In this article, a synthesis of N’-(benzylidene)-2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazides and their structural interpretation by NMR experiments is described in an attempt to explain the duplication of some peaks in their ¹H- and ¹³C-NMR spectra. Twenty new 6-methyl-1H-pyrazolo[3,4-b]quinoline substituted N-acylhydrazones 6(a–t) were synthesized from 2-chloro-6-methylquinoline-3-carbaldehyde (1) in four steps. 2-Chloro-6-methylquinoline-3-carbaldehyde (1) afforded 6-methyl-1H-pyrazolo[3,4-b]quinoline (2), which upon N-alkylation yielded 2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetate (3). The hydrazinolysis of 3 followed by the condensation of resulting 2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazide (4) with aromatic aldehydes gave N-acylhydrazones 6(a–t). Structures of the synthesized compounds were established by readily available techniques such as FT-IR, NMR and mass spectral studies. The stereochemical behavior of 6(a–t) was studied in dimethyl sulfoxide-d₆ solvent by means of ¹H NMR and ¹³C NMR techniques at room temperature. NMR spectra revealed the presence of N’-(benzylidene)-2-(6-methyl-1H-pyrazolo[3,4-b]quinolin-1-yl)acetohydrazides as a mixture of two conformers, i.e., E_(C=N)(N-N) synperiplanar and E_(C=N)(N-N)antiperiplanar at room temperature in DMSO-d₆. The ratio of both conformers was also calculated and E_{(C=N) (N-N)} syn-periplanar conformer was established to be in higher percentage in equilibrium with the E_{(C=N) (N-N)}anti-periplanar form.

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.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer’s heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, ¹H- and ¹³C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC₅₀ values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC₅₀ values of 9.68 and 11.59 μM, respectively. Various informative structure–activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.

Triazole is an imperative heterocycle renowned for its broad-spectrum biological significance. In this manuscript, facile microwave-assisted synthesis of a series of 4-(benzylideneamino)-3-(1-(2-fluoro-[1,1′-biphenyl]-4-yl)ethyl)-1H-1,2,4-triazole-5(4H)-thione 6(a–m) derivatives along with their in vivo analgesic activity is reported. 2-(2-Fluoro-[1,1′-biphenyl]-4-yl)propanoic acid (flurbiprofen) was converted to methyl 2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanoate using microwave irradiation, followed by its hydrazinolysis with hydrazine monohydrate. 2-(2-Fluoro-[1,1′-biphenyl]-4-yl)propanehydrazide thus obtained was converted to 4-amino-3-(1-(2-fluoro-[1,1′-biphenyl]-4-yl)ethyl)-1H-1,2,4-triazole-5(4H)-thione, followed by its condensation with different aromatic aldehydes to get the title compounds. Structures of all the synthesized compounds were established using different methods (¹H NMR and ¹³C NMR spectroscopies, mass spectrometry, and elemental analysis) and evaluated for their potential as analgesic agents by tail flick, hot plate, and writhing methods. The results of this in vivo study revealed several compounds as potent analgesic agents among which compound 6e showed significant analgesic effect for all the three assays employed.

P2X receptors have the ability to regulate various physiological functions like neurotransmission, inflammatory responses, and pain sensation. Such physiological properties make these receptors a new target for the treatment of pain and inflammation. Several antagonists of P2X receptors have been studied for the treatment of neuropathic pain and neurodegenerative disorders but potency and selectivity are the major issues with these known inhibitors. Sulfonamide derivatives were reported to be potent inhibitors of P2X receptors. In this study, sulfonamide carrying precursor hydrazide was synthesized by a facile method that was subsequently condensed with methyl (hetero)arylketones to obtain a series of new (hetero)aryl ethylidenes. These compounds were screened for inhibitory potential against h-P2X2, h-P2X4, h-P2X5, and h-P2X7 receptors to find their potency and selectivity. Computational studies were performed to confirm the mode of inhibition as well as type of interaction between ligand and target site. In calcium signaling experiments, compound 6h was found to be the most potent and selective inhibitor of h-P2X2 and h-P2X7 receptors with IC₅₀ ± standard error of the mean (SEM) values of 0.32 ± 0.01 and 1.10 ± 0.21 μM, respectively. Compounds 6a and 6c exhibited selective inhibition for h-P2X7 receptor, whereas 6e, 7a, and 7b expressed selective inhibitions toward h-P2X2 receptor that were comparable to the positive control suramin and pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS).