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Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation. The best compound 6e with a sulfonyl scaffold displayed EC50 values of 0.0356 μmol/L against WT and 0.0228 μmol/L against HIV K103N mutant strain. More pronounced, it had a lower cytotoxicity (CC50 = 99.6 μmol/L), higher selectivity index (SIWT = 2799, SIK103N = 4375) and better calculated logarithm of the octanol-water partition coefficient (cLogP) than the lead compound 3. Molecular docking and dynamics provided the binding modes of these compounds with reverse transcriptase, explaining their activity. Collectively, the new compounds could be candidates for anti-HIV drug discovery.

Magnolol, the most abundant bioactive constituent of the Chinese herb Magnolia officinalis, has been found with multiple biological activities, including anti-oxidative, anti-inflammatory and enzyme-regulatory activities. In this study, the inhibitory effects and inhibition mechanism of magnolol on human carboxylesterases (hCEs), the key enzymes responsible for the hydrolytic metabolism of a variety of endogenous esters as well as ester-bearing drugs, have been well-investigated. The results demonstrate that magnolol strongly inhibits hCE1-mediated hydrolysis of various substrates, whereas the inhibition of hCE2 by magnolol is substrate-dependent, ranging from strong to moderate. Inhibition of intracellular hCE1 and hCE2 by magnolol was also investigated in living HepG2 cells, and the results showed that magnolol could strongly inhibit intracellular hCE1, while the inhibition of intracellular hCE2 was weak. Inhibition kinetic analyses and docking simulations revealed that magnolol inhibited both hCE1 and hCE2 in a mixed manner, which could be partially attributed to its binding at two distinct ligand-binding sites in each carboxylesterase, including the catalytic cavity and the regulatory domain. In addition, the potential risk of the metabolic interactions of magnolol via hCE1 inhibition was predicted on the basis of a series of available pharmacokinetic data and the inhibition constants. All these findings are very helpful in deciphering the metabolic interactions between magnolol and hCEs, and also very useful for avoiding deleterious interactions via inhibition of hCEs.

Modulation of the opioid system has re-emerged as a potential therapeutic avenue for treating depression, with efficacy of a fixed-dose combination of buprenorphine (BUP), a partial mu-opioid receptor (MOR) agonist and kappa-opioid receptor (KOR) antagonist, and samidorphan (SAM), a potent MOR antagonist, as an adjuvant treatment in patients with major depressive disorder (MDD). To advance understanding of the mechanism of action underlying this combination, we examined BUP, SAM and their combination in a series of rat behavioural assays. We examined effects on locomotor activity in Sprague Dawley (SD) rats over an extended period of time in a home-cage tracking system, and behavioural despair (immobility) in the forced swim test (FST), a commonly-used test to study antidepressants, in SD and Wistar-Kyoto (WKY) rats. Strain differences in opioid receptor and prepropeptide mRNA expression in the brain (prefrontal cortex, amygdala, hippocampus and striatum) were examined using qRT-PCR. BUP produced locomotor hyperactivity in SD rats from 2 to 6 h following administration, which was attenuated by SAM. In SD rats, a low, but not a high, dose of SAM in combination with BUP counteracted swim-stress induced immobility. This effect was not seen with BUP alone. In contrast, BUP alone reduced immobility in WKY rats, and this effect was enhanced by a low, but not high, dose of SAM. In WKY rats, MOR mRNA expression was higher in the hippocampus and lower in the striatum vs. SD rats. KOR mRNA expression was higher in the amygdala and nociceptin receptor (NOP) mRNA expression was lower in the hippocampus vs. SD rats. Differences in opioid receptor expression may account for the differential behavioural profile of WKY and SD rats. In summary, administration of BUP, a MOR receptor agonist together with a MOR opioid-receptor antagonist, SAM, reduces behavioural despair in animal models traditionally used to study effects of antidepressants. This study was supported by an Industry-Academia collaboration with funding and samidorphan provided by Alkermes Inc; and a Strategic Partnership Programme Grant from Science Foundation Ireland and Alkermes Inc (14/SPP/B3051). peer-reviewed 2019-12-13

Herein, alkenylpiperidine and alkynylpiperidine moieties were introduced into the left wing of DAPYs (diarylpyrimidines) to explore the new site of the NNIBP (non-nucleoside inhibitor binding pocket) protein-solvent interface region via the structure-based drug design strategy. All the synthesized compounds displayed nanomolar to submicromolar activity against WT (wild-type) HIV-1. Among all, compound FT1 (EC50 = 19 nM) was found to be the most active molecule, which is better than NVP (EC50 = 0.10 μM). In addition, most of the compounds displayed micromolar activity against K103N and E138K mutant strains, while FT1 (EC50(K103N) = 50 nM, EC50(E138K) = 0.19 µM) still has the most effective activity. The molecular dynamics simulation studies revealed that the presence of pyridine moiety of FT1 was essential and played a significant role in its binding with RT (reverse transcriptase). ispartof: BIOORGANIC CHEMISTRY vol:116 ispartof: location:United States status: published

Aim: The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non-small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC.Patients and methods: A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1-14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, +/- bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination.Results: All 66 treated patients experienced at least one adverse event (AE). Grade >= III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients.Conclusion: Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary antitumour activity was observed.

The aim of this study was to examine the acute effect of a range of novel hydroxycinnamic acid derivatives of spermine on the development of spermine-induced CNS excitation and convulsions in female Laca mice, and to assess the chronic adverse behavioural effect profile of these compounds over a 5day period. Four of the six novel polyamine analogues dose-dependently inhibited body tremor and tonic convulsions caused by spermine, when administered centrally (icv) or peripherally (ip). BU43b was the most potent analogue tested, but BU31b, 33b, and 36b were also effective (p

The synthesis and structure-activity relationships of novel 4-(4 '-fluorophenyl)imidazoles as selective p38 alpha MAPK, CK1 delta and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via 'click' reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38 alpha MAPK with IC50 = 250 nM and 96 nM, respectively. Pyridine 3 gave CK1 delta inhibition with IC50 = 89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50 = 62 nM. (C) 2014 Elsevier Ltd. All rights reserved.

Herein we propose the benzimidazole-2-one substructure as a suitable tryptophan mimic and thus a reasonable starting point for the design of p53 Mdm2 antagonists. We devise a short multicomponent reaction route to hitherto unknown 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamides by reacting mono N-carbamate protected phenylenediamine in a Ugi-3CR followed by base induced cyclisation. Our preliminary synthesis and screening results are presented here. The finding of the benzimidazolone moiety as a tryptophan replacement in mdm2 is significant as it offers access to novel scaffolds with potentially higher selectivity and potency and improved biological activities. Observing low μM affinities to mdm2 by NMR and fluorescence polarization we conclude that the 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide scaffold might be a good starting point to further optimize the affinities to Mdm2.

A variety of 2-(aminomethyl)aziridines was prepared and converted into the corresponding 1,2,3-triaminopropanes through a novel, microwave-assisted and regioselective ring opening by diethylamine in acetonitrile. Antiplasmodial assays revealed antimalarial activity for 2-[(1,2,4-triazol-1-yl)methyl]aziridines and 2-(N,N-diethylaminomethyl)aziridines, as well as for the corresponding 1-(diethylamino)propanes obtained through ring opening, pointing to the relevance of both the 2-(aminomethyl)aziridine and the 1,2,3-triaminopropane unit as novel antimalarial pharmacophores.

The synthesis of nine nostocarboline derivatives with substitutions of the 2-methyl group by alkyl, aryl and functionalized residues, 10 symmetrical bis cationic dimers linking 6-Cl-norharmane through the 2-position and fifteen derivatives of the marine alkaloids eudistomin N and O is reported. These compounds were evaluated in vitro against four parasites (Trypanosoma brucei rhodesiense STIB 900, Trypanosoma cruzi Tulahuen C2C4, Leishmania donovani MHOM-ET-67/L82 axenic amastigotes, and Plasmodium falciparum K1 strain), against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc(2)155 and Corynebacterium glutamicum ATCC13032, and cytotoxicity was determined against L6 rat myoblast cells. Nostocarboline and derivatives displayed potent and selective in vitro inhibition of P. falciparum with weak cytotoxicity. The dimers displayed submicromolar inhibition of L. donovani and T. brucei, and nanomolar activity against P. falciparum, albeit with pronounced cytotoxicity. One dimer showed a MIC(99) value against M. tuberculosis of 2.5 microg/ml. The alkylated eudistomin N and O derivatives displayed activities down to 18 nM against P. falciparum for N-Me Eudistomin N. Four dimers, nostocarboline and three eudostomin derivatives were evaluated in an in vivo Plasmodium berghei mouse model. No significant activity was observed for the dimers, but a 50% reduction in parasitaemia was observed at 4 x 50 mg/kg ip for nostocarboline.

A series of sulfonium salts derived from 1,5-dithiopent-1-enopyranosides was prepared in a three-step sequence from protected D- and L-erythrofuranoses. The key step is the nucleophilic displacement of a leaving group by a sulfur atom of carbohydrate-derived ketene dithioacetals. Such compounds were assayed for their properties as glycosidase inhibitors. (C) 2009 Elsevier Ltd. All rights reserved.

2-Substituted hydrazinecarbothioamides and N ,2-disubstituted hydrazinecarbothioamides react in high yield with dimethyl acetylenedicarboxylate (DMAD) to give 4-oxo-Z-(thiazolidin-5-ylidene) acetate derivatives. Several mechanistic options involving interaction are presented. The structures of thiazolidin-4-ones have been unambiguously confirmed by single crystal X-ray crystallography. (C) 2014 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.

A series of novel benzofuran analogues of N,N-di-n-hexyl-2-phenylindole-3-acetamide (5, FGIN-1-27), a potent and highly specific mitochondrial DBI receptor complex ligand, were synthesized by a modified Fischer method and found in vitro and in vivo to be equally potent and selective as FGIN-1-27. (C) 1998 Elsevier Science Ltd. All rights reserved.

Dual targeting can in principle be achieved by using intrinsically active carriers that not only deliver the conjugated drug but also otherwise influence the pathological process. Potential carriers of this kind are monoclonal antibodies, certain interferons and interleukins, as well as certain enzymes, peptide hormones and antivirally active (glyco)-proteins. The low molecular weight protein lysozyme, that is easily filtered and reabsorbed in kidney tubular cells, was used as a carrier for renal delivery of various drugs including anti-bacterial agents. The carrier itself can add to the anti-infective effect through its lysing effect on bacterial cell walls. Albumins derivatized with various sugars were used for delivery of the anti-inflammatory drug naproxen to hepatocytes, endothelial cells and Kupffer cells. Naproxen-albumin exhibited a potent hepatoprotective effect if delivered to sinusoidal cell types. Negatively charged and enzymatically active protein carriers can contribute to therapeutic effects, among others, through receptor antagonism and detoxification of endotoxins. Some (glyco)-proteins, designed as a drug carrier for anti-HIV agents, exhibited an intrinsic antiviral activity even without coupling of antiviral drugs. This activity was caused by an increased negative charge of the particular (glyco)-proteins. The in vitro IC50 values of some of these polyanionic proteins were in the nanomolar concentration range. The mechanism of action was found to be inhibition of a post binding virus/cell fusion event. The particular negatively charged albumins (NCAs) showed, in the therapeutic dose range, favorable pharmacokinetics with regard to lymphatic distribution and residence time in the blood stream. They have little acute toxicity and, in contrast to other polyanionic compounds, such as dextran sulfate are readily biodegradable. The NCAs lack an anticoagulant activity and exhibit low immunogenicity. Importantly, a high activity against primary clinical HIV isolates was observed. We detected a high affinity binding to the V3 loop of the envelope glycoprotein gp120, explaining the potent effect on virus/cell fusion and HIV-1 replication as well as the significant activity on syncytium-inducing HIV variants. The particular antiviral proteins can in principle be applied as intrinsically active drug carriers for the targeting of nucleoside analogues such as AZT, protease inhibitors and glycosidase inhibitors. A major advantage would be the concomitant blocking of sequential steps in the viral replication process with the aims to obtain synergism and prevention of drug resistance.

NOTICE: this is the author’s version of a work that was accepted for publication in Toixcon. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Toxicon, [Volume 57, Issue 6, May 2011] doi:10.1016/j.toxicon.2011.03.014 http://www.sciencedirect.com/science/article/pii/S0041010111001000, peer-reviewed, For many years, the presence of yessotoxins (YTXs) in shellfish has contributed to the outcome of the traditional mouse bioassay and has on many occasions caused closure of shellfisheries. Since YTXs do not appear to cause diarrhoea in man and exert low oral toxicity in animal experiments, it has been suggested that they should be removed from regulation. Before doing so, it is important to determine whether the oral toxicity of YTXs is enhanced when present together with shellfish toxins known to cause damage to the gastrointestinal tract. Consequently, mice were given high doses of YTX, at 1 or 5 mg/kg body weight, either alone or together with azaspiracid-1 (AZA1) at 200 μg/kg. The latter has been shown to induce damage to the small intestine at this level. The combined exposure caused no clinical effects, and no pathological changes were observed in internal organs. These results correspond well with the very low levels of YTX detected in internal organs by means of LCMS/MS and ELISA after dosing. Indeed, the very low absorption of YTX when given alone remained largely unchanged when YTX was administered in combination with AZA1. Thus, the oral toxicity of YTX is not enhanced in the presence of sub-lethal levels of AZA1.

A method is described for the rapid production and purification of new potential dopamine agonists. Via thermal heating (refluxing in an oil bath) and microwave exposure 2-[ N -n-3-fluoropropyl- N -(4-methylphenyl)ethylamino]-5-hydroxytetralin ( 12 ), 2-[ N -n-3-fluoropropyl- N -(4-fluorophenyl)ethylamino]-5-hydroxytetralin ( 13 ), and their isotopic fluorine-18 derivatives were synthesized, respectively. The fluorine-18 label was introduced via N -fluoroalkylation with no-carrier-added (n.c.a.) 18 FCH 2 CH 2 CH 2 I. In 115 min, radiochemical yields of 11% (corrected for decay) were achieved for both compounds. The specific activity ranged from 15–75 GBq/μmol. After i.v. injection in rats, the fluorine-18 labeled compounds were evaluated for their in vivo binding to the D 2 -receptors. The radioactivity levels in the striatum, nucleus accumbens and tuberculum olfactorius were not significantly higher than in the cerebellum and frontal cortex at 15, 30 and 60 min after administration of the tetralin derivatives. Dopamine depletion with reserpine did not affect the uptake in the dopamine D 2 -receptor rich area. Remarkable high uptakes were found in the adrenal for both compounds.