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Novel scaffolds of stilbene were identified as inhibitors ofMycobacterium tuberculosisby targeting the nucleoid-associated protein, HU, using molecular docking. Based on the proposed combinatorial libraries I to VI, structures I and III had significantly greater docking binding energy that was comparable to that of the reference ligand, protein HU, fromMycobacterium tuberculosis.Using these docking results, 18 compounds were synthesized, characterized and evaluated forin vitroantitubercular (anti-TB) efficacy in theMycobacterium tuberculosisstrain, H37Rv. Thein vitroscreening results indicated a significant positive correlation between the docking binding efficacy (r2> 0.5) and clogp. Compounds3f,3dand4fwere ranked as top scoring ligands that interacted with amino acids ARG 53, ARG 55, PRO 81, PHE 79, and LYS 13, where the -NO2or -Cl substitution at theparaposition of the 3-phenyl ring was essential for interacting of the HU protein. The hydrogen bonding with ARG 55 and LYS 13 of these compounds was similar to that with the reference ligand that inhibits the HUMtbprotein. Compounds3d,3f, and4fwere evaluated as active leads, with MIC90 values of 21.3, 23.2 and 44.1 μM, respectively. The above mentioned compounds were also evaluated for antibacterial and antifungal efficacy in a panel of selected bacteria and fungi. Compound3dhad efficacy (MIC90: 6.82 μM) inS. aureusandE. coli. Compound3fwas also efficacious inE. coliandA. Niger, with an MIC90 value of 7.42 μM for both microorganisms. The fluoro-phenyl derivatives,3iand4i, were efficacious inC. albicans(MIC90 values of 8.2 and 7.8 μM, respectively) andA. niger(MIC90 values of 4.1 and 3.1 μM, respectively). Our results suggest that substitutions at theparaposition of 3-phenyl acryl derivatives with -NO2and -Cl significantly affected the binding interactions with the HUMtb protein in the docking studies. Furthermore these compounds had antitubercular and antimicrobial efficacy. The substituted phenyl acrylic acid and hydrazides could be inhibitors of the HUMtb protein ofMycobacterium tuberculosis.

The Mannich reaction has been used for decades to prepare many pharmaceutically important molecules. Here, using a "double-Mannich-β-elimination" synthetic sequence, we report the synthesis and the characterization details of a novel class of β-amino diaryldienones with prominent antiprostate cancer activity. Through these studies, we correct an erroneous structure in the current literature, present a discussion of the stereochemical outcome of a new reaction, and probe the mechanism(s) of byproduct formation through isotopic studies.

The present disclosure provides compounds and methods for inhibiting or degrading the N-terminal domain of the androgen receptor, as well as methods for treating cancers such as prostate cancer.

Twenty-eight compounds with a new scaffold were designed and synthesized by assembling fragments derived from known agents such as stilbenes and piperazinyl pyrimidines. Many strategies have been explored to improve the druggability of these series of compounds, such as increasing the distance between two benzene rings in the scaffold and introducing functional groups at designated positions. These compounds were validated for their anti-neuroinflammatory activity in BV2 cells. Experimental results reveal that the most active compound 8b can inhibit nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) production with IC50 values of 1.0, 2.6, and 0.5 μM, respectively. The compound can also significantly modulate the MAPK pathways through inhibiting the phosphorylation of JNK, ERK1/2, and p38 MAPK without disturbing NF-κB pathway. Parallel artificial membrane permeation assay demonstrated that the most active compound can overcome the blood-brain barrier (BBB). Therefore, this compound can be a promising lead for the treatment of Alzheimer's disease.

Epigenetics alterations including histone methylation and acetylation, and DNA methylation, are thought to play important roles in the onset and progression of cancer in numerous tumour cell lines. Lysinespecific demethylase 1 (LSD1 or KDM1A) is highly ex

The present invention is directed to guanidine derivatives as inhibitors of transient receptor potential canonical channels (TRPC channels), in particular TRPC3 and/or TRPC6 and/or TRPC7 activity, more particularly TRPC6 activity. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders mediated by TRPC channels (Formula (I))

The rate coefficients for the base-catalysed ring fission of a series of 2-phenyl-3-(2-, 3-or 4-substituted phenyllcycloprop-2-en-1-ones to give the corresponding (E)-2,3-diphenylacrylic acids have heen determined in water at 30.0 °C, as well as for the unsubstituted compound at 40.0, 50.0 and 60.0 °C. The effects of meta-and para-substituents on the rates have been correlated using the Hammett equation to give a reaction constant, p, equal to ca 1.2 at 30 °C. For the unsubstituted compound, the activation parameters have been calculated and the kinetic solvent isotope effect has been studied. The effects of ortho-substituents on the rates appear to be mainly polar, rather than steric, in origin. The evidence indicates a mechanistic pathway which proceeds by addition of hydroxide anion to the ketone, which is rate-determining. The adduct suffers ring fission to give the final product via a carbanionic intermediate.

Z-1,1-Dichloro-2,3-diphenylcyclopropane (1) is an effective anti-breast cancer agent in rodents and in cell culture. We recently determined that 1 inhibits tubulin assembly in vitro, and causes microtubule loss in breast cancer cells, leading to accumulat

To evaluate better the effects of N2p-P(IV) through-space interactions in Wittig reactions, a thorough study of metal ion effects in Wittig reactions lacking such interactions has been completed.As in the case of Wittig reactions with stabilized ylides, it has been determined that, with a moderated ylide, the stereochemistry (E:Z ratio) of alkene formation with an aldehyde is determined at the point that a new carbon-carbon bond has been formed to give a betaine or an oxaphosphetane intermediate.The observations that in most cases where lithium ion is present, theproduct mixture is enriched with the Z alkene, while when sodium or potassium ions are present, the E isomer predominates, are deemed to support the concept that a spin-paired diradical is formed as an unstable intermediate when sodium or potassium ions are present but that an ionic reaction occurs when lithium ions are present.The evidence that has been accumulated suggests that the reactions studied here (involving aromatic, heterocyclic, and aliphatic aldehydes and benzylidenediphenylmethylphosphorane or the preformed betaines, in THF at -78 deg C) occur under kinetic control and without any significant degree of equilibration or Wittig reversal.

The dissociation equilibrium constants of some E-α-phenyl-β-arylacrilic acids (Ar=2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, anthracen-9-yl) have been measured in 80percent aqeous 2-methoxyethanol at 25 deg C., The pKa values of these acids, together with those of p-substituted phenyl, 2-furyl, 2-thienyl and selenophen-2-yl derivitives, have been rationalized by an equation involving separate contributions of polar, conjugative and steric effects of heterocycles.The pKa values of some E-α-phenyl-β-alkylacrilic acids (alk=methyl; ethyl; n-propyl; i-propyl; n-butyl; i-butyl) are also reported.

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