Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer's Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 µM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 µM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer's disease.

Methoxy-Substituted Tyramine Derivatives Synthesis, Computational Studies and Tyrosinase Inhibitory Kinetics.

Targeting tyrosinase for melanogenesis disorders is an established strategy. Hydroxyl-substituted benzoic and cinnamic acid scaffolds were incorporated into new chemotypes that displayed in vitro inhibitory effects against mushroom and human tyrosinase for the purpose of identifying anti-melanogenic ingredients. The most active compound 2-((4-methoxyphenethyl)amino)-2-oxoethyl (E)-3-(2,4-dihydroxyphenyl) acrylate (Ph9), inhibited mushroom tyrosinase with an IC50 of 0.059 nM, while 2-((4-methoxyphenethyl)amino)-2-oxoethyl cinnamate (Ph6) had an IC50 of 2.1 nM compared to the positive control, kojic acid IC50 16700 nM. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound (Ph9) and Ph6 exhibited 94.6% and 92.2% inhibitory activity respectively while the positive control kojic acid showed 72.9% inhibition. Enzyme kinetics reflected a mixed type of inhibition for inhibitor Ph9 (Ki 0.093 nM) and non-competitive inhibition for Ph6 (Ki 2.3 nM) revealed from Lineweaver-Burk plots. In silico docking studies with mushroom tyrosinase (PDB ID:2Y9X) predicted possible binding modes in the catalytic site for these active compounds. Ph9 displayed no PAINS (pan-assay interference compounds) alerts. Our results showed that compound Ph9 is a potential candidate for further development of tyrosinase inhibitors.

Design, synthesis, crystal structure, in vitro cytotoxicity evaluation, density functional theory calculations and docking studies of 2-(benzamido) benzohydrazide derivatives as potent AChE and BChE inhibitors.

A series of hydrazone derivatives of 2-(benzamido) benzohydrazide was designed, synthesized, and characterized utilizing FTIR, NMR and UV spectroscopic techniques along with mass spectrometry. Compound 10 was also characterized through X-ray crystallography. These synthesized compounds were assessed for their potential as anti-Alzheimer's agents by checking their AChE and BChE inhibition properties by in vitro analysis. The synthesized derivatives were also evaluated for their antioxidant potential along with cytotoxicity studies. The results clearly indicated that dual inhibition of both the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was achieved by most of the compounds (03-13), showing varying IC50values. Remarkably, compound 06 (IC50 = 0.09 ± 0.05 for AChE and 0.14 ± 0.05 for BChE) and compound 13 (IC50 = 0.11 ± 0.03 for AChE and 0.10 ± 0.06 for BChE) from the series showed IC50 values comparable to the standard donepezil (IC50 = 0.10 ± 0.02 for AChE and 0.14 ± 0.03 for BChE). Moreover, the derivative 11 also exhibited selective inhibition against BChE with IC50 = 0.12 ± 0.09. Meanwhile, compounds 04 and 10 exhibited good anti-oxidant activities, showing % scavenging of 95.06% and 82.55%, respectively. Cytotoxicity studies showed that the synthesized compounds showed cell viability greater than 80%; thus, these compounds can be safely used as drugs. DFT and molecular docking studies also supported the experimental findings.

5-Methyl-1-[(4-methyl-phen-yl)sulfon-yl]-1H-pyrazol-3-yl 4-methyl-benzene-sulfonate.

In the title compound, C(18)H(18)N(2)O(5)S(2), the tolyl rings are oriented at a dihedral angle of 16.15 (11)° with respect to one another. The 5-methyl-1H-pyrazol-3-ol ring is roughly planar (r.m.s. deviation = 0.0231 Å) and subtends angles of 73.82 (8) and 89.85 (8)° with the tolyl rings. In the crystal, very weak π-π inter-actions between tolyl groups, with centroid-centroid distances of 4.1364 (19) and 4.0630 (16) Å, together with a C-H⋯π contact generate a three-dimensional network.

Ethyl (3E)-3-[2-(4-bromo-phenyl-sulfon-yl)hydrazin-1-yl-idene]butano-ate.

The asymmetric unit of title compound, C(12)H(15)BrN(2)O(4)S, contains two mol-ecules (A and B), with slightly different conformations: the bromo-phenyl rings and the SO(2) planes of the sulfonyl groups are oriented at dihedral angles of 50.2 (2) (mol-ecule A) and 58.24 (7)° (mol-ecule B), and the ethyl acetate groups make dihedral angles of 63.99 (19)° (A) and 65.35 (16)° (B) with their bromo-phenyl groups. In the crystal, both mol-ecules exist as inversion dimers linked by pairs of N-H⋯O hydrogen bonds, which generate R(2) (2)(14) loops. The dimers are linked by C-H⋯O inter-actions.

2-[(2-Amino-phen-yl)sulfan-yl]-N-(4-meth-oxy-phen-yl)acetamide.

In the title compound, C(15)H(16)N(2)O(2)S, the dihedral angle between the 4-meth-oxy-aniline and 2-amino-benzene-thiole fragments is 35.60 (9)°. A short intra-molecular N-H⋯S contact leads to an S(5) ring. In the crystal, mol-ecules are consolidated in the form of polymeric chains along [010] as a result of N-H⋯O hydrogen bonds, which generate R(3) (2)(18) and R(4) (3)(22) loops. The polymeric chains are interlinked through C-H⋯O inter-action and complete R(2) (2)(8) ring motifs.