A Highly Chemically Robust 3D Interpenetrated MOF Heterogeneous Catalyst for the Synthesis of Hantzsch 1,4-Dihydropyridines and Drug Molecules.

Metal-organic frameworks (MOFs) have attracted immense attention as efficient heterogeneous catalysts over other solid catalysts, however, their chemical environment instability often limits their catalytic potential. Herein, utilizing a flexible unexplored tetra-acid ligand and employing the mixed ligand approach, a 3D interpenetrated robust framework is strategically developed, IITKGP-51 (IITKGP stands for Indian Institute of Technology Kharagpur), which retained its crystallinity over a wide range of pH solution (4-12). Having ample open metal sites (OMSs), IITKGP-51 is explored as a heterogeneous catalyst in one-pot Hantzsch condensation reaction, with low catalyst loading for a broad range of substrates. The synthesis of drug molecules remains one of the most significant and emergent areas of organic and medicinal chemistry. Considering such practical utility, biologically important Nemadipine B and Nifedipine drug molecules (calcium channel protein inhibitor) are synthesized for the first time by using this catalyst and fully characterized via SC-XRD and other spectroscopic methods. This report inaugurates the usage of a MOF material as a catalyst for the synthesis of drug molecules.

18F-Labeled dihydropyridines via Hantzsch reaction for positron emission tomography of P-glycoprotein dysfunction.

Despite the availability of various 11C-labeled positron emission tomography (PET) tracers for assessing P-glycoprotein (P-gp) function, there are still limitations related to complex metabolism, high lipophilicity, and low baseline uptake. This study aimed to address these issues by exploring a series of customized dihydropyridines (DHPs) with enhanced stability and reduced lipophilicity as alternative PET tracers for P-gp dysfunction. Compared with verapamil and the rest DHPs, dimethyl 4-(4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1) exhibited superior cellular uptake differences between the human gastric cancer cell line SGC7901 and its drug-resistant counterpart. [18F]1 is successfully synthesized using a novel "hot-Hantzsch" approach in 22.1 ± 0.1 % radiochemical yields. MicroPET/CT imaging demonstrated that the uptake of [18F]1 in the brains of P-gp blocked mice increased by > 3 times compared to the control group. Additionally, [18F]1 displayed favorable lipophilicity (log D = 2.3) and excellent clearance characteristics, making it a promising tracer candidate with low background noise and high contrast.

New Dihydropyridine Derivative Attenuates NF-κB Activation via Suppression of Calcium Influx in a Mouse BV-2 Microglial Cell Line.

Activated microglia contribute to many neuroinflammatory diseases in the central nervous system. In this study, we attempted to identify an anti-inflammatory compound that could suppress microglial activation. We performed high-throughput screening with a chemical library developed at our institute. We performed a luciferase assay of nuclear factor-kappa B (NF-κB) reporter stable HT22 cells and identified a compound that was confirmed to inhibit the anti-inflammatory response in BV2 microglial cells. The selected dihydropyridine derivative can suppress the expression response of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor (TNF), as well as NF-κB phosphorylation and nuclear translocation, and reduce the intracellular calcium level. Thus, our identified compound has a potential role in suppressing microglial activation and may contribute to the development of a new therapeutic molecule against neuroinflammatory diseases.

Design, Synthesis and In-Silico Studies of Piperidine-Dihydropyridine Hybrids as Anticancer Agents.

In this study, we designed, synthesized and characterized a novel series of piperidine-dihydropyridine hybrid compounds and characterized them by 1H-NMR, 13C NMR, mass spectrometry (MS), and elemental analysis. Subsequently, we assessed their in vitro anticancer potentials against the human breast adenocarcinoma cell line MCF-7 and the lung cancer cell line A-549. Several of these compounds demonstrated significant activity, with IC50 values ranging from 15.94 µM to 48.04 µM for A-549 and 24.68 µM to 59.12 µM for MCF-7, when compared to the reference drug Cisplatin.Notably, a compound featuring a 3-fluoro substitution in the carboxamide series exhibited robust inhibitory effects, with an IC50 of 15.94±0.201 µM against A-549 cells and an IC50 of 22.12±0.213 µM against MCF-7 cells, respectively. Additionally, a compound containing a cyclobutyl ring displayed potent activity, with an IC50 of 16.56±0.125 µM against A-549 and an IC50 of 24.68±0.217 µM against MCF-7 cells, respectively. Furthermore, molecular docking studies against the Epidermal Growth Factor Receptor (EGFR) (PDB ID: 2J6M) revealed favourable binding scores and interactions, suggesting their potential as promising candidates for further investigation in the context of anticancer drug development.

The foundation of excitation-contraction coupling in skeletal muscle: Communication between the transverse tubules and sarcoplasmic reticulum.

The expression excitation-contraction (EC) coupling in skeletal muscle was coined in 1952 (1). The term evolved narrowly to include only the processes at the triad that intervene between depolarization of the transverse tubular (T-tubular) membrane and Ca2+ release from the sarcoplasmic reticulum (SR). From 1970 to 1988, the foundation of EC coupling was elucidated. The channel through which Ca2+ was released during activation was located in the SR by its specific binding to the plant insecticide ryanodine. This channel was called the ryanodine receptor (RyR). The RyR contained four subunits that together constituted the "SR foot" structure that traversed the gap between the SR and the T-tubular membrane. Ca2+ channels, also called dihydropyridine receptors (DHPRs), were located in the T-tubular membrane at the triadic junction and shown to be essential for EC coupling. There was a precise relationship between the two channels. Four DHPRs, organized as tetrads, were superimposed on alternate RyRs. This structure was consistent with the proposal that EC coupling was mediated via a movement of intramembrane charge in the T-tubular system. The speculation was that the DHPR acted as a voltage sensor transferring information to the RyRs of the SR by protein-protein interaction causing the release of Ca2+ from the SR. A great deal of progress was made by 1988 toward understanding EC coupling. However, the ultimate question of how voltage-sensing is coupled to opening of the SR Ca2+ release channel remains unresolved.

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction.

An efficient protocol for the synthesis of polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates was developed by a three-component reaction. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile afforded polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates in high yields and with high diastereoselectivity. The reaction was finished by in situ generation of activated 5-(alkylimino)cyclopenta-1,3-dienes from addition of alkyl isocyanide to two molecules of but-2-ynedioates and sequential formal [3 + 2] cycloaddition reaction with 5,6-unsubstituted 1,4-dihydropyridine.

Development of Self-Assembling bis-1,4-Dihydropyridines: Detailed Studies of Bromination of Four Methyl Groups and Bromine Nucleophilic Substitution.

One of the most important steps in the synthesis of 1,4-dihydropyridine (1,4-DHP) amphiphiles is the bromination of methyl groups in positions 2 and 6 of the entire ring. However, up to now, only N-bromosuccinimide was mainly used for bromination 1,4-DHPs. In this work, the synthesis of bis-1,4-DHP derivatives with ethyl and dodecyl ester groups attached to 1,4-DHP ring at positions 3 and 5 was performed by Hantzsch synthesis. The experimental studies were carried out to find out the best conditions and the agent for the tetra bromination of bis-1,4-DHP methyl groups at positions 2 and 6. Four different brominating agents were screened. The use of pyridinium bromide-perbromide in ethyl acetate was found to be optimal for the bromination of methyl groups. The bromination reaction was followed by the synthesis of cationic pyridine moiety containing amphiphilic bis-1,4-DHP derivatives. By nucleophilic substitution of bromine with various substituted pyridines, 12 new amphiphilic bis-1,4-DHP derivatives were obtained. Evaluation of self-assembling properties of tetracationic bis-1,4-dihydropyridine derivatives by dynamic light scattering (DLS) measurements was also performed.

Etiology of Drug-Induced Edema: A Review of Dihydropyridine, Thiazolidinedione, and Other Medications Causing Edema.

Edema is an accumulation of fluid in the body's tissues that affects millions of Americans yearly. It can affect multiple body parts, for example, the brain or eyes, but often occurs in the periphery, including the feet and legs. Medications, such as dihydropyridine and thiazolidinediones (TZDs), can be the etiology of edema. Edema can develop in association with problems in the vasculature or lymphatic flow. In recent years, a better understanding of these drug-induced mechanisms has been appreciated. Specifically, dihydropyridines can increase hydrostatic pressure and cause selective pre-capillary vessel vasodilation. TZDs can cause edema through increased vascular permeability and increased hydrostatic pressure. Specifically, peroxisome proliferator-activated receptor gamma (PPARγ) stimulation increases vascular endothelial permeability, vascular endothelial growth factor (VEGF) secretion, renal sodium, and fluid retention. Other drugs that can cause edema include neuropathic pain agents, dopamine agonists, antipsychotics, nitrates, nonsteroidal anti-inflammatory (NSAIDS), steroids, angiotensin-converting enzyme (ACE) inhibitors, and insulin. There are various clinical presentations of edema. Since multiple mechanisms can induce edema, it is important to understand the basic mechanisms and pathophysiology of drug-induced edema. Edema can even become fatal. For example, angioedema can occur from ACE inhibitor therapy. In this regard, it is considered a medical emergency when there is laryngeal involvement. This review aims to thoroughly appreciate the multiple causes of drug-induced edema and the ways it can be treated or prevented.

A versatile magnetic nanocomposite based on cellulose-cyclodextrin hydrogel embedded with graphene oxide and Cu2O nanoparticles for catalytic application.

The study focused on creating a novel and environmentally friendly nanocatalyst using cellulose (Cell), ß-Cyclodextrin (BCD), graphene oxide (GO), Cu2O, and Fe3O4.The nanocatalyst was prepared by embedding GO and Cu2O into Cell-BCD hydrogel, followed by the in-situ preparation of Fe3O4 magnetic nanoparticles to magnetize the nanocomposite. The effectiveness of this nanocatalyst was evaluated in the one-pot, three-component symmetric Hantzsch reaction for synthesizing 1,4-dihydropyridine derivatives with high yield under mild conditions. This novel nanocatalyst has the potential for broad application in various organic transformations due to its effective catalytic activity, eco-friendly nature, and ease of recovery.

Positron Emission Tomography of Nitric Oxide by a Specific Radical-Generating Dihydropyridine Tracer.

Nitric oxide (NO) plays a pivotal role as a biological signaling molecule, presenting challenges in its specific detection and differentiation from other reactive nitrogen and oxygen species within living organisms. Herein, a 18F-labeled (fluorine-18, t1/2 = 109.7 min) small-molecule tracer dimethyl 4-(4-(4-[18F]fluorobutoxy)benzyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate ([18F]BDHP) is developed based on the dihydropyridine scaffold for positron emission tomography (PET) imaging of NO in vivo. [18F]BDHP exhibits a highly sensitive and efficient C-C cleavage reaction specifically triggered by NO under physiological conditions, leading to the production of a 18F-labeled radical that is readily retained within the cells. High uptakes of [18F]BDHP are found within and around NO-generating cells, such as macrophages treated with lipopolysaccharide or benzo(a)pyrene. MicroPET/CT imaging of arthritic animal model mice reveals distinct tracer accumulation in the arthritic legs, showcasing a higher distribution of NO compared with the control legs. In summary, a specific radical-generating dihydropyridine tracer with a unique radical retention strategy has been established for the marking of NO in real-time in vivo.

Optimization of diastereomeric dihydropyridines as antimalarials.

The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity. Structure-activity relationship studies focusing on the 2-, 3-, 4-, 6-, and 7-positions of the DHP core led to the identification of compounds potent (EC50 < 10 nM) against all strains of P. falciparum tested, including the drug-resistant parasite strains K1, W2, and TM90-C2B. Evaluation of efficacy of several compounds in vivo identified two compounds that reduced parasitemia by >75 % in mice 6 days post-exposure following a single 50 mg/kg oral dose. Resistance acquisition experiments with a selected dihydropyridine led to the identification of a single mutation conveying resistance in the gene encoding for Plasmodium falciparum multi-drug resistance protein 1 (PfMDR1). The same dihydropyridine possessed transmission blocking activity. The DHPs have the potential for the development of novel antimalarial drug candidates.

Evaluation of diethyl 4-(5-bromo-1H-indol-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate: synthesis, anti-corrosion potential, and biomedical applications.

The pursuit of advanced multifunctional compounds has gained significant momentum in recent scientific endeavours. This study is dedicated to elucidating the synthesis, rigorous characterization, and multifaceted applications-encompassing anti-corrosion, antimicrobial, and antioxidant properties-of Diethyl 4-(5-bromo-1H-indol-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. The 1,4-dihydropyridine derivative was meticulously synthesized through a strategic reaction of ethyl acetoacetate, ammonium acetate, and 5-bromoindole-3-carboxaldehydein the ethanol medium at 60  C. Subsequent spectral validations were conducted using sophisticated techniques, namely FTIR, NMR, and Mass spectrometry, resulting in data that perfectly resonated with the hypothesized chemical structure of the compound. Its anti-corrosive potential was assessed on mild steel subjected to an aggressive acidic environment, employing comprehensive methodologies like gravimetric analysis, Tafel polarization, and EIS. Concurrently, its antimicrobial prowess was ascertained against a spectrum of bacterial and fungal pathogens viz., Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas, Candida albicansandAspergillusniger, leveraging the disc diffusion method and using Gentamicin as a reference standard.The empirical results illustrated a substantial decrement in corrosion rates with ascending concentrations of the organic compound, achieving an apex of anti-corrosive efficacy at 81.89% for a concentration of 2 × 103 M. Furthermore, the compound outperformed Gentamicin in antimicrobial screenings, manifesting superior efficacy against all tested pathogens. The antioxidant potential, quantified using the DPPH free radical scavenging assay against ascorbic acid as a benchmark, was found to have an IC50 value of 113.964 ± 0.076 µg/ml.This comprehensive investigation accentuates the paramount potential of the synthesized dihydropyridine derivative in diverse domains-from industrial applications as a corrosion inhibitor to therapeutic avenues given its pronounced antimicrobial and antioxidant capabilities. The compelling results obtained pave the way for expansive research and development initiatives cantered around this multifaceted compound.

Turn-on fluorescence of mirabegron for its sensitive detection in human plasma: Box-Behnken-Design for optimization.

Here, a novel fluorescence strategy was established for the detection of mirabegron (MBG) sensitively on the basis of hantzsch dihydropyridine synthesis. The developed method adopts turn-on fluorescence of MBG for the first time, permitting its selective determination in spiked human plasma at 486 nm after excitation at 410 nm. The developed method exhibited a good linear range from 0.5 µgmL-1 to 2.0 µgmL-1 with detection and quantification limits of 0.05 and 0.2 (µgmL-1), respectively. The profitable applicability of the developed method in spiked human plasma samples was demonstrated, achieving limit of detection below the previously levels reported by spectroscopic methods, allowing application of the developed method for selective determination of MBG in its tablets and spiked human plasma samples with good recovery.

Rabbit muscle pyruvate kinase activators: Synthesis, molecular docking and theoretical studies of N-substituted sulfonamide derivatives.

Pyruvate kinase (PK) activators have potential therapeutic applications in diseases such as sickle cell anemia. In this study, N-Substituted sulfonamide derivatives of 1,4-dihydropyridines were synthesized and evaluated as PK activators in vitro and using molecular docking studies. The compounds were synthesized by reacting dicarbonyl compounds with ammonium acetate, 5-nitrobenzaldehyde, and alumina sulfuric acid (ASA), followed by reduction and sulfonylation. The structures of the compounds were analyzed using spectroscopic techniques. DFT calculations provided insights into the electronic properties. Molecular docking of the compounds into the active site of PK showed favorable binding interactions. ADME evaluation indicated suitable solubility, BBB permeation, and lack of CYP450 inhibition. Overall, this study demonstrates the potential of new hybrid 1,4-dihydropyridine substituted sulfonamides as PK activators for further development. According to AC50 values, the compound (DTSF7, 0.97µM) is about 100-fold higher affective than the clinically used sulfonamide compound (AC50 = 90µM) for PK.

Design and synthesis of novel dihydropyridine- and benzylideneimine-based tyrosinase inhibitors.

Tyrosinase (TYR) inhibitors are very significant as they inhibit enzyme tyrosinase activity, and its inhibition is vital for skin care, anticancer medication, and antibrowning of fruits and vegetables. This work presents a novel and economical route for the preparation of new synthetic tyrosinase inhibitors using amlodipine (4). The novel conjugates 6 (a-o) were designed, synthesized, and characterized by spectroscopic analyses, including Fourier transform infrared and low- and high-resolution mass spectroscopy. The purified compound 4 was refluxed with various aldehydes and ketones 5 (a-o) for 5-8 h in methanol at 60°C-90°C. This research modified the drug in a step-by-step manner to develop therapeutic properties as a tyrosinase inhibitor. The structures of synthesized ligands 6 (a-o) were established based on spectral and analytical data. The synthesized compounds 6 (a-o) were screened against tyrosinase enzyme. Kojic acid was taken as standard. All the prepared compounds 6 (a-o) have good inhibition potential against the enzyme tyrosinase. Compounds 6o, 6b, 6f, and 6k depicted excellent antityrosinase activity. Compound 6k, with an IC50 value of 5.34 ± 0.58 µM, is as potent as the standard kojic acid (IC50 6.04 ± 0.11 µM), standing out among all synthesized compounds 6 (a-o). The in silico studies of the conjugates 6 (a-o) were evaluated via PatchDock. Compound 6k showed a binding affinity score of 8,999 and an atomic contact energy (ACE) value of -219.66 kcal/mol. The structure-activity relationship illustrated that the presence of dihydropyridine nuclei and some activating groups at the ortho and para positions of the benzylideneimine moiety is the main factor for good tyrosinase activity. The compound 6k could be used as a lead compound for drug modification as a tyrosinase inhibitor for skin care, anticancer medication, and antibrowning for fruits and vegetables.

Effects of 1,4-dihydropyridine derivatives on cell injury and mTOR of HepG2 and 3D-QSAR study.

1,4-dihydropyridine derivatives (1,4-DHPs) are a class of drugs used to treat cardiovascular diseases, but these drugs can cause liver injury. To reveal the toxicity characteristics of these compounds, we used a series of assays, including cell viability, enzyme activity detection, and western blotting, to investigate the toxicity of seven kinds of 1,4-DHPs (0-100 µM) on HepG2 cells and establish 3D-QSAR model based on relevant toxicity data. After HepG2 cells were treated with 1,4-DHPs for 24 h, high-dose (100 µM) 1,4-DHPs decreased cell viability to varying degrees, while ROS and MDA contents were significantly increased, and ATP content was reduced. Moreover, with the concentration of 100 µM 1,4-DHPs (Nimodipine, Nitrendipine, Cilnidipine, and Manidipine) were markedly inhibited the phosphorylation levels of mTOR protein. The results of the 3D-QSAR model showed that the non-cross validation coefficient (R2) and cross validation coefficient (Q2) of the model were 0.982 and 0.652, respectively. Combined with external validation and the Williams diagram, the model showed good predictability and application domain. Based on the CoMSIA 3D contour map, the introduction of large volume and hydrogen bond receptor groups on the carbonyl oxygen side chains of the 1,4-DHPs ring 3- and 5- was beneficial for reducing the toxicity of 1,4-DHPs. The results of this study could supplement information on the cytotoxicity of 1,4-DHPs, and could provide theoretical support for predicting the toxicity of 1,4-DHPs.

A novel "turn-on" fluorescent probe based on thiocarbamoyl-DHP for Hg2+ detection in water samples and living cells.

In this study, two fluorescent sensing probes, dihydropyridine (DHP) derivatives (DHP-CT1 and DHP-CT2) bearing phenoxy thiocarbonyl group, have been developed for Hg2+ detection. The tandem trimerization-cyclization of methylpropiolate with ammonium acetate gave 1.4-DHP and 1,2-DHP derivatives, which were reacted with O-phenylcarbonochloridothioate to produce DHP-CT1 and DHP-CT2, respectively. DHP-CT1 exhibits superior sensitivity and selectivity of fluorescence enhancement towards Hg2+ in aqueous media. The fluorescence intensity shows a good linear relationship with the concentration of Hg2+ in the range of 0-10 µM providing the extremely low LOD of 346 nM (69.4 ppb). The fluorescence enhancement is caused by the Hg2+ promoted hydrolysis of the thioamide bond releasing the fluorescent 1,4-DHP that was confirmed by NMR and HRMS. The quantitative analysis of Hg2+ in water samples using DHP-CT1 probe was demonstrated in aqueous solution and paper-based sensing strips. Furthermore, DHP-CT1 was also applied for monitoring intracellular Hg2+ in living RAW264.7 macrophages through fluorescence cell imaging.

Rational Design, Synthesis, and Computational Investigation of Dihydropyridine [2,3-d] Pyrimidines as Polyphenol Oxidase Inhibitors with Improved Potency.

Polyphenol oxidase (PPO) is an industrially important enzyme associated with browning reactions. In the present study, a set of ten new dihydropyridine [2,3-d] pyrimidines (TD-Hid-1-10) were synthesized and was found to be proven characteristically by 1H NMR, 13C NMR, IR, elemental analysis, and assessed as possible PPO inhibitors. PPO was purified from banana using three-phase partitioning, achieving an 18.65-fold purification and 136.47% activity recovery. Enzyme kinetics revealed that the compounds TD-Hid-6 and TD-Hid-7 are to be the most potent inhibitors, exhibiting mixed-type inhibition profile with IC50 values of 1.14 µM, 5.29 µM respectively against purified PPO enzyme. Electronic structure calculations at the B3LYP/PBE0 level of theories using def-2 SVP, def2-TZVP basis sets with various molecular descriptors characterized the electronic behavior of studied derivatives TD-Hid-1-10. Molecular electrostatic potential (MEP) and reduced density gradient analyses of RDG-NCI provided insights into charge distributions and weak intermolecular interactions. Docking study simulations predicted binding poses within crucial amino acid sequence in the 2y9x enzyme's active site, which is typically similar in sequence to the PPO form is not allowed. Ligands were analysed in terms of binding energies, inhibitor concentrations (mM) and various molecular interactions such as H-bonds, H-carbon, π-carbon, π-sigma, π-sigma, π-π T-shaped, π-π stacked, π-alkyl, Van der Waals and Cu interactions. The lowest binding energy (-7.83 kcal/mol) and the highest inhibitory effect (1.83 mM) were shown by the ligand Td-Hid-6, which forms H-bonds with Met280 and Asn260, exhibits π-sigma interactions with His61 and π-alkyl interactions with Val283. Other ligands also showed different interactions with various amino acids; for example, the Td-Hid-1 ligand formed H-bonds with His244 and showed π-sigma interactions with His244 and Val283.

Evaluating the Physicochemical Properties-Activity Relationship and Discovering New 1,2-Dihydropyridine Derivatives as Promising Inhibitors for PIM1-Kinase: Evidence from Principal Component Analysis, Molecular Docking, and Molecular Dynamics Studies.

In this study, we evaluated the physicochemical properties related to the previously reported anticancer activity of a dataset comprising thirty 1,2-dihydropyridine derivatives. We utilized Principal Component Analysis (PCA) to identify the most significant influencing factors. The PCA analysis showed that the first two principal components accounted for 59.91% of the total variance, indicating a strong correlation between the molecules and specific descriptors. Among the 239 descriptors analyzed, 18 were positively correlated with anticancer activity, clustering with the 12 most active compounds based on their IC50 values. Six of these variables-LogP, Csp3, b_1rotN, LogS, TPSA, and lip_don-are related to drug-likeness potential. Thus, we then ranked the 12 compounds according to these six variables and excluded those violating the drug-likeness criteria, resulting in a shortlist of nine compounds. Next, we investigated the binding affinity of these nine shortlisted compounds with the use of molecular docking towards the PIM-1 Kinase enzyme (PDB: 2OBJ), which is overexpressed in various cancer cells. Compound 6 exhibited the best docking score among the docked compounds, with a docking score of -11.77 kcal/mol, compared to -12.08 kcal/mol for the reference PIM-1 kinase inhibitor, 6-(5-bromo-2-hydroxyphenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile. To discover new PIM-1 kinase inhibitors, we designed nine novel compounds featuring hybrid structures of compound 6 and the reference inhibitor. Among these, compound 31 displayed the best binding affinity, with a docking score of -13.11 kcal/mol. Additionally, we performed PubChem database mining using the structure of compound 6 and the similarity search tool, identifying 16 structurally related compounds with various reported biological properties. Among these, compound 52 exhibited the best binding affinity, with a docking score of -13.03 kcal/mol. Finally, molecular dynamics (MD) studies were conducted to confirm the stability of the protein-ligand complexes obtained from docking the studied compounds to PIM-1 kinase, validating the potential of these compounds as PIM-1 kinase inhibitors.

Syntheses, characterizations, crystal structures and Hirshfeld surface analyses of methyl 4-[4-(di-fluorometh-oxy)phen-yl]-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, isopropyl 4-[4-(di-fluoro-meth-oxy)phen-yl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate and tert-butyl 4-[4-(di-fluoro-meth-oxy)phen-yl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate.

The crystal structures and Hirshfeld surface analyses of three similar compounds are reported. Methyl 4-[4-(di-fluoro-meth-oxy)phen-yl]-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, (C21H23F2NO4), (I), crystallizes in the monoclinic space group C2/c with Z = 8, while isopropyl 4-[4-(di-fluoro-meth-oxy)phen-yl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-oxyl-ate, (C23H27F2NO4), (II) and tert-butyl 4-[4-(di-fluoro-meth-oxy)phen-yl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, (C24H29F2NO4), (III) crystallize in the ortho-rhom-bic space group Pbca with Z = 8. In the crystal structure of (I), mol-ecules are linked by N-H⋯O and C-H⋯O inter-actions, forming a tri-periodic network, while mol-ecules of (II) and (III) are linked by N-H⋯O, C-H⋯F and C-H⋯π inter-actions, forming layers parallel to (002). The cohesion of the mol-ecular packing is ensured by van der Waals forces between these layers. In (I), the atoms of the 4-di-fluoro-meth-oxy-phenyl group are disordered over two sets of sites in a 0.647 (3): 0.353 (3) ratio. In (III), the atoms of the dimethyl group attached to the cyclo-hexane ring, and the two carbon atoms of the cyclo-hexane ring are disordered over two sets of sites in a 0.646 (3):0.354 (3) ratio.