Monu Joy

Exploration of chlorinated thienyl chalcones: A new class of monoamine oxidase-B inhibitors

Chalcone has been reported to be a valid scaffold for the design of monoamine oxidase (MAO) inhibitors. This scenario has amplified the momentum for the discovery of heteroaryl based chalcone MAO inhibitors. In the present study, we have synthesized a series of eleven chlorinated thienyl chalcone derivatives substituted with a different functional groups at the para- position on the ring B and investigated for their ability to inhibit human MAO-A and -B. With the exception of compound (2E)-1-(4-chlorocyclopenta-1,3-dien-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one (TC7), which was a selective MAO-A inhibitor, all the other derivatives inhibited hMAO-B potently and selectively with competitive mode of inhibition. The most potent compound (2E)-1-(4-chlorocyclopenta-1,3-dien-1-yl)-3-(4-ethylphenyl)prop-2-en-1-one (TC6) was found to be the best activity and higher selectivity towards hMAO-B with Ki and SI values of 0.31±0.02μM and 16.84, respectively. All the compounds presented in the current study are completely non-toxic with 74-88% viable cells to hepatic cells at 100μM concentration. Molecular docking and molecular dynamics simulation studies were carried out using Autodock-4.2 and Amber 14 to understand the molecular level interaction and energy relation of MAO isoforms with selective MAO-B inhibitor TC6.

Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO-B Inhibitors.

A series of (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(para‐substituted phenyl)prop‐2‐en‐1‐ones (TB1–TB11) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO‐B except (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one (TB7) and (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐chlorophenyl)prop‐2‐en‐1‐one (TB8), which were selective inhibitors of hMAO‐A. The most potent compound, (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐[4‐(dimethylamino)phenyl]prop‐2‐en‐1‐one (TB5), showed the best inhibitory activity and higher selectivity toward hMAO‐B, with Ki and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood–brain barrier. Moreover, the most potent MAO‐B inhibitor, TB5, was found to be nontoxic at 5 and 25 μm, with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.

Pharmacophore-Based 3D-QSAR Analysis of Thienyl Chalcones as a New Class of Human MAO-B Inhibitors: Investigation of Combined Quantum Chemical and Molecular Dynamics Approach

Selective monoamine oxidase-B (MAO-B) inhibitors are imperative in the treatment of various neurodegenerative disorders. Herein, we describe the pharmacophore generation and atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of previously reported thiophene-based hMAO-B inhibitors by our research group. The aim of this study was to identify the principal structural features that could potentially be responsible for the inhibitory activity of hMAO-B inhibitors. The best pharmacophore model generated was the four-point assay of AHRR.8. The pharmacophore model exhibited good correlation with its predictability of the statistically valid 3D-QSAR analyses. Density functional theory calculations were further employed on the lead molecule (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino) phenyl] prop-2-en-1-one (Tb5) to investigate the electrostatic potential surface and analyze the natural bond orbital toward the binding characteristics. Molecular dynamics simulations were performed to characterize the molecular level interactions and relative energies of the hMAO isoforms: hMAO-A and hMAO-B with three potent and selective hMAO-B inhibitors (Tb5, Tb6, and Tb9). The results of both continuous and accelerated molecular dynamics simulations demonstrate a distinct preference of the three ligands to bind to hMAO-B rather than hMAO-A.

Monoamine oxidase inhibitory activity of methoxy-substituted chalcones

The MAO-B inhibitory activity of chalcone (1, 3- diphenyl-2-propen-1-one) based compounds arise from its structural similarity with 1, 4-diphenyl-2-butene, a known MAO-B inhibitor. Based on our previous report, the methoxy-substituted with fluorine containing chalcones are promising reversible MAO-B inhibitors, while in the present study, a series of methoxylated chalcones (C1-C9) bearing substitution on the para position of ring B was synthesized and evaluated for their human monoamine oxidase inhibitory activity. With the exception of (2E)-1-(4-methoxyphenyl)-3-(4-nitrophenyl) prop-2-en-1-one (C7), which is a nonselective inhibitor, the chalcones exhibited competitive, selective, and reversible inhibition of hMAO-B. The most potent compound, (2E)-3-[4-(dimethylamino) phenyl]-1-(4-methoxyphenyl) prop-2-en-1-one (C5), showed the best inhibitory activity towards hMAO-B (IC50=0.29±0.011μM;Ki=0.14±0.001μM). The reversibility of MAO-B inhibition by compound C5 was demonstrated by the recovery of enzyme activity after dialysis of mixtures containing enzyme and inhibitor. The reversiblity of C5 was 25.38±1.40 and 92.00±3.87% before and after dialysis, respectively. PAMPA was carried out to evaluate the blood-brain barrier effects of the designated compounds. Moreover, the most potent MAO-B inhibitor, C5, was found to be nontoxic towards cultured hepatic cells at 5 and 25μM, with 97 and 90% viability. Molecular docking study was performed against hMAO-B to observe the binding site interactions of the lead compound.

CCDC 1842427: Experimental Crystal Structure Determination

Related Article: Monu Joy, Nirmala Joseph, Varughese Mary, Vibin Jose, C. Sudarsanakumar|2018|J.Mol.Struct.|1173|964|doi:10.1016/j.molstruc.2018.07.033

CCDC 1842430: Experimental Crystal Structure Determination

Related Article: Monu Joy, Nirmala Joseph, Varughese Mary, Vibin Jose, C. Sudarsanakumar|2018|J.Mol.Struct.|1173|964|doi:10.1016/j.molstruc.2018.07.033

Structural and optical profile of a multifunctionalized 2-pyridone derivative in a crystal engineering perspective

The supramolecular structural features of organic molecules are very important with regard to their widespread properties in both solids and solutions. Herein, we describe the synthesis of a novel multifunctional 2-pyridone derivative, namely 6-(4-chlorophenyl)-5-formyl-4-methylsulfanyl-2-oxo-1,2-dihydropyridine-3-carbonitrile, C14H9ClN2O2S, denoted P1, and its structural features were established through X-ray crystallography. A Hirshfeld surface analysis followed by a two-dimensional fingerprint plot analysis was carried out. A frontier molecular orbital investigation and natural bond orbital (NBO) calculations explored the charge-transfer interactions associated with the molecular system. The optical properties of the 2-pyridone derivative were elucidated through UV-Vis absorption and emission spectroscopy, indicating a strong blue emissive nature with a colour purity of 82.5%, a short-lived lifetime and a large Stokes shift. Time-dependent density functional theory (TD-DFT) was used to gain some insight into the absorption behaviour and emissive characteristics of P1.