Structure-Guided Discovery and Preclinical Assessment of Novel (Thiophen-3-yl)aminopyrimidine Derivatives as Potent ERK1/2 Inhibitors.

The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.

Design, synthesis, biological assessment and molecular modeling studies of novel imidazothiazole-thiazolidinone hybrids as potential anticancer and anti-inflammatory agents.

A new series of imidazothiazole derivatives bearing thiazolidinone moiety (4a-g and 5a-d) were designed, synthesized and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer and anti-inflammatory activity, cardiomyopathy toxicity and hepatotoxicity. Compound 4c inhibited EGFR kinase at a concentration of 18.35 ± 1.25 µM, whereas standard drug erlotinib showed IC50 value of 06.12 ± 0.92 µM. The molecular docking, dynamics simulation and MM-GBSA binding energy calculations revealed strong interaction of compound 4c with binding site of EGFR. The synthesized compounds were evaluated for their anticancer activity by MTT assay against three human cancer cell lines A549 (Lung), MCF-7 (Breast), HCT116 (Colon), one normal human embryonic kidney cell line HEK293 and also for their EGFR kinase inhibitory activity. Few compounds of the series (4a, 4b, 4c) showed promising growth inhibition against all the tested cancer cell lines and against EGFR kinase. Among these, compound 4c was found to be most active and displayed IC50 value of 10.74 ± 0.40, 18.73 ± 0.88 against cancer cell lines A549 and MCF7 respectively whereas it showed an IC50 value of 96.38 ± 1.79 against HEK293 cell line indicating lesser cytotoxicity for healthy cell. Compounds 4a, 4b and 4c were also examined for their apoptosis inducing potential through AO/EB dual staining assay and it was observed that their antiproliferative activity against A549 cells is mediated via induction of apoptosis. Cardiomyopathy studies showed normal cardiomyocytes with no marked sign of pyknotic nucleus of compounds 4b and 4c. Hepatotoxicity studies of compounds 4b and 4c also showed normal architecture of hepatocytes. Compounds 4a-g and 5a-d were also evaluated for their in-vitro anti-inflammatory activity by protein albumin denaturation assay. Among the tested compounds 4a-d and 5a-b showed promising activity and were selected for in-vivo inflammatory activity against carrageenan rat paw edema test. Among these compounds, 4b was found to be most active in the series showing 84.94% inhibition, whereas the standard drug diclofenac sodium showed 84.57% inhibition. Compound 4b also showed low ulcerogenic potential and lipid peroxidation. Thus, compounds 4c and 4b could be a promising lead compounds for developing anticancer and anti-inflammatory agents with low toxicity and selectivity.

Synthesis, molecular docking and DFT analysis of novel bis-Schiff base derivatives with thiobarbituric acid for α-glucosidase inhibition assessment.

A library of novel bis-Schiff base derivatives based on thiobarbituric acid has been effectively synthesized by multi-step reactions as part of our ongoing pursuit of novel anti-diabetic agents. All these derivatives were subjected to in vitro α-glucosidase inhibitory potential testing after structural confirmation by modern spectroscopic techniques. Among them, compound 8 (IC50 = 0.10 ± 0.05 µM), and 9 (IC50 = 0.13 ± 0.03 µM) exhibited promising inhibitory activity better than the standard drug acarbose (IC50 = 0.27 ± 0.04 µM). Similarly, derivatives (5, 6, 7, 10 and 4) showed significant to good inhibitory activity in the range of IC50 values from 0.32 ± 0.03 to 0.52 ± 0.02 µM. These derivatives were docked with the target protein to elucidate their binding affinities and key interactions, providing additional insights into their inhibitory mechanisms. The chemical nature of these compounds were reveal by performing the density functional theory (DFT) calculation using hybrid B3LYP functional with 6-311++G(d,p) basis set. The presence of intramolecular H-bonding was explored by DFT-d3 and reduced density gradient (RGD) analysis. Furthermore, various reactivity parameters were explored by performing TD-DFT at CAM-B3LYP/6-311++G(d,p) method.

Advanced quality assessment of Sanshishi (Gardenia jasminoides Ellis) and Kampo medicines using a monoclonal antibody against geniposide.

Gardenia jasminoides Ellis, a plant widely used in traditional medicine, is known for its array of biological activities. A key bioactive compound, geniposide (GE), an iridoid glycoside, significantly contributes to the medicinal properties of the plant, with potential side effects. Thus, a reliable and efficient method for GE detection is required to ensure the quality of medicinal-grade G. jasminoides Ellis. This study developed such a method by first synthesizing GE-bovine serum albumin conjugates to function as immunizing agents in mice. This led to the production of a monoclonal antibody (mAb 3A6) against GE from the fusion of splenocytes from immunized mice with myeloma cells (P3U1), resulting in a hybridoma that produces mAb 3A6. Thereafter, we developed a mAb 3A6-based indirect competitive enzyme-linked immunosorbent assay (icELISA). The icELISA exhibited satisfactory sensitivity (0.391-12.5 µg/ml) and repeatability (coefficients of variation <10%). The accuracy of this method was validated through a spike-recovery assay (recovery of 101-112%). Furthermore, the icELISA was employed to determine the GE content in plant and Kampo medicine samples. The GE content positively correlated with those determined by high-performance liquid chromatography-ultraviolet. The proposed icELISA is rapid, cost-effective, and reliable for high-throughput GE detection in G. jasminoides Ellis, thereby contributing to the improved quality control and standardization of this valuable medicinal plant.

Novel azole-sulfonamide conjugates as potential antimicrobial candidates: synthesis and biological assessment.

Background: Azole and sulfonamide molecular frameworks are endowed with potent antimicrobial activity. Materials & methods: A series of azole-sulfonamide conjugates were synthesized using click reaction of N-propargylated imidazole with azide of sulfonamide and its antimicrobial efficacy was evaluated. Results: The compounds 7c, 7i and 7r displayed promising antibacterial activities, better than the standards sulfonamide and norfloxacin. All molecules exhibited promising antifungal activity, more potent than fluconazole. Docking studies of the active conjugates signified the importance of hydrophobic interactions in hosting the molecules in the active site of dihydrofolate reductase. Conclusion: Azole-sulfonamide conjugates are more active than single sulfonamide moieties and 7c, 7i and 7r may prove valuable leads for further optimization as novel antimicrobial agents.

Novel terpyridines as Staphylococcus aureus gyrase inhibitors: efficient synthesis and antibacterial assessment via solvent-drop grinding.

Aim: This study was designed to synthesize a novel series of terpyridines with potential antibacterial properties, targeting multidrug resistance. Materials & methods: Terpyridines (4a-h and 6a-c) were synthesized via a one-pot multicomponent reaction using 2,6-diacetylpyridines, benzaldehyde derivatives and malononitrile or ethyl 2-cyanoacetate. The reactions, conducted under grinding conditions with glacial acetic acid, produced high-yield compounds, confirmed by spectroscopic data. Results: The synthesized terpyridines exhibited potent antibacterial activity. Notably, compounds 4d and 4h demonstrated significant inhibition zones against Staphylococcus aureus and Bacillus subtilis, outperforming ciprofloxacin. Conclusion: Molecular docking studies highlighted compounds 4d, 4h and 6c as having strong binding affinity to DNA gyrase B, correlating with their robust antibacterial activity, suggesting their potential as effective agents against multidrug-resistant bacterial strains.

An assessment of EGFR and HER2 inhibitors with structure activity relationship of fused pyrimidine derivatives for breast cancer: a brief review.

Epidermal growth factor receptor (EGFR) and its subtype human epidermal growth factor receptor 2 (HER2) gets activated when its endogenous ligand(s) bind to its ATP binding site of target receptors. In breast cancer (BC), EGFR and HER2 are two proteins are overexpressed which leads to overexpression of cells proliferation and decreases cell death/apoptosis. Pyrimidine is one of the most widely studied heterocyclic scaffolds for EGFR as well as HER2 inhibition. We gather some remarkable results for fused-pyrimidine derivatives on various cancerous cell lines (in-vitro) and animal (in-vivo) evaluation to highlight their potency. The heterocyclic (five, six-membered, etc.) moieties which are coupled with pyrimidine moiety are potent against EGFR and HER2 inhibitions. Hence structure-activity relationship (SAR) plays important role in study of heterocyclic moiety along pyrimidine and effects of substituents, groups for increase or decrease in the cancerous activity and toxicity. By thoughtful of fused pyrimidines SAR study, it facilitates in receiving excellent overview of the compounds by concerning of efficacy and potential summary for future EGFR inhibitors. Furthermore, we studied the in-silico interactions of synthesized compounds to evaluate binding affinity towards the key amino acids..Communicated by Ramaswamy H. Sarma.

Assessment of cell wall degrading enzymes by molecular docking and dynamics simulations: Effects of novel infrared treatment.

Cell wall-degrading enzymes' activities under infrared treatment are vital for peeling; it is critical to elucidate the mechanisms of the novel infrared peeling in relation to its impact on cell wall-degrading enzymes. In this study, the activities, and gene expressions of eight degrading enzymes closely related to pectin, cellulose and hemicellulose were determined. The most influential enzyme was selected from them, and then the mechanism of its changes was revealed by molecular dynamics simulation and molecular docking. The results demonstrated that infrared had the most significant effect on ß-glucosidase among the tested enzymes (increased activity and up-regulated gene expression of 195.65 % and 7.08, respectively). It is suggested infrared crucially promotes cell wall degradation by affecting ß-glucosidase. After infrared treatment, ß-glucosidase's structure moderately transformed to a more open one and became flexible, increasing the affinity between ß-glucosidase and substrate (increasing 75 % H-bonds and shortening 15.89 % average length), thereby improving ß-glucosidase's activity. It contributed to cell wall degradation. The conclusion is that the effect of infrared on the activity, gene expression and molecular structure of ß-glucosidase causes damage to the peel, thus broadening the applicability of the new infrared dry-peeling technique, which has the potential to replace traditional wet-peeling methods.

Synthesis, molecular modeling Insights, and anticancer assessment of novel polyfunctionalized Pyridine congeners.

The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1-18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and HepG-2 among one non-cancerous BJ-1 human normal cell. Most compounds were precisely potent anticancer candidate drugs. The molecular impact of the most active compounds 9, 10, 11, 13, 15, and 17 was evaluated after MCF-7 treatment. The gene expression of pro- and ant-apoptosis markers P53, Bax, Caspase-3 and Bcl-2 as well as VEGFR-2 and HER2 were determined. Compounds 13 and 15 induced upregulation of pro-apoptosis of P53, Bax, Caspase-3 and downregulation of anti-apoptosis Bcl-2 gene. However, compound 15 showed higher effect compared to 13 and respective control. Moreover, a slight reduction in HER2 gene expression was detected due to compound 15 treatment, while VEGFR-2 gene was upregulated. In agreement, the immunoblotting analysis showed higher accumulation of P53, Bax, Caspase-3 proteins and of decrease the Bcl-2 protein levels. Furthermore, docking studies united with molecular dynamic simulation exposed compounds 13 and 15 fitting in the middle of the active site at the interface linking the ATP binding site and the allosteric hydrophobic binding pocket. Finally, we performed Petra/Osiris/ Molinspiration (POM) analysis for the newly synthesized compounds. The evaluation of primary in silico parameters revealed significant differences among individual polyfunctionalized pyridine compounds, highlighting the most promising candidates. These preliminary results may help in coordinating and initiating other research projects focused on polyfunctionalized pyridine compounds, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives.

Development and Assessment of 1,5-Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK-2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation.

New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a-j, 8a-j, 9a-c, and 10a-c. The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds 8d, 8g, 8i, and 10c inhibited EGFR with IC50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d, 8g, 8i, and 10c exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.

DP4+App: Finding the Best Balance between Computational Cost and Predictive Capacity in the Structure Elucidation Process by DP4+. Factors Analysis and Automation.

DP4+ is one of the most popular methods for the structure elucidation of natural products using NMR calculations. While the method is simple and easy to implement, it requires a series of procedures that can be tedious, coupled with the fact that its computational demand can be high in certain cases. In this work, we made a substantial improvement to these limitations. First, we deeply explored the effect of molecular mechanics architecture on the DP4+ formalism (MM-DP4+). In addition, a Python applet (DP4+App) was developed to automate the entire process, requiring only the Gaussian NMR output files and a spreadsheet containing the experimental NMR data and labels. The script is designed to use the statistical parameters from the original 24 levels of theory (employing B3LYP/6-31G* geometries) and the new 36 levels explored in this work (over MMFF geometries). Furthermore, it enables the development of customizable methods using any desired level of theory, allowing for a free choice of test molecules.

Design, semi-synthesis, anti-cancer assessment, docking, MD simulation, and DFT studies of novel theobromine-based derivatives as VEGFR-2 inhibitors and apoptosis inducers.

A group of theobromine derivatives was designed based on the key pharmacophoric characteristics of VEGFR-2 inhibitors. HepG2 and MCF-7 cancer cell lines were used to test the obtained compounds for their in vitro anti-proliferative activities. Compound 15 (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(4-(1-(2-(4-hydroxybenzoyl)hydrazono)ethyl) phenyl)acetamide) was the most potent cytotoxic member against MCF-7 (IC50 = 0.42 µM) and HepG2 (IC50 = 0.22 µM). The effectiveness of VEGFR-2 inhibition was assessed for compound 15, and its IC50 value was calculated to be 0.067 µM. Additional cellular mechanistic investigations showed that compound 15 dramatically increased the population of apoptotic HepG2 cells in both early and late apoptosis. The investigation of apoptotic markers confirmed that compound 15 upregulated the levels of BAX (2.26-fold) and downregulated the levels of Bcl-2 (4.4-fold). The molecular docking investigations, MM-GPSA, PLIP studies, and MD simulations validated the potential of compound 15 to be a VEGFR-2 inhibitor. DFT calculations have been completed to comprehend how the electrical charge is distributed within compound 15 and to predict how it would bond to VEGFR-2. Lastly, ADMET prediction showed that the designed members have drug-like characteristics and minimal levels of toxicity. In conclusion, our in vitro and in silico investigations showed that compound 15 exhibited promising apoptotic anticancer potential through the suppression of VEGFR-2.

Synthesis of flurbiprofen thiadiazole urea derivatives and assessment of biological activities and molecular docking studies.

Totally 15 novel flurbiprofen urea derivatives were synthesized bearing the thiadiazole ring. Their inhibition effects on tyrosinase were determined. 3c was found to be the strongest inhibitor with the IC50 value of 68.0 µM against tyrosinase. The enzyme inhibition types of the synthesized compounds were determined by examining the kinetic parameters. The inhibition type of 3c was determined as uncompetitive and the Ki value was calculated as 36.3 µM. Moreover, their cytotoxic effects on hepatocellular carcinoma (HepG2), colorectal carcinoma (HT-29), and melanoma (B16F10) cell lines were evaluated. According to the cytotoxicity results, 3l (IC50 = 14.11 µM) showed the highest cytotoxicity on the HT-29 cells, while 3o (IC50 = 4.22 µM) exhibited the strongest cytotoxic effect on HepG2 cell lines. Also, 3j (IC50 = 7.55 µM strongly affected B16F10. The effects of synthesized compounds on the healthy cell line were evaluated on the CCD-986Sk cell line. Molecular modelling studies have indicated the potential binding interactions of the uncompetitive inhibitor 3c with the enzyme-substrate complex.

Cordia oncocalyx and oncocalyxones: From the phytochemistry to the anticancer action and therapeutic benefits against chronic diseases.

Cordia oncocalyx Allemão is an endemic economically underexploited plant from Brazilian semi-arid region. Herein, we carried out a well-defined bibliographic review about the pharmacological activities of oncocalyxones from C. oncocalyx and mechanisms responsible for the biomedical properties. MeSH terms were used in the scientific databases for a narrative exploration. Technological development and bioproducts were also examined. Cordia oncocalyx is a deciduous tree of sexual reproduction rich in terpenoid quinones. Among them, oncocalyxone A, a 1,4-benzoquinone, the main compound from heartwood ethanol extracts, revealed anti-inflammatory and anti-edematogenic actions induced by carrageenan and dextran and antinociceptive potential in mice provoked by acetic acid and formalin. Oncocalyxone A inhibits platelet aggregation via activation of the soluble guanylate cyclase enzyme and blocks glycation processes. In addition to the antimicrobial effects against protozoa, fungi and bacteria and relaxation of smooth muscles, oncocalyxone A reduces mean blood pressure and glycemia in diabetic rats, decreases glomerular filtration parameters and tubular transport of electrolytes, and presents in vitro antimitotic and cytotoxic action upon different types of cancers, including resistant lung carcinoma lines. It has low oral acute toxicity (LD50 > 2000 mg/kg) and activates cellular apoptosis through the production of free radicals and interactions with DNA. However, no patents were found, which also emphasizes that Brazil, as the cradle of the main articles on C. oncocalyx, is wasting time and money. Moreover, slight systemic deleterious effects in mammals stimulate the use of oncocalyxone A and related compounds as lead constituents of safer drugs against chronic diseases.

Piperazin incorporated Schiff Base derivatives: Assessment of in vitro biological activities, metabolic enzyme inhibition properties, and molecular docking calculations.

The cytotoxic activities of the compounds were determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) method in human breast cancer (MCF-7), human cervical cancer (HeLa), and mouse fibroblast (L929) cell lines. The compounds MAAS-5 and four modified the supercoiled tertiary structure of pBR322 plasmid DNA. MAAS-5 showed the highest cytotoxic activity in HeLa, MCF-7, and L929 cells with IC50 values of 16.76 ± 3.22, 28.83 ± 5.61, and 2.18 ± 1.22 µM, respectively. MAAS-3 was found to have almost the lowest cytotoxic activities with the IC50 values of 93.17 ± 9.28, 181.07 ± 11.54, and 16.86 ± 6.42 µM in HeLa, MCF-7, and L929 cells respectively at 24 h. Moreover, the antiepileptic potentials of these compounds were investigated in this study. To this end, the effect of newly synthesized Schiff base derivatives on the enzyme activities of carbonic anhydrase I and II isozymes (human carbonic anhydrase [hCA] I and hCA II) was evaluated spectrophotometrically. The target compounds demonstrated high inhibitory activities compared with standard inhibitors with Ki values in the range of 4.54 ± 0.86-15.46 ± 8.65 nM for hCA I (Ki value for standard inhibitor = 12.08 ± 2.00 nM), 1.09 ± 0.32-29.94 ± 0.82 nM for hCA II (Ki value for standard inhibitor = 18.22 ± 4.90 nM). Finally, the activities of the compounds were compared with the Gaussian programme in the B3lyp, HF, M062X base sets with 6-31++G (d,p) levels. In addition, the activities of five compounds against various breast cancer proteins and hCA I and II were compared with molecular docking calculations. Also, absorption, distribution, metabolism, excretion, and toxicity analysis was performed to investigate the possibility of using five compounds as drug candidates.

Synthesis and Cytotoxicity Assessment against Human Colorectal Cancer Cell Lines of Quaternary 8-Dichloromethyl Protoberberine Alkaloids.

Twenty-two quaternary 8-dichloromethylprotoberberine alkaloids were synthesized from unmodified quaternary protoberberine alkaloids (QPAs) to improve their physical and chemical properties and to obtain selectively anticancer derivatives. The synthesized derivatives showed more appropriate octanol/water partition coefficients by up to values 3-4 compared to unmodified QPA substrates. In addition, these compounds exhibited significant antiproliferative activity against colorectal cancer cells and lower toxicity on normal cells, resulting in more significant selectivity indices than unmodified QPA compounds in vitro. The IC50 values of antiproliferative activity of quaternary 8-dichloromethyl-pseudoberberine 4-chlorobenzenesulfonate and quaternary 8-dichloromethyl-pseudopalmatine methanesulfonate against colorectal cancer cells are 0.31 µM and 0.41 µM, respectively, significantly stronger than those of other compounds and positive control 5-fluorouracil. These findings suggest that 8-dichloromethylation can be used as one of the modification strategies to guide the structural modification and subsequent investigation of anticancer drugs for CRC based on QPAs.

Achyrocline satureioides review: From the pharmacochemical diversity to the technological development of products.

Achyrocline satureioides (Lam.) DC (Asteraceae) is a native species of the southeastern subtropical and temperate region of South America, popularly known as "marcela" or "macela". This species is recognized, in traditional medicine, by diverse biological activities such as digestive, antispasmodic, anti-inflammatory, antiviral, sedative, hepatoprotective, among others. Some of these activities have been related to the presence of phenolic compounds, including flavonoids, phenolic acids, terpenoids in the essential oils, coumarins and phloroglucinol derivatives reported to the species. The approaches on the technological development of phytopharmaceutical products of this species provided relevant advances in the optimization of the extraction and product obtention, especially spray-dried powders, hydrogels, ointments, granules, films, nanoemulsions and nanocapsules. The most relevant biological activities described for the extracts or derivative products from A. satureioides were antioxidant, neuroprotective, antidiabetic, antiobesity, antimicrobial, anticancer effects, and obstructive sleep apnea syndrome. The scientific and technological findings reported for the species, in conjunction with its traditional use and cultivation, reveal the high potential of the species for diverse industrial applications.

Step-Economical Mechanosynthesis of Hybrid Azoles: Deciphering Their π-Orbital and Pharmacological Characteristics.

A hybrid pharmacophore strategy for unifying 1,2,3-triazole with 1,2,4-triazole cores to prepare mixed triazoles was accomplished by a ball-milling approach. The developed chemistry works under the catalysis of cupric oxide nanoparticles with salient features like one-jar operation, lower number of synthetic steps, catalyst recyclability, time-dependent product control, and good overall yields. π-Orbital properties based on theoretical calculations supported the suitability of these molecules for pharmacological screening. Therefore, the biological potency of the synthesized molecules was evaluated for antioxidant, anti-inflammatory, and anti-diabetic activities. By virtue of their proton-donating tendency, all compounds showed promising radical-scavenging activity with the inhibition level reaching up to 90 %. These molecular hybrids also exhibited anti-inflammatory and anti-diabetic potencies similar to those of standard compounds, owing to their electron-rich nature. Finally, α-amylase inhibitory potential was demonstrated in silico; significant regions necessary for enzyme inhibition were identified by hydrogen bonding interactions.

Ultrasound-Assisted Synthesis of Piperidinyl-Quinoline Acylhydrazones as New Anti-Alzheimer's Agents: Assessment of Cholinesterase Inhibitory Profile, Molecular Docking Analysis, and Drug-like Properties.

Alzheimer's disease (AD) is one of the progressive neurological disorders and the main cause of dementia all over the world. The multifactorial nature of Alzheimer's disease is a reason for the lack of effective drugs as well as a basis for the development of new structural leads. In addition, the appalling side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with the marketed treatment modalities and many failed clinical trials significantly limit the use of drugs and alarm for a detailed understanding of disease heterogeneity and the development of preventive and multifaceted remedial approach desperately. With this motivation, we herein report a diverse series of piperidinyl-quinoline acylhydrazone therapeutics as selective as well as potent inhibitors of cholinesterase enzymes. Ultrasound-assisted conjugation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes (4a,b) and (un)substituted aromatic acid hydrazides (7a-m) provided facile access to target compounds (8a-m and 9a-j) in 4-6 min in excellent yields. The structures were fully established using spectroscopic techniques such as FTIR, 1H- and 13C NMR, and purity was estimated using elemental analysis. The synthesized compounds were investigated for their cholinesterase inhibitory potential. In vitro enzymatic studies revealed potent and selective inhibitors of AChE and BuChE. Compound 8c showed remarkable results and emerged as a lead candidate for the inhibition of AChE with an IC50 value of 5.3 ± 0.51 µM. The inhibitory strength of the optimal compound was 3-fold higher compared to neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 8g exhibited the highest potency and inhibited the BuChE selectively with an IC50 value of 1.31 ± 0.05 µM. Several compounds, such as 8a-c, also displayed dual inhibitory strength, and acquired data were superior to the standard drugs. In vitro results were further supported by molecular docking analysis, where potent compounds revealed various important interactions with the key amino acid residues in the active site of both enzymes. Molecular dynamics simulation data, as well as physicochemical properties of the lead compounds, supported the identified class of hybrid compounds as a promising avenue for the discovery and development of new molecules for multifactorial diseases, such as Alzheimer's disease (AD).

Non-Covalent Interactions in the Self-Assembly of Dihydropyridone Supramolecules and In Vitro Anti-Cancer Assessment in Human Lung Adenocarcinoma Cell Line (A549).

The synthesis of dihydropyridone derivatives has been reported by ring rearrangement of pyrans using iodine and formic acid as a catalyst separately. Dihydropyridones were crystallized subjected for single-crystal X-ray crystallography to acquire their structural parameters. The different non-covalent interactions involved within the supramolecular systems were studied and validated using Hirshfeld surface plot analysis. N-H⋅⋅⋅O interactions between the lactam group dominate. Still, other non-covalent interactions such as C-H⋅⋅⋅N, C-H⋅⋅⋅O, C-H⋅⋅⋅C, N-H⋅⋅⋅N, C-H⋅⋅⋅π, and lone pair⋅⋅⋅π systems act as the driving force in facilitating the self-assembly of the dihydropyridone supramolecules. The synthesized compounds were analyzed by in vitro techniques using human lung adenocarcinoma (A549) to evaluate their cytotoxic activities. Ethyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-oxo-1,4,5,6- tetrahydropyridine-3-carboxylate has shown the highest cytotoxicity among all the synthesized compounds. Molecular recognition properties of the dihydropyridone compounds were also studied, employing molecular docking tools to gain insight into the binding mode inside the allosteric binding pocket of the Eg5 protein through non-covalent interactions.