is 0.024 μM to the MCF-7 cell line. In addition, the mechanism of action of these new analogues was investigated by molecular docking studies, insulin-like growth factor 1-receptor (IGF-1R) kinase assay and apoptosis induced assay. These studies confirmed that these new phenylpiperazine derivatives maintain their mechanisms of action by disrupting IGF-1R kinase. [ABSTRACT FROM AUTHOR]

Theinhibition of kallikreins 5 and 7, and possibly kallikrein14 and matriptase, (that initiates the kallikrein proteolytic cascade)constitutes an innovative way to treat some skin diseases such asNetherton syndrome. We present here the inhibitory properties of coumarin-3-carboxylatederivatives against these enzymes. Our small collection of these versatileorganic compounds was enriched by newly synthesized derivatives inorder to obtain molecules selective against one, two, three enzymesor acting on the four ones. We evidenced a series of compounds withIC50values in the nanomolar range. A suicide mechanismwas observed against kallikrein 7 whereas the inactivation was eitherdefinitive (suicide type) or transient for kallikreins 5 and 14, andmatriptase. Most of these potent inhibitors were devoid of cytotoxicitytoward healthy human keratinocytes. In situzymographyinvestigations on skin sections from human kallikrein 5 transgenicmouse revealed significant reduction of the global proteolytic activityby several compounds. [ABSTRACT FROM AUTHOR]

5-(4′-Methoxyphenyl)-oxazole (MPO), originally reported as a synthetic compound, was isolated from fungal culture broth as an inhibitor of hatch and growth of Caenorhabditis elegans. Nineteen MPO derivatives were chemically synthesized, but showed no effect on C. elegans hatch and growth. These findings strongly suggested that the whole structure of MPO is essential for anti- C. elegans activity. [ABSTRACT FROM AUTHOR]

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2- c ]quinolin-4(5 H )-one inhibitor ( 10 ) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV), a mosquito-borne arthrogenic Alphavirus , causes an acute febrile illness in humans, that is, accompanied by severe joint pains. In many cases, the infection leads to persistent arthralgia, which may last for weeks to several years. The re-emergence of this infection in the early 2000s was exemplified by numerous outbreaks in the eastern hemisphere. Since then, the virus is rapidly spreading. Currently, no drugs have been approved or are in development for the treatment of CHIKV, which makes this viral infection particularly interesting for academic medicinal chemistry efforts. Several molecules have already been identified that inhibit CHIKV replication in phenotypic virus-cell-based assays. One of these is arbidol, a molecule that already has been licensed for the treatment of influenza A and B virus infections. For structural optimization, a dedicated libraries of 43 indole-based derivatives were evaluated leading to more potent analogues ( IIIe and IIIf ) with anti-chikungunya virus (CHIKV) activities higher than those of the other derivatives, including the lead compound, and with a selective index of inhibition 13.2 and 14.6, respectively, higher than that of ARB (4.6). [ABSTRACT FROM AUTHOR]

Leishmaniasis is a public health problem in tropical and subtropical areas of the world, including Venezuela. The incidence of treatment failure and the number of cases with Leishmania-HIV co-infection underscore the importance of developing alternative, economical and effective therapies against this disease. The work presented here analyzed whether terpenoids derived from betulin are active against New World Leishmania parasites. Initially we determined the concentration that inhibits the growth of these parasites by 50% or IC 50 , and subsequently evaluated the chemotactic effect of four compounds with leishmanicidal activity in the sub-micromolar and micromolar range. That is, we measured the migratory capacity of Leishmania ( V .) braziliensis in the presence of increasing concentrations of compounds. Finally, we evaluated their cytotoxicity against the host cell and their effect on the infectivity of L. ( V .) braziliensis . The results suggest that (1) compounds 14 , 17 , 18 , 25 and 27 are active at concentrations lower than 10 μM; (2) compound 26 inhibits parasite growth with an IC 50 lower than 1 μM; (3) compounds 18 , 26 and 27 inhibit parasite migration at pico- to nanomolar concentrations, suggesting that they impair host–parasite interaction. None of the tested compounds was cytotoxic against J774.A1 macrophages thus indicating their potential as starting points to develop compounds that might affect parasite–host cell interaction, as well as being leishmanicidal. [ABSTRACT FROM AUTHOR]

Inhibitory effects on neutrophils' chemotaxis, phagocytosis and production of reactive oxygen species ( ROS) are among the important targets in developing anti-inflammatory agents and immunosuppressants. Eight series of chalcone derivatives including five newly synthesized series were assessed for their inhibitory effects on chemotaxis, phagocytosis and ROS production in human polymorphonuclear neutrophils ( PMNs). Inhibition of PMNs' chemotaxis and phagocytosis abilities were investigated using the Boyden chamber technique and the Phagotest kit, respectively, while ROS production was evaluated using luminol- and lucigenin-based chemiluminescence assay. The new derivatives ( 4d and 8d), which contain 4-methylaminoethanol functional group were active in all the assays performed. It was also observed that some of the compounds were active in inhibiting chemotaxis while others suppressed phagocytosis and ROS production. The information obtained gave new insight into chalcone derivatives with the potential to be developed as immunomodulators. [ABSTRACT FROM AUTHOR]

Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O7-Nitrooxyethyl-O3′,O4′-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50 =(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure–activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications. [ABSTRACT FROM AUTHOR]

Highlights: [•] A novel tamoxifen derivative, Ridaifen-B induces apoptosis and autophagy. [•] Estrogen receptor is not involved in Ridaifen-B induced apoptosis and autophagy. [•] Ridaifen-B induced apoptosis is inhibited by Bcl-2. [•] RID-B-induced autophagy is independent of Bcl-2. [•] RID-B-induced autophagy different from RID-B-induced apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Aminopeptidase N (APN/CD13) over expressed on tumor cells, plays a critical role in tumor invasion, metastasis, and tumor angiogenesis. Here we described the design, synthesis and preliminary activity studies of novel leucine ureido derivatives as aminopeptidase N (APN/CD13) inhibitors. The results showed that compound 8c had the most potent inhibitory activity against APN with the IC50 value to 0.06±0.041μM, which could be used for further anticancer agent research. [Copyright &y& Elsevier]

Abstract: Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer. Hence, GSK-3 has emerged as an attractive target molecule for the treatment of metabolic disorders. Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor. Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1,1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor. An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3β. The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells. Stabilization of glycogen synthase and β-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286. In mouse 3T3-L1 preadipocytes, compound 1a markedly blocked adipocyte differentiation. Consistently, intraperitoneal administration of compound 1a to diet-induced obese mice significantly ameliorated their key symptoms such as body weight gain, increased adiposity, dyslipidemia, and hepatic steatosis due to the marked reduction of whole-body lipid level. In vitro and in vivo effects were accompanied by upregulation of β-catenin stability and downregulation of the expression of several critical genes related to lipid metabolism. From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment. [Copyright &y& Elsevier]

Abstract: A series of hesperidin derivatives were prepared and identified by IR, 1H NMR, and MS spectra. These compounds were evaluated in vitro and in vivo based on α-glucosidase inhibition, glucose consumption of HepG2 cells, and blood glucose level in streptozotocin-induced diabetic mice. The results revealed that all the compounds exhibited anti-hyperglycemic activities. The inhibition at 10−3 M of compounds 3 and 7a on α-glucosidase were 55.02% and 53.34%, respectively, as compared to 54.80% by acarbose. Treated by compound 3 and the reference drug metformin, glucose consumption of HepG2 cell were 1.78 and 2.11mM, respectively. After the streptozotocin-induced diabetic mice were oral administrated with compound 3 at 100mgkg−1 d−1 for 10days, the blood glucose level of 3 treated mice (13.23mM, P <0.05) showed significant difference when compared to model control (23.03mM). Thus, compound 3 exhibited promising anti-hyperglycemic activity. [Copyright &y& Elsevier]

On the basis of the enzyme-binding features of known potent inhibitors of dipeptidyl peptidase IV, novel α-aminoacyl-containing proline analogs ( 8Aa-8Ak, 8Ba-8Bj, 8Ca-8Ck, and 8Da-8Di) with the S configuration were designed, synthesized, and their activity profiled. Their structural features were determined by nuclear magnetic resonance (NMR) spectroscopy, low- and high-resolution mass spectroscopy. Five compounds ( 8Aa, 8Aj, 8Ch, 8Ck, and 8Dc) were shown to have promising inhibitory activities against dipeptidyl peptidase IV. Two of them, compounds 8Aa and 8Aj inhibited dipeptidyl peptidase IV with IC50 values of 4.56 and 8.4 μ m, respectively, and displayed no inhibition at other dipeptidyl peptidase IV. The possible binding modes of compounds 6, 7, 8Aa, and 8Aj with dipeptidyl peptidase IV were also explored by molecular docking simulation. This study provides promising new templates for the further development of antidiabetic agents. [ABSTRACT FROM AUTHOR]

Abstract: A new family of protein farnesyltransferase inhibitors, based on a phenothiazine scaffold, was designed and synthesized. The biological evaluation of these products showed that compounds 28 and 30 were the most active, with protein farnesyltransferase inhibition potencies in the low micromolar range. Compounds were also evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. Indenopyrazole 30 exhibited the most potent in vitro cytostatic activity inhibiting the growth of HCT-116, LOX IMVI and SK-MEL-5 cell lines. [Copyright &y& Elsevier]

Abstract: Orally bioavailable inhibitors of β-(1,3)-d-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. [Copyright &y& Elsevier]

A series of 2,4,6-trihydroxychalcone derivatives were synthesized and identified as reversible and competitive protein tyrosine phosphatase (PTP) 1B inhibitors with IC50 values in the micromolar range. Compound 4a had the greatest in vitro inhibition activity against PTP1B (IC50 = 0.27 ± 0.01 μ m) and the best selectivity (6.9-fold) for PTP1B relative to T-cell protein tyrosine phosphatases. The compounds identified herein provide a foundation on which to design specific inhibitors of PTP1B and other PTPs. [ABSTRACT FROM AUTHOR]

Evodiamine is a quinazolinocarboline alkaloid isolatedfrom the fruits of traditional Chinese herb Evodiaefructus. Previously, we identified N13-substitutedevodiamine derivatives as potent topoisomerase I inhibitors by structure-basedvirtual screening and lead optimization. Herein, a library of novelevodiamine derivatives bearing various substitutions or modified scaffoldwere synthesized. Among them, a number of evodiamine derivatives showedsubstantial increase of the antitumor activity, with GI50values lower than 3 nM. Moreover, these highly potent compoundscan effectively induce the apoptosis of A549 cells. Interestingly,further computational target prediction calculations in combinationwith biological assays confirmed that the evodiamine derivatives actedby dual inhibition of topoisomerases I and II. Moreover, several hydroxylderivatives, such as 10-hydroxyl evodiamine (10j) and3-amino-10-hydroxyl evodiamine (18g), also showed goodin vivo antitumor efficacy and low toxicity at the dose of 1 mg/kgor 2 mg/kg. They represent promising candidates for the developmentof novel antitumor agents. [ABSTRACT FROM AUTHOR]

Abstract: The Claisen condensation of 3β-acetoxypregna-5,16-dien-20-one (1) with ethyl formate in the presence of sodium methylate in pyridine is known to lead to 3β-hydroxy-21-hydroxymethylidenepregna-5,16-dien-20-one (2) in good yield. With the methods described for the preparation of the saturated D-ring pyrazolyl series, the reactions of 2 with phenylhydrazine and its p-substituted derivatives in acetic acid resulted in mixtures of two steroidal regioisomers, the 1′-aryl-3′-pyrazolyl-(4a–e) and 1′-aryl-5′-pyrazolyl (5a–e) steroids. Compounds 4a–e are unknown in the literature. The arylpyrazoles produced were tested against 17α-hydroxylase/C17,20-lyase (P45017α) in vitro and neither of the regioisomers exerted efficient inhibition. [Copyright &y& Elsevier]

Abstract: Inhibitors of dipeptidyl peptidase-4 (DPP4) have been shown to be effective treatments for type 2 diabetes. Several series of β-amino amide containing piperazine derivatives have been prepared and evaluated as a inhibitor of DPP4. Finally compound 5m was selected for further evaluation. [Copyright &y& Elsevier]

Several 9 H-carbazole derivatives are used for various pharmacological applications. Many of these compounds demonstrated cytotoxic and anticancer activities. In this work, we have investigated the cytotoxic activity of some substituted carbazoles against cancer cell lines (MCF-7, and ISK). The derivative 2a showed the highest inhibitory activity against both cell lines. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, 38 millepachine derivatives have been designed, synthesized and evaluated for their in vitro and in vivo antiproliferative activity. Among these novel derivatives, 15 displayed more potent antiproliferative activity than millepachine against HepG2, K562, SK-OV-3, HCT116, HT29, and SW620 tumor cells (mean IC50 = 0.64 vs. 2.86 μM, respectively). Furthermore, 15 could effectively inhibit tubulin polymerization in HepG2 cells, and induce the HepG2 cell cycle arrest at the G2/M phase in a concentration-dependant manner. Further studies confirmed that 15 significantly suppressed the growth of tumor volume and exerted more potent anticancer potency than millepachine and anticancer drug cisplatin in A549 lung xenograft tumor model. [Copyright &y& Elsevier]

Abstract: Direct inhibition of coagulation factor Xa (FXa) carries significant promise for developing effective and safe anticoagulants. Although a large number of FXa inhibitors have been studied, each can be classified as either possessing a highly flexible or a rigid core scaffold. We reasoned that an intermediate level of flexibility will provide high selectivity for FXa considering that its active site is less constrained in comparison to thrombin and more constrained as compared to trypsin. We studied several core scaffolds including 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid for direct FXa inhibition. Using a genetic algorithm-based docking and scoring approach, a promising candidate 23 was identified, synthesized, and found to inhibit FXa with a K i of 28 μM. Optimization of derivative 23 resulted in the design of a potent dicarboxamide 47, which displayed a K i of 135 nM. Dicarboxamide 47 displayed at least 1852-fold selectivity for FXa inhibition over other coagulation enzymes and doubled PT and aPTT of human plasma at 17.1 μM and 20.2 μM, respectively, which are comparable to those of clinically relevant agents. Dicarboxamide 47 is expected to serve as an excellent lead for further anticoagulant discovery. [Copyright &y& Elsevier]

Abstract: A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores. [Copyright &y& Elsevier]

Abstract: In an attempt to search for many target compounds with excellent activities, a series of vinyl ether-containing azole derivatives were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against Trichophyton rubrum in vitro indicated that most of the synthesized compounds showed excellent activities. In comparison with fluconazole, itraconazole, voriconazole, omoconazole and amphotericin B, several compounds (such as 7d, 7g and 7h) exhibited more potent inhibitory activities, suggesting that they were promising leads for the development of novel antifungal agents. [Copyright &y& Elsevier]

Abstract: Haloenol pyran-2-ones and morpholin-2-ones were synthesized and evaluated as inhibitors of cell growth in two different prostate human cancer cell lines (PC-3 and LNCaP). Analogs derived from l- and d-phenylglycine were found to be the most effective antagonists of LNCaP and PC-3 cell growth. Additional studies reveal that the inhibitors induced G2/M arrest and the (S)-enantiomer of the phenylglycine-based derivatives was a more potent inhibitor of cytosolic iPLA2β. [Copyright &y& Elsevier]

Abstract: Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation. [Copyright &y& Elsevier]

Abstract: After the widespread use of the acyclic purine nucleoside analogues for therapy of herpes simplex virus (HSV) infection since the 1980s, new antiviral strategies are urgently needed to counter the emergence of drug-resistant clinical isolates. In this report, we define the anti-HSV efficacies of three optimized 2-aminobenzamide derivatives in vitro and in vivo. The synthetic analogues SNX-25a, SNX-2112 and SNX-7081, which selectively bind to the N-terminal ATP pocket of heat shock protein 90 (HSP90), exhibited significant anti-HSV-1 and HSV-2 activities at non-cytotoxic concentrations in Vero cells, with EC50 values close to that of acyclovir (ACV). The in vivo antiviral potentials were then confirmed using a herpes simplex keratitis (HSK) rabbit model, where eye gels containing 0.1% or 0.025% SNX-25a displayed the highest efficacies against HSV-1 infection, which were better than that obtained with 0.1% ACV. SNX-2112 and SNX-7081 gels were also effective against HSV-1 with different magnitude of activities. Our results for the first time confirmed the anti-HSV efficacies of these 2-aminobenzamide derivatives and suggest that with alternative mechanisms of action these novel HSP90 inhibitors, especially SNX-25a, could be potent as new anti-HSV clinical trial candidates. [Copyright &y& Elsevier]

Abstract: Dual PI3Kγ/δ inhibitors have recently been shown to be suitable targets for inflammatory and respiratory diseases. In a recent study we described the discovery of selective PI3Kγ inhibitors based on a triazolopyridine scaffold. Herein, we describe the elaboration of this structural class into dual PI3Kγ/δ inhibitors with excellent selectivity over the other PI3K isoforms and the general kinome. Structural optimization led to the identification of two derivatives which showed significant efficacy in an acute model of lung inflammation. [Copyright &y& Elsevier]

Abstract: C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes. [Copyright &y& Elsevier]

Abstract: We recently discovered that five- and pseudo-five-fused-ring derivatives in an imidazonaphthyridine series were promising hit compounds for the development of new DNA-intercalators. In this study, novel (dihydro)imidazo[1,6] and [1,7]naphthyridi(no)nes were prepared including pseudo-pentacycles. All the compounds synthesized were screened against four tumor cell lines. Compounds 3(b–d) showed significant in vitro cytotoxicity, and DNA intercalation properties were demonstrated at 25μM. Imidazonaphthyridinones exhibited no DNA binding affinity despite significant growth inhibition activity. Interestingly, when a pyridinone pharmacophore was linked to the imidazo[1,2-a]pyridine scaffold, the geometric orientation of the link had a strong impact on the growth inhibition activity. From these results we conclude that the moderate cytotoxicity observed for these compounds is independent of their DNA-binding and topoisomerase inhibition activities. [Copyright &y& Elsevier]

Abstract: In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities. [Copyright &y& Elsevier]

Abstract: In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach. [Copyright &y& Elsevier]

Abstract: A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure–activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K+ channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels). [Copyright &y& Elsevier]

Abstract: Dihydrodipicolinate synthase is a key enzyme in the lysine biosynthesis pathway that catalyzes the condensation of pyruvate and aspartate semi-aldehyde. A series of phenolic ketoacid derivatives that mimic the proposed enzymatic intermediate were designed as potential inhibitors of this enzyme and were synthesized from simple precursors. The ketoacid derivatives were shown to act as slow and slow-tight binding inhibitors. Mass spectrometric experiments provided further evidence to support the proposed model of inhibition, demonstrating either an encounter complex or a condensation product for the slow and slow-tight binding inhibitors, respectively. [Copyright &y& Elsevier]

Abstract: In continuing our search for novel tyrosinase inhibitors, a series of 5-(substituted benzylidene)thiazolidine-2,4-diones were rationally designed and synthesized, and their inhibitory effects on mushroom tyrosinase activity were evaluated. Twelve target compounds 2a–2l were designed and synthesized based on the structural characteristics of N-phenylthiourea, a tyrosinase inhibitor, and tyrosine and l-DOPA, the natural substrates of tyrosinase. Among them, (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (2a) and (Z)-5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (2f) exhibited much higher tyrosinase inhibitory activities, with IC 50 values of 13.36 and 9.87 μM, respectively, than kojic acid (IC 50 = 24.72 μM). Kinetic analysis of tyrosinase inhibition revealed that 2a and 2f are competitive inhibitors of mushroom tyrosinase. In addition, through prediction of the potato catechol oxidase tertiary structure and simulation of docking with compounds 2a and 2f using DOCK6, we found that these inhibitors likely bind to the active site of the enzyme. Docking simulation results suggested that 2a and 2f have high binding affinities with potato catechol oxidase. In addition, compounds 2a and 2f effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-melanocyte-stimulating hormone (α-MSH). These data strongly suggest that compounds 2a and 2f suppress the production of melanin via the inhibition of tyrosinase activity. [Copyright &y& Elsevier]

Abstract: Structure-based studies led to the identification of a constrained derivative of S-trityl-l-cysteine (STLC) scaffold as a candidate inhibitor of hepatitis C virus (HCV) NS5B polymerase. A panel of STLC derivatives were synthesized and investigated for their activity against HCV NS5B. Three STLC derivatives, 9, F-3070, and F-3065, were identified as modest HCV NS5B inhibitors with IC50 values between 22.3 and 39.7 μM. F-3070 and F-3065 displayed potent inhibition of intracellular NS5B activity in the BHK-NS5B-FRLuc reporter and also inhibited HCV RNA replication in the Huh7/Rep-Feo1b reporter system. Binding mode investigations suggested that the STLC scaffold can be used to develop new NS5B inhibitors by further chemical modification at one of the trityl phenyl group. [Copyright &y& Elsevier]

Abstract: A new series of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety has been synthesized, and the depigmenting and tyrosinase inhibitory activities of the molecules were evaluated. The lipophilic character of the adamantyl moiety appeared to confer greater depigmentation power on the benzamide derivatives as compared to those lacking adamantyl substitution. Molecular modeling was applied in order to elucidate the interactions between ligands and tyrosinase that led to inhibition. [Copyright &y& Elsevier]

Abstract: As potential inhibitors of Escherichia coli pyruvate dehydrogenase complex E1 (PDHc E1), a series of novel 2-methylpyrimidine-4-ylamine derivatives were designed based on the structure of the active site of PDHc E1 and synthesized using ‘click chemistry’. Their inhibitory activity in vitro against PDHc E1 and fungicidal activity were examined. Some of these compounds such as 3g, 3l, 3n, 3o, and 5b demonstrated to be effective inhibitors of PDHc E1 from E. coli and exhibited antifungal activity. SAR analysis indicated that both, the inhibitory potency against E. coli PDHc E1 and the antifungal activity of title compounds, could be increased greatly by optimizing substituent groups in the compounds. The structures of substituent group in 5-position on the 1,2,3-triazole and 4-position on the benzene ring in title compounds were found to play a pivotal role in both above-mentioned biological activities. Amongst all the compounds, compound 5b with iodine in the 5-position of 1,2,3-triazole and with nitryl group in the 4-position of benzene ring acted as the best inhibitor against PDHc E1 from E. coli. It was also found to be the most effective compound with higher antifungal activity against Rhizoctonia solani and Botrytis cinerea at the dosage of 100μgmL−1. Therefore, in this study, compound 5b was used as a lead compound for further optimization. [Copyright &y& Elsevier]

Abstract: Calreticulin transacetylase (CRTAase) is known to catalyze the transfer of acetyl group from polyphenolic acetates (PA) to certain receptor proteins (RP), thus modulating their activity. Herein, we studied for the first time the substrate specificity of CRTAase towards N-acetylamino derivatives of coumarins and quinolones. This study is endowed with antiplatelet action by virtue of causing CRTAase catalyzed activation of platelet Nitric Oxide Synthase (NOS) by way of acetylation leading to the inhibition of ADP/Arachidonic acid (AA)-dependent platelet aggregation. Among all the N-acetylamino/acetoxy coumarins and quinolones screened, 7-N-acetylamino-4-methylcoumarin (7-AAMC, 17) was found to be the superior substrate to platelet CRTAase and emerged as the most promising antiplatelet agent both in vitro and in vivo. Further it caused the inhibition of cyclooxygenase-1 (Cox-1) resulting in the down regulation of thromboxane A2 (TxA2), modulation of tissue factor and the inhibition of platelet aggregation. It was also found effective in the inhibition of LPS induced pro-thrombotic conditions. [Copyright &y& Elsevier]

Abstract: 5-Methoxyflavenes and 6-methoxyflavenes were found to undergo stereoselective acid-catalyzed rearrangement to generate a range of novel chromeno[2,3-b]chromene derivatives. When subjected to an in vitro antiplasmodial growth inhibition assay using Plasmodium falciparum (3D7 line) the chromene analogues were shown to display IC50 values ranging from 6.8 to 39.8μM. [Copyright &y& Elsevier]

Abstract: A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53–MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC50 values in the low micromolar range. Compound 6c exhibited marked p53–MDM2 binding inhibitory activity (IC50 =0.59μM) which was eightfold more potent than that of Nutlin-1 (IC50 =4.78μM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q 2 =0.645, r 2 =0.979). [Copyright &y& Elsevier]

Abstract: A series of novel N-phenylsulfonylnicotinamide derivatives (1–24) have been synthesized and evaluated as potential EGFR tyrosine kinase (TK) inhibitors. Among all the compounds, compound 10 (5-bromo-N-(4-chlorophenylsulfonyl)nicotinamide) showed the most potent growth inhibitory activity against EGFR TK and antiproliferative activity of MCF-7 cancer cell line in vitro, with IC50 value of 0.09 and 0.07μM. Docking simulation was performed to insert compound 10 into the EGFR TK active site to determine the probable binding model. Based on the preliminary results, compound 10 with potent inhibitory activity to tumor growth may be a potential anticancer agent. [Copyright &y& Elsevier]

Abstract: Monoamine oxidase B (MAO-B) inhibitors are used to treat Parkinson’s disease. In this study, we searched for novel MAO-B inhibitors using a scaffold hopping approach based on our experience with the thiazolidinedione (TZD) class of compounds as MAO-B inhibitors. Several novel compounds were identified, with potencies in the low nanomolar and low micromolar range. We also found that derivatives of the natural product sulfuretin are potent MAO-A and MAO-B inhibitors. [Copyright &y& Elsevier]

Abstract: In this study, we analyzed the structure–activity relationship properties of the small molecule Jak2 inhibitor G6. We synthesized a set of derivatives containing the native para-hydroxyl structure or an alternative meta-hydroxyl structure and examined their Jak2 inhibitory properties. We found that the para-hydroxyl derivative known as NB15 had excellent Jak2 inhibitory properties in silico, in vitro, and ex vivo when compared with meta-hydroxyl derivatives. These results indicate that NB15 is a potent derivative of the Jak2 inhibitor G6, and that maintaining the para-hydroxyl orientation of G6 is critical for its Jak2 inhibitory potential. [Copyright &y& Elsevier]

Abstract: The Naturally occurring novel cyclohexanonyl bromophenol 2(R)-2-(2,3,6-tribromo-4,5-dihydroxybenzyl)cyclohexanone (4) was synthesized as a racemic compound. Cyclohexylphenyl methane derivatives (10–17) with Br, OMe, CO, and OH were also obtained. Inhibition of four human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I, II, IV, and VI, with compounds 2–4, 8, and 10–26 was investigated. These compounds were found to be promising carbonic anhydrase inhibitors and some of them showed interesting inhibitory activity. Some of the compounds investigated here showed effective hCA inhibitory activity, and might be used as leads for generating novel carbonic anhydrase inhibitors which are valuable drug candidates for the treatment of glaucoma, epilepsy, gastric and duodenal ulcers, neurological disorders, and osteoporosis. [Copyright &y& Elsevier]