Antidiabetes and antioxidant potential of Schiff bases derived from 2-naphthaldehye and substituted aromatic amines: Synthesis, crystal structure, Hirshfeld surface analysis, computational, and invitro studies.

Three Schiff bases were synthesised by the condensation reaction between 2-napthaldehyde and aromatic amines to afford (E)-N-mesityl-1-(naphthalen-2-yl)methanimine (L1), (E)-N-(2,6-dimethylphenyl)-1-(naphthalen-2-yl)methanimine (L2) and (E)-N-(2,6-diisopropylphenyl)-1-(naphthalen-2-yl)methanimine (L3). The synthesised compounds were characterised using UV-visible, NMR (13C & 1H), and Fourier transform infrared spectroscopic methods while their purity was ascertained by elemental analysis. Structural analysis revealed that the naphthalene ring is almost coplanar with the imine functional group as evident by C1-C10-C11-N1 torsion angles of 176.4(2)° and 179.4(1)° in L2 and L3, respectively. Of all the various intermolecular contacts, H⋯H interactions contributed mostly towards the Hirshfeld surfaces of both L2 (58.7 %) and L3 (69.7 %). Quantum chemical descriptors of L1 - L3 were determined using Density Functional Theory (DFT) and the results obtained showed that the energy band gap (ΔE) for L1, L2 and L3 are 3.872, 4.023 and 4.004 eV respectively. The antidiabetic potential of the three compounds were studied using α-amylase and α-glucosidase assay. Compound L1 showed very promising antidiabetic activities with IC50 values of 58.85 µg/mL and 57.60 µg/mL while the reference drug (Acarbose) had 405.84 µg/mL and 35.69 µg/mL for α-amylase and α-glucosidase respectively. In-silico studies showed that L1 docking score as well as binding energies are higher than that of acarbose, which are recognized inhibitors of α-amylase together with α-glucosidase. Further insight from the RMSF, RMSD and RoG analysis predicted that, throughout the simulation L1 showcased evident influence on the structural stability of α-amylase. The antioxidant potential of the compounds was carried out using nitric oxide (NO), ferric reducing ability power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. The compounds exhibited good to fairly antioxidant properties with L1 as well as L3 having IC50 values of 70.91 and 91.21 µg/mL respectively for NO scavenging activities assay, which comparatively outshined acarbose (reference drug) with IC50 value of 109.95 µg/mL. Pharmacology and pharmacokinetics approximations of L1 - L3 showed minimal violation of Lipinski's Ro5 and this projects them to be less toxic and orally bioavailable as potential templates for the design of therapeutics with antioxidant and antidiabetic activities.

Ni2+ and Cu2+ complexes of N-(2,6-dichlorophenyl)-N-mesityl formamidine dithiocarbamate structural and functional properties as CYP3A4 potential substrates.

Metal compounds continued to attract diverse applications due to their malleability in several capacities. In this study, we present our findings on the crystal structures and functional properties of Ni2+ and Cu2+ complexes of N'-(2,6-dichlorophenyl)-N-mesitylformamidine dithiocarbamate (L) comprising [Ni-(L)2] (1) and [Cu-(L)2] (2) with a four-coordinate metal center. We established the two complex structures through 1H and 13C nuclear magnetic resonance (NMR), elemental, and single-crystal X-ray analysis. The analyses showed that the two complexes are isomorphous, having P21/c as a space group and a unit-cell similarity index (π) of 0.002. The two complexes conform to a distorted square planar geometry around the metal centers. The calculated and experimental data, including bond lengths, angles, and NMR values, are similar. Hirshfeld surface analysis revealed the variational contribution of the different types of intermolecular contacts driven by the crystal lattice of the two solvated complexes. Our knowledge of the potential biological implication of these structures enabled us to probe the compounds as prospective CYP3A4 inhibitors. This approach mimics current trends in pharmaceutical design and biomedicine by incorporating potentially active molecules into various media to predict their biological efficacies. The simulations show appreciable binding of compounds 1 and 2 to CYP3A4 with average interaction energies of -97 and -87 kcal/mol, respectively. The protein attains at least five conformational states in the three studied models using a Gaussian Mixture Model-based clustering and free energy prediction. Electric field analysis shows the crucial residues to substrate binding at the active site, enabling CYP3A4 structure to function prediction. The predicted inhibition with these Ni2+ and Cu2+ complexes indicates that CYP3A4 overexpression in a diseased state like cancer would reduce, thereby increasing the chemotherapeutic compounds' shelf-lives for adsorption. This multidimensional study addresses various aspects of molecular metal electronics, including their application as substrate-mimicking inhibitors. The outcome would enable further research on bio-metal compounds of critical potential.

Computational insights into the mechanisms and origins of switchable selectivity in gold(i)-catalyzed annulation of ynamides with isoxazoles via 6π-electrocyclizations of azaheptatrienyl cations.

Electrocyclizations of acyclic conjugated π-motifs have emerged as a versatile and effective strategy for accessing various ring systems with excellent functional group tolerability and controllable selectivity. Typically, the realization of 6π-electrocyclization of heptatrienyl cations to afford seven-membered motif has proven difficult due to the high-energy state of the cyclizing seven-membered intermediate. Instead, it undergoes the Nazarov cyclization, affording a five-membered pyrrole product. However, the incorporation of a Au(i)-catalyst, a nitrogen atom and tosylamide group in the heptatrienyl cations unexpectedly circumvented the aforementioned high energy state to afford a seven-membered azepine product via 6π-electrocyclization in the annulation of 3-en-1-ynamides with isoxazoles. Therefore, extensive computational studies were carried out to investigate the mechanism of Au(i)-catalyzed [4+3] annulation of 3-en-1-ynamides with dimethylisoxazoles to produce a seven-membered 4H-azepine via the 6π-electrocyclization of azaheptatrienyl cations. Computational results showed that after the formation of the key α-imino gold carbene intermediate, the annulation of 3-en-1-ynamides with dimethylisoxazole occurs via the unusual 6π-electrocyclization to afford a seven-membered 4H-azepine exclusively. However, the annulation of 3-cyclohexen-1-ynamides with dimethylisoxazole occurs via the commonly proposed aza-Nazarov cyclization pathway to majorly generate five-membered pyrrole derivatives. The results from the DFT predictive analysis revealed that the key factors responsible for the different chemo-, and regio-selectivities observed are the cooperating effect of the tosylamide group on C1, the uninterrupted π-conjugation pattern of the α-imino gold(i) carbene and the substitution pattern at the cyclization termini. The Au(i)-catalyst is believed to assist in the stabilization of the azaheptatrienyl cation.

Ligand-Guided Investigation of a Series of Formamidine-Based Thiuram Disulfides as Potential Dual-Inhibitors of COX-1and COX-2.

A series of thiuram disulfides 1-6 which had been previously synthesized and characterized,[1] were studied for their potential therapeutic properties. Target-fishing analyses through HitPick and SwissTarget prediction identified COX1 and COX2, which are essential biomolecules in cancer-related inflammations, as the possible targets for compounds 1 and 4 among all the compounds tested. These two proteins have enjoyed interest as targets for treating some neoplastic cancer types such as breast, colorectal, skin, pancreatic, haematological and head cancers. The inhibitory potency of 1 and 4 as lead anticancer drug candidates with dual-target ability against COX1 and COX2 was examined through molecular docking, molecular dynamics simulation and post-MD analyses such as binding energy calculation, RMSD, RMSF, and RoG. The two compounds had better docking scores and binding energies than the known inhibitors of COX1 and COX2. Insights from the RMSD, RMSF, and RoG suggested that both 1 and 4 showed observable influence on the structural stability of these targets throughout the simulation. The reported observations of the effects of 1 and 4 on the structures of COX1 and COX2 indicate their probable inhibitory properties against these target proteins and their potential as lead anticancer drug candidates.

Formamidine-Based Thiuram Disulfides as Efficient Inhibitors of Acid Corrosion of Mild Steel: Electrochemical, Surface, and Density Functional Theory/Monte Carlo Simulation Studies.

Electrochemical, surface, and density functional theory (DFT)/Monte Carlo (MC) simulation studies were used in investigating the characteristics of N,N'-(disulfanne-1,2-dicarbonothioyl)bis(N,N'-bis(2,6-dimethylphenyl)formimidamide) (DS1), N,N'-(disulfanne-1,2-dicarbonothioyl)bis(N,N'-bis(2,6-diisopropylphenyl)formimidamide) (DS2), N,N'-(disulfanne-1,2-dicarbonothioyl)bis(N,N'-dimesitylformimidamide) (DS3), and N,N'-(disulfanne-1,2-dicarbonothioyl)bis(N,N'-bis(2,6-dichlorophenyl)formimidamide) (DS4) as inhibitors of acid corrosion of mild steel. The inhibitors were found to effectively reduce the rates of steel dissolution at the anode as well as cathodic hydrogen evolution. The order of inhibition efficiencies of studied compounds is DS1 (PDP/LPR/EIS: 98.60/97.98/96.94%) > DS2 (PDP/LPR/EIS: 98.36/96.86/96.90%) > DS3 (PDP/LPR/EIS: 94.66/87.44/94.30%) > DS4 (PDP/LPR/EIS: 83.57/77.02/75.17%) at 1.00 mM, and the overall efficiencies appeared to depend on the molecular and electronic structures of the compounds. The compounds offered high resistance to charge transfer across the electrode/electrolyte system by forming adsorbed film whose resistance increased with an increase in concentration. Findings suggested that the adsorption process involved combined chemisorption and physisorption. DFT calculations and MC simulations provided theoretical justifications for the experimental results.

Copper(II)-N-hydroxy-N,N'-diarylformamidine complexes: Synthesis, crystal structures, antibacterial and molecular docking studies.

A series of Cu(II) complexes were synthesized by using N-hydroxy-N,N'-diarylformamidine ligands: N-hydroxy-N,N'-(phenyl)formamidine (L1), N-hydroxy-N'-(4-methylphenyl)formamidine (L2), N-hydroxy-N,N'-(2,6-dimethylphenyl)formamidine (L3), N-hydroxy-N,N'-(2,6-diisopropylphenyl)formamidine (L4). Reaction of ligands L1-L4 with hydrated copper acetate furnished mononuclear Cu(II) complexes 1-4 with general formula [Cu-(L)2]. The molecular structures of complexes 3 and 4, as determined by single crystal X-ray diffraction, showed both to have square planar geometry with a near C2 symmetry. The antimicrobial potency of all four complexes was evaluated against three gram-(-) bacteria (S. typhimurium, P. aeruginosa, and E. coli) and two gram-(+) bacteria (Methicillin-resistant S. aureus (MRSA) and S. aureus), with ciprofloxacin as the reference drug. All tested complexes were inactive against gram-(+) bacteria strains except for complex 1, which displayed excellent activity when compared to the reference. Molecular docking studies showed that hydrogen bonding, pi-sigma and van der Waals interactions are prominent complex-protein connections, with complex 2 displaying good binding affinities with the studied biological targets.

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4.

We report the synthesis and crystal structures of three new copper(II) Schiff-base complexes. The complexes have been characterized by elemental analysis and Fourier transform infrared (FT-IR) and UV-visible spectroscopies. The X-ray diffraction (XRD) analysis reveals that complexes 1 and 3 crystallize in a monoclinic space group C2/c and 2 in a triclinic space group P1̅, each adopting a square planar geometry around the metal center. We use a density functional theory method to explore the quantum chemical properties of these complexes. The calculation proceeds with the three-dimensional (3D) crystal structure characterization of the complexes in which the calculated IR and UV-vis values are comparable to the experimental results. Charge distribution and molecular orbital analyses enabled quantum chemical property prediction of these complexes. We study the drug-likeness properties and binding potentials of the synthesized complexes. The in silico outcome showed that they could serve as permeability-glycoprotein (P-gp) and different cytochrome P450 substrates. Our calculations showed that the complexes significantly bind to cytochrome P450 3A4.