Cholinesterases inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones.

Super-activation of cholinesterases (acetylcholinesterase and butyrylcholinesterase) are linked to various neurological problems most precisely Alzheimer's disease (AD), which leads to senile dementia. Therefore, cholinesterases (AChE & BChE) inhibition are considered as a promising strategy for the treatment of Alzheimer's disease. FDA approved drugs for the treatment of AD, belong to a group of cholinesterase inhibitors. However, none of them is able to combat or completely abrogate the disease progression. Herein, we report a series of newly synthesized chalcone derivatives with anti-AD potential. For this purpose, a series of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones were tested for their cholinesterases (AChE & BChE) inhibitory activity. All compounds were found as selective inhibitor of AChE. In piperidyl chalcones derivatives compound 1e having IC50 of 0.16 ± 0.008 µM and 2m in 2-pyrazoline chalcones with IC50 of 0.13 ± 0.006 µM, were found to be the most potent inhibitors of AChE, exhibiting ≈142 and ≈ 173-fold greater inhibitory potential compared to the reference inhibitor i.e., Neostigmine (IC50 ± SEM = 22.2 ± 3.2 µM). Molecular docking studies of most potent inhibitors were carried out to investigate the binding interactions inside the active site. Molecular docking study revealed that potent compounds and co-crystalized ligand had same binding orientation within the active site of target enzyme. Most of these compounds are selective inhibitors of AChE with a potential use against progressive neurodegenerative disorder and age related problems.

Molecular docking and antiviral activity of N-substituted benzyl/phenyl-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides.

Two series of fifteen N-substituted benzyl/phenyl-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides were screened for anti-HIV-1 activity and cytotoxicity. The compounds 6a, 6d, 6e, 6g and 6i from the series 6a-i of benzylamides and 7a, 7b, 7c, 7d and 7e from the series 7a-f of anilides were identified as effective anti-HIV-1 agents with EC50 values <20µM. Among these compounds that displayed anti-HIV-1 activity, 6a, 6e, 6g and 6i showed no toxicity in human PBM, CEM and Vero cells, with the exception of 6a which displayed toxicity in Vero cells. Molecular docking of these compounds provided insight into the molecular mechanism and it was found that 6e, 6g and 6i bound deeply in the NNRTI binding pocket of the HIV-1 reverse transcriptase, using RT-bound nevirapine X-ray data and molecular docking for validation, showing the potential of these new structures as inhibitors of this viral enzyme.

Quinolinyl-thienyl chalcones as monoamine oxidase inhibitors and their in silico modeling studies.

Mitochondrial enzymes monoamine oxidases were thought to be an emerging and useful therapeutic target for neurodegenerative disorders. Monoamine oxidases have two isoforms, A and B. MAO-A is related with metabolism of amine neurotransmitters in the brain whereas MAO-B is concerned with aging related neurodegenerative disorders. Therefore the identification, characterization and discovery of potent MAO-A and B inhibitors is very crucial in research. A series of quinolyl-thienyl chalcones were tested against MAO-A and B. Among the screened compounds, most of them revealed potent MAO-A and B inhibition. Compound 5i presented most potent MAO-A inhibition having IC50 values 0.047 µM, while 4l showed excellent inhibitory potency against MAO-B among all the tested compound having IC50 values 0.063 µM. Molecular modelling studies were performed against human MAO-A and MAO-B for the explanation of binding site interactions.

Discovery and molecular docking of quinolyl-thienyl chalcones as anti-angiogenic agents targeting VEGFR-2 tyrosine kinase.

Vascular endothelial growth factor Receptor-2 (VEGFR-2) kinase inhibition is one of the well established strategies to promptly tackle tumor growth by suppression of angiogenesis. In the current study, structure-based virtual screening methodology of a series of quinolyl-thienyl chalcones indicated their strong potential as VEGFR-2 kinase inhibitors. In vitro VEGFR-2 kinase inhibitory activity was found to be significant (compound 19, IC(50): 73.41nM). All compounds showed significant inhibition of human umbilical vein endothelial cells (HUVEC) proliferation (compound 19, IC(50): 21.78nM). Molecular interactions of the compounds were studied using molecular docking studies.

Antimicrobial and antileishmanial studies of novel (2E)-3-(2-chloro-6-methyl/methoxyquinolin-3-yl)-1-(aryl)prop-2-en-1-ones.

Thirty eight heterocyclic chalcones were synthesized by condensing formylquinolines with diverse methyl arylketones. The target compounds were characterized by spectroscopic techniques (NMR, IR, MS) and elemental analysis. The X-ray crystallographic study of (2E)-3-(2-chloro-6-methylquinolin-3-yl)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-en-1-one (1p) was also performed for the structure confirmation. The title compounds were screened for anti-microbial and antileishmanial activities. The compounds 1c-e, 1g, 1j-m, 1p, 1r-s, 2g, 2j-p, and 2r-s were found potentially active antileishmanial agents, while 1f-i, 1l, 1o-p, 2f-i, 2l, and 2o-p showed remarkable antibacterial activity. Only compounds 1g and 2g-h exhibited significant antifungal activity.

N'-[(E)-4-(Diethyl-amino)benzyl-idene]-4-nitro-benzohydrazide monohydrate.

In the title compound, C(18)H(20)N(4)O(3)·H(2)O, the two aromatic rings are linked through a methyl-idenehydrazide fragment, which is fully extended with C-C-N-N, C-N-N=C and N-N=C-C torsion angles of 179.4 (2), 174.7 (2) and 178.3 (2)°, respectively. The dihedral angle between the two aromatic rings is 7.01 (8)°. In the crystal structure, the water of hydration is involved in extensive hydrogen bonding. Inter-molecular O-H⋯O, N-H⋯O and O-H⋯N hydrogen bonds link the components of the structure into a two-dimensional network and additional stabilization is provided by weak inter-molecular C-H⋯O hydrogen bonds.

(E)-3-(2-Chloro-6-methyl-3-quinol-yl)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)prop-2-en-1-one.

In the title mol-ecule, C(21)H(16)ClNO(3), the quinoline and benzene rings are inclined at 56.96 (6)° with respect to each other and the dioxine ring is in a twist-chair conformation. The structure is devoid of any classical hydrogen bonds. Rather weak inter-molecular hydrogen-bonding inter-actions of the types C-H⋯N and C-H⋯O are present, consolidating the crystal structure.

(2E)-3-(2-Chloro-6-methyl-3-quinol-yl)-1-(1-naphth-yl)prop-2-en-1-one.

In the title mol-ecule, C(23)H(16)ClNO, the quinoline and naphthalene ring systems are individually planar, with maximum deviations of 0.020 (2) and 0.033 (2) Å, respectively, and are inclined at a dihedral angle of 30.01 (4)°. Intra-molecular C-H⋯O and C-H⋯Cl inter-actions occur. The crystal structure is devoid of any classical hydrogen bonds, but symmetry-related mol-ecules are linked via weak C-H⋯Cl inter-actions, forming chains propagating in [001].