New tetrahydroisoquinoline-4-carbonitrile derivatives as potent agents against cyclin-dependent kinases, crystal structures, and computational studies.

The synthesis of two new hexahydroisoquinoline-4-carbonitrile derivatives (3a and 3b) is reported along with spectroscopic data and their crystal structures. In compound 3a, the intramolecular O-H···O hydrogen bond constraints the acetyl and hydroxyl groups to be syn. In the crystal, inversion dimers are generated by C-H···O hydrogen bonds and are connected into layers parallel to (10-1) by additional C-H···O hydrogen bonds. The layers are stacked with Cl···S contacts 0.17 Å less than the sum of the respective van der Waals radii. The conformation of the compound 3b is partially determined by the intramolecular O-H···O hydrogen bond. A puckering analysis of the tetrahydroisoquinoline unit was performed. In the crystal, O-H···O and C-H···O hydrogen bonds together with C-H···π(ring) interactions form layers parallel to (01-1) which pack with normal van der Waals interactions. To understand the binding efficiency and stability of the title molecules, molecular docking, and 100 ns dynamic simulation analyses were performed with CDK5A1. To rationalize their structure-activity relationship(s), a DFT study at the B3LYP/6-311++G** theoretical level was also done. The 3D Hirshfled surfaces were also taken to investigate the crystal packings of both compounds. In addition, their ADMET properties were explored.Communicated by Ramaswamy H. Sarma.

Synthesis, Characterization, DFT, and In Silico Investigation of Two Newly Synthesized ß-Diketone Derivatives as Potent COX-2 Inhibitors.

Despite extensive genetic and biochemical characterization, the molecular genetic basis underlying the biosynthesis of ß-diketones remains largely unexplored. ß-Diketones and their complexes find broad applications as biologically active compounds. In this study, in silico molecular docking results revealed that two ß-diketone derivatives, namely 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione and 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione, exhibit anti-COX-2 activities. However, recent docking results indicated that the relative anti-COX-2 activity of these two studied ß-diketones was influenced by the employed docking programs. For improved design of COX-2 inhibitors from ß-diketones, we conducted molecular dynamics simulations, density functional theory (DFT) calculations, Hirshfeld surface analysis, energy framework, and ADMET studies. The goal was to understand the interaction mechanisms and evaluate the inhibitory characteristics. The results indicate that 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione shows greater anti-COX-2 activity compared to 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione.

Synthesis, crystal structure, DFT, Hirshfeld surface analysis, energy framework, docking and molecular dynamic simulations of (E)-4-(4-methylbenzyl)-6-styrylpyridazin-3(2H)-one as anticancer agent.

In this work, a novel crystal, (E)-4-(4-methylbenzyl)-6-styrylpyridazin-3(2H)-one (E-BSP) was synthesized via Knoevenagel condensation of benzaldehyde and (E)-6-(4-methoxystyryl)-4,5-dihydropyridazin-3(2H)-one. The molecular structure of E-BSP was confirmed by using FT-IR, 1H-NMR, 13C-NMR, UV-vis, ESI-MS, TGA/DTA thermal analyses and single crystal X-ray diffraction. The DFT/B3LYP methods with the 6-311++G(d,p) basis set were used to determine the vibrational modes over the optimized structure. Potential energy distribution (PED) and the VEDA 4 software were used to establish the theoretical mode assignments. The same approach was used to compute the energies of frontier molecular orbitals (HOMO-LUMO), global reactivity descriptors, and molecular electrostatic potential (MEP). Additionally, experimental and computed UV spectral parameters were determined in methanol and the obtained outputs were supported by FMO analysis. Molecular docking and molecular dynamics (MD) simulation analyses of the E-BSP against six proteins obtained from different cancer pathways were carried out. The proteins include; epidermal growth factor receptor (EGFR), Estrogen receptor (ERα), Mammalian target of rapamycin (mTOR), Progesterone receptor (PR) (Breast cancer), Human cyclin-dependent kinase 2 (CDK2) (Colorectal cancer), and Survivin (Squamous cell carcinoma/Non-small cell lung cancer). The results of the analyses showed that the compound had less binding energies ranging between -6.30 to -9.09 kcal/mol and formed stable complexes at the substrate-binding site of the proteins after the 50 ns MD simulation. Therefore, E-BSP was considered a potential inhibitor of different cancer pathways and should be used for the treatment of cancer after experimental validation and clinical trial.Communicated by Ramaswamy H. Sarma.

Insight into the Crystal Structures and Potential of Two Newly Synthesized Naproxen-Based Hydrazide Derivatives as Potent COX-2 Inhibitors.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are medicines that are widely used to relieve pain, reduce inflammation, and bring down high temperature, literature confirmed that they still have harmful side effects. Most of their side effects are in the digestive system due to the carboxylic group. As naproxen is one of the NSAIDs, in this work, we try to mask the carboxylic group in naproxen with a relatively safe functional group. So, herein, we report the synthesis of new naproxen-based hydrazones derivatives, namely, (E)-N'-1-(4-chlorophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propane hydrazide (4a) and (E)-N'-(4-hydroxybenzylidene)-2-(6-methoxynaphthalen-2-yl)propane hydrazide ethanol solvate (4b). The compounds were confirmed by X-ray diffraction studies. Hirshfeld surface analyses and energy frameworks of 4a and 4b have been carried out and blind molecular docking studies of them to the COX-2 enzyme were undertaken to obtain binding affinities for judging whether the compounds could act as anti-inflammatory agents. The compounds interact with the key residues: Arg120, Val349, Leu352, Tyr355, Val523, Ala527, Ser530, and Leu531 of the active enzyme pocket. Molecular dynamics studies predicted that the complexes of 4a and 4b with COX-2 are structurally stable and no major conformational changes were observed. Confirmation of the docking and simulation data was achieved by a binding free energies analysis that indicated the dominance of van der Waals energy. The compounds are drug-like molecules as they obey all prominent drug-like rules and have acceptable pharmacokinetic profiles. To investigate the relationship between their intrinsic electronic properties and their possible similarities to actual drugs, the gas-phase DFT optimizations and NBO analyses were also performed in this study.

Synthesis, crystal structure, and a molecular modeling approach to identify effective antiviral hydrazide derivative against the main protease of SARS-CoV-2.

In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)-N'-(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N-H···O and C-H···O hydrogen bonds and C-H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C-H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization.

Synthesis, crystal structure investigation and computational approach to discover potential hydrazide derivatives as a potent inhibitor of cyclooxygenase-2 enzyme.

This study reports the synthesis of two new hydrazide derivatives, namely, (E)-N'-(4- bromobenzylidene)-2-(4-isobutylphenyl)propanehydrazide (4a) and (E)-N'-benzylidene-2-(4-isobutylphenyl)propanehydrazide (4b), respectively. The compounds were synthesized by the reaction of benzaldehyde with Ibuprofen acid hydrazide. Their structures were confirmed by X-ray crystallography. To try to do a more detailed investigation, computational studies including Hirshfeld surface analyses, energy frameworks, density functional theory (DFT) optimizations, frontier orbital analyses, molecular electrostatic potential analyses, and natural bond orbital analyses of the studied compounds are performed. Moreover, molecular docking and dynamics simulations of complexes of the compounds with the cyclooxygenase-2 (COX-2) enzyme were performed to determine the anti-inflammatory potential of the compounds. These analyses predicted the compounds to show maximum chemical interactions and be dynamically stable during simulation time. Furthermore, estimation of binding free energies confirmed the high binding affinity of the compounds for the COX-2 enzyme.

Regiodivergent Synthesis of Methylene and Methyl Ring-Fused Isoquinolinones: Base-Promoted Isomerization of N-Allyl Amides.

Methylene and methyl tricyclic isoquinolinones were selectively prepared using a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a base- and temperature-controlled Heck reaction catalyzed by palladium(0). Exo- to endo-double-bond migration in isoquinolinones was achieved with 93-99% yields by treatment of the Heck products with Cs2CO3 in dimethyl sulfoxide (DMSO) at 150 °C. A probable mechanism for Cs2CO3-promoted olefin isomerization was proposed and examined using D-isotope labeling experiments. Finally, yuanamide, a 13-methyl-8-oxoprotoberberine alkaloid, was synthesized using the palladium-catalyzed aza-Wacker/Heck/migration sequence.

Insights into the crystal structure of two newly synthesized quinoxalines derivatives as potent inhibitor for c-Jun N-terminal kinases.

Two new compounds namely, ethyl (2E)-3-(dimethylamino)-2-(3-methoxyquinoxalin-2-yl)propen-2-enoate (II) and ethyl 2-(3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydroquinoxalin-2-yl)-3-phenylpropanoate (III) have been synthesized from ethyl 2-(oxo-3,4-dihydroquinoxalin-2-yl) acetate (I). The compounds were characterized using NMR (1H and 13C), Fourier transform infrared and confirmed by single crystal X-ray diffraction studies. The quinoxaline portion of II is almost planar with the substituent containing the dimethylamino and carboxyethyl groups rotated well out of its mean plane. In the crystal, C-H···O and C-H···N hydrogen bonds as well as C-H···π(ring) interactions form chains having a U-shaped cross-section and running along the c-axis direction. Two sets of pair-wise C-H···O hydrogen bonds connect the chains into corrugated sheets. In III, the three substituents on the dihydroquinoxaline moiety are rotated well out of its mean plane. Three sets of C-H···O hydrogen bonds as well as C-H···π(ring) and π-π-stacking interactions form layers approximately parallel to [001]. These are associated along the c-axis direction by additional C-H···π(ring) interactions. Additionally, the Hirshfeld surface analyses showed that the H···H contact is the most important interaction for both II and III. In addition to this, molecular docking and dynamics studies were carried for these two compounds with the c-Jun N-terminal kinases (JNK1) molecule.Communicated by Ramaswamy H. Sarma.

Novel 3-chloro-6-nitro-1H-indazole derivatives as promising antileishmanial candidates: synthesis, biological activity, and molecular modelling studies.

An efficient pathway was disclosed for the synthesis of 3-chloro-6-nitro-1H-indazole derivatives by 1,3-dipolar cycloaddition on dipolarophile compounds 2 and 3. Faced the problem of separation of two regioisomers, a click chemistry method has allowed us to obtain regioisomers of triazole-1,4 with good yields from 82 to 90% were employed. Also, the antileishmanial biological potency of the compounds was achieved using an MTT assay that reported compound 13 as a promising growth inhibitor of Leishmania major. Molecular docking demonstrated highly stable binding with the Leishmania trypanothione reductase enzyme and produced a network of hydrophobic and hydrophilic interactions. Molecular dynamics simulations were performed for TryR-13 complex to understand its structural and intermolecular affinity stability in a biological environment. The studied complex remained in good equilibrium with a structure deviation of ∼1-3 Å. MM/GBSA binding free energies illustrated the high stability of TryR-13 complex. The studied compounds are promising leads for structural optimisation to enhance the antileishmanial activity.

Copper(I)-Catalyzed Nitrile-Addition/N-Arylation Ring-Closure Cascade: Synthesis of 5,11-Dihydro-6H-indolo[3,2-c]quinolin-6-ones as Potent Topoisomerase-I Inhibitors.

In this paper, we present a copper(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis[2-(dimethylamino)ethyl]-5,12-dihydro-6H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top-DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones as topoisomerase-I inhibitors.

Synthesis, spectroscopy, crystal structure, TGA/DTA study, DFT and molecular docking investigations of (E)-4-(4-methylbenzyl)-6-styrylpyridazin-3(2H)-one.

In this study, we present the synthesis of novel pyridazin-3(2H)-one derivative namely (E)-4-(4-methylbenzyl)-6-styrylpyridazin-3(2H)-one (MBSP). The chemical structure of MBSP was characterized using spectroscopic techniques such as FT-IR, 1H NMR, 13C NMR, UV-Vis, ESI-MS, and finally, the structure was confirmed by single X-ray diffraction studies. The DFT calculation was performed to compare the gas-phase geometry of the title compound to the solid-phase structure of the title compound. Furthermore, a comparative study between theoretical UV-Vis, IR, 1H- and 13C NMR spectra of the studied compound and experimental ones have been carried out. The thermal behavior and stability of the compound were analyzed by using TGA and DTA techniques which revealed that the compound is thermostable up to its melting point. Finally, the in silico docking and ADME studies are performed to investigate whether MBSP is a potential therapeutic for COVID-19.

Exploring the twisted molecular configurations for tuning their optical and nonlinear optical response properties: A quantum chemical approach.

Unlike the previous several investigations on planar donor-π-acceptor chromophores, the present investigation highlights the importance of twisted molecular configurations to effectively tune the optical and nonlinear optical (NLO) response properties. A variety of substitutions are made to design several twisted molecular compounds (1-7). These compounds are designed using pyrenyl and naphthalimide moieties, which are twisted with each other in their molecular configurations. The calculated versus experimental highest intensity absorption energy peaks (3.482 V. 3.444 eV) and experimental ionization potentials (6.07 V. 5.93 eV) of parent compound 1 reproduced reasonably well at M06/6-311G∗∗ methodology. The twisted chromophores show significantly larger amplitudes of third-order NLO polarizabilities (<γ>), which are found to be as large as 778.31 × 10-36 esu for compound 7 at the M06/6-311G∗∗ methodology. The <γ> amplitudes were also compared with planar donor-π-acceptor prototype para-nitroaniline (p-NA) molecule to provide the semi-quantitative assessment. For instance, the <γ> amplitudes of all compounds are about ∼7-∼39 times bigger from the amplitude of p-NA at the same computational level. The origin of larger amplitudes has been traced though three-level model using the TD-DFT results. The larger oscillator strengths, lower transitions energies and larger change between the electronic dipole moment between the ground and the excited states. We believe the present study will not only put these compounds under the spotlight of material science but also provide structure-property relationships in designed compounds.

Unexpected synthesis of novel 2-pyrone derivatives: crystal structures, Hirshfeld surface analysis and computational studies.

Here we report synthesis of three new compounds namely, 1-acetyl-1H-benzimidazolo-2(3H)-one (I), N-(5-acetyl-6-methyl-2-oxo-2H-pyran-4-yl)-N-(2-acetamidophenyl)acetamide (II) and N-(2-acetamidophenyl)-N-2-oxo-2H-pyran-4-yl)acetamide (III) have been synthesized and characterized by single crystal X-ray diffraction. Compounds I and II crystallize in the monoclinic space groups P21/n, and P21/c, respectively, while III crystallizes in the triclinic space group P-1. The theoretical parameters of I-III have been calculated through density functional theory (DFT) by using the hybrid functional B3LYP and basis set 6-311++G**. These theoretical parameters have been compared with the experimental ones obtained by XRD. The significant intermolecular interactions arising in crystal packing are rationalized by means of the Hirshfeld surface analysis method. The major intermolecular contacts in the Hirshfeld surfaces of I-III are from H…H contacts. In addition, binding modes of I-III within Tyrosine-protein kinase JAK2 were investigated using molecular docking and molecular dynamics simulation studies.Communicated by Ramaswamy H. Sarma.

Palladium-Catalyzed Stereoselective Aza-Wacker-Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles.

Palladium-catalyzed intramolecular tandem cyclization reactions were conducted for the synthesis of densely cis/cis-fused aza-tetracyclic structures. The process involved a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a palladium(0)-catalyzed Heck reaction. The effects of the solvent and benzene substitution pattern on the one-pot, two-step cascade reaction were studied systematically, and a probable mechanism was proposed. Strained pentahydrobenzo[f]cyclopenta[hi]indolizin-6-one and racemic γ-lycorane can also be synthesized rapidly using this palladium-catalyzed aza-Wacker-Heck cyclization reaction.

Synergy of Ionic and Dipolar Effects by Molecular Design for pH Sensing beyond the Nernstian Limit.

Knowledge of interfacial interactions between analytes and functionalized sensor surfaces, from where the signal originates, is key to the development and application of electronic sensors. The present work explores the tunability of pH sensitivity by the synergy of surface charge and molecular dipole moment induced by interfacial proton interactions. This synergy is demonstrated on a silicon-nanoribbon field-effect transistor (SiNR-FET) by functionalizing the sensor surface with properly designed chromophore molecules. The chromophore molecules can interact with protons and lead to appreciable changes in interface dipole moment as well as in surface charge state. In addition, the dipole moment can be tuned not only by the substituent on the chromophore but also by the anion in the electrolyte interacting with the protonated chromophore. By designing surface molecules to enhance the surface dipole moment upon protonation, an above-Nernstian pH sensitivity is achieved on the SiNR-FET sensor. This finding may bring an innovative strategy for tailoring the sensitivity of the SiNR-FET-based pH sensor toward a wide range of applications.

Crystal structure, computational study and Hirshfeld surface analysis of ethyl (2S,3R)-3-(3-amino-1H-1,2,4-triazol-1-yl)-2-hy-droxy-3-phenyl-propano-ate.

In the title mol-ecule, C13H16N4O3, the mean planes of the phenyl and triazole rings are nearly perpendicular to one another as a result of the intra-molecular C-H⋯O and C-H⋯π(ring) inter-actions. In the crystal, layers parallel to (101) are generated by O-H⋯N, N-H⋯O and N-H⋯N hydrogen bonds. The layers are connected by inversion-related pairs of C-H⋯O hydrogen bonds. The experimental mol-ecular structure is close to the gas-phase geometry-optimized structure calculated by DFT methods. Hirshfeld surface analysis indicates that the most important inter-action involving hydrogen in the title compound is the H⋯H contact. The contribution of the H⋯O, H⋯N, and H⋯H contacts are 13.6, 16.1, and 54.6%, respectively.

Nanostructured silver dendrites for photon-induced Cysteine dimerization.

Under a controlled adsorption environment, L-cysteine molecules can be chemically adsorbed to the dendritic silver (Ag-D) surface by electrochemical methods with different functional groups. It is verified by surface-enhanced Raman spectroscopy that under alkaline conditions (pH = 13.50), the two functional groups of thiol and acid are simultaneously adsorbed on the surface of Ag-D, while NH2 is far from the surface; under acidic conditions (pH = 1.67), adsorption behavior suggests that both NH3+ and COO- are oriented toward the Ag-D surface, and that SH is far from the surface. The structure of L-cysteine adsorption under acidic conditions can be further verified by the addition of an L-cysteine molecule through light-induced coupling reaction to form cystine. Finally, in-situ two-dimensional Raman scattering spectroscopy confirmed the feasibility and uniformity of the coupling reaction.

Crystal structure, DFT study and Hirshfeld surface analysis of 1-nonyl-2,3-di-hydro-1H-indole-2,3-dione.

In the title mol-ecule, C17H23NO2, the di-hydro-indole portion is planar (r.m.s. deviation = 0.0157 Å) and the nonyl substituent is in an 'extended' conformation. In the crystal, the nonyl chains inter-calate and the di-hydro-indole-dione units are associated through C-H⋯O hydrogen bonds to form micellar blocks. Based on the Hirshfeld surface analysis, the most important inter-molecular inter-action is the H⋯H inter-action.

Synthesis, crystal structure, DFT calculations and Hirshfeld surface analysis of 2-(1-decyl-2-oxo-indolin-3-yl-idene)propanedi-nitrile.

In the title mol-ecule, C21H25N3O, the 1-decyl substituents are in an extended conformation and inter-calate in the crystal packing to form hydro-phobic bands. The packing is further organized by π-π-stacking inter-actions between pyrrole and phenyl rings [centroid-centroid distance = 3.6178 (11) Å] and a C=O⋯π(pyrrole) inter-action [3.447 (2) Å]. Hirshfeld surface analysis indicates that the H⋯N/N⋯H inter-actions make the highest contribution (17.4%) to the crystal packing.

A systematic study of the effects of thionation in naphthalene dimide derivatives to tune their nonlinear optical properties.

In the present study, the number and position of sulfur atoms on naphthalene diimide (NDI) is systematically investigated to tune its nonlinear optical (NLO) response properties. Our DFT calculations for third-order polarizability (γ) show that the thionation significantly influences the nonlinear optical property of NDI as it is seen among its several designed derivatives (NDI-1 to NDI-10). The smallest and the largest γzzzz amplitudes are 503.49 × 10-36 and 1299.5 × 10-36 esu for NDI-1 (having tetraone group) and NDI-10 (having tetrathione group), respectively. The increase in γzzzz amplitude for NDI-10 is 796 × 10-36 esu, which is ∼150% from the γzzzz amplitude of NDI-1. A comparison of the γzzzz amplitudes of our designed derivatives are made with para-nitroaniline i.e. a prototype NLO molecule. The γzzzz amplitude of pNA is found to be 42.64 × 10-36 esu at the same B3LYP/DZVP2 level of theory. Using two-level model, the origin of larger γzzzz amplitudes is traced in lower transition energy of NDI-10. Furthermore, the calculation of vertical ionization potentials (VIPs) shows that the thionation does not affect the stability of designed derivatives, where a slight difference of 0.06 eV is seen between the VIPs of NDI-1 (6.63 eV) and NDI-10 (6.57 eV). Thus, a systematic comparison of the third-order polarizability and other electro-optical properties of our designed derivatives shows that our derivative systems possess good potential for their practical realization in the field of optical and NLO materials.