Current Physical Chemistry - Volume 12, Issue 3, 2022

Background: The chemical dependency caused by recreational drug abuse is highly detrimental to humans and has direct implications for society. Cannabis sativa is still at the top ranking of most used drugs in the world, and its major chemical component is Δ9-THC. This molecule is the main cause of addiction in chronic users, and its action is measured by the CB1 receptor present in the CNS. So far, there is no approved drug for the treatment of abstinence in C. sativa. Objective: In this sense, the objective of this research is to propose analogues of stemphol (2-methyl-5-pentylbenzene-1,3-diol) molecule that can serve as treatment for withdrawal crises in C. sativa addicts, initially through in silico methods. Methods: 28 structural modifications were carried out in the molecule stemphol. These were subjected to in silico predictions of pharmacokinetics, toxicology, pharmacological activity, synthetic viability and the prediction of drug-receptor interaction through molecular docking. For this, the software and web servers PreADMET, DEREK 2.1, PASS, SEA, SYLVIA 2.4 and GOLD were used. Results: 22 analogues demonstrated good pharmacokinetic results, and 16 analogues gave no warning of hepatotoxicity, mutagenicity, nephropathies and carcinogenicity in mammals. Biological activity predictions were performed on the PASS server, resulting in 28 analogues exhibiting adenylate cyclase inhibition and/or MAP kinase stimulating activity; in SEA, the performance of the CB1 receptor was analyzed, resulting in 20 analogues with action on CB1 receptors in humans. The selected analogues 1, 4, 16, 17, 19, 24, 25 and 26 were submitted to synthetic accessibility prediction in the SYLVIA software because they presented better results in terms of their pharmacokinetic, toxicological and predictive properties. Conclusion: Of these, analogues 17 and 25 provided a very satisfactory result in the interaction with the CB1 receptor through the molecular docking method, and can be considered great proposals for future in vitro and in vivo studies, with the ability to further elucidate their actions.

Background: Thiazoles are an important heterocycle that exhibit various bioactivities. Thiazole ring is found in the core structure of various medicinally useful compounds. It shows biological activities like anti-inflammatory, antibacterial, antifungal, antioxidant, cytotoxicity, anticonvulsant, insecticidal, anticancer and antitumor. Thioamides are reported to show bioactivities like antibacterial, antileukemia, antifungal, anti-arthritic, antimalarial and cytotoxic. Hantzsch synthesis is one of the most efficient reactions for thiazole formation, which is a cyclization reaction between thioamides and α-halo carbonyl compounds. Very few reports on the kinetic investigation of thiazole formation are available. Previously we have studied thiazole formation using 3-chloroacetylacetone and substituted thioureas by pH metric study. The reaction between 3-chloroacetylacetone and Thioamides is not reported yet. The present work deals with the kinetics and mechanistic study of ring closure of thiazole using thioamides and 3-chloroacetylacetone. The reaction was carried out in a water-ethanol system at 303 K. The kinetic investigations are carried out pH metrically. The nature of the reaction is explained on the basis of thermodynamic parameters. Reaction products are isolated and characterized on the basis of spectral data. The effect of temperature on reaction rate is studied at 30 °C to 50 °C. Thermodynamic parameters are evaluated. Objectives: To determine the order of the reaction. To determine the rate of reaction. To evaluate the rate of reaction at various temperatures. To determine the rate of reaction in different media. To study the effect of dielectric constant, ionic strength etc. To observe calculation of the energy of activation, enthalpy of activation, entropy of activation and free energy of activation. To propose a reaction mechanism considering various thermodynamic parameters. Methods: Measuring the change in pH, the concentration of H+ ion will be determined and accordingly, the rate of reaction will be calculated. Results: Van’t Hoff’s differential method and the stoichiometric study suggested that one mole of Thioamides reacts with one mole of 3-chloroacetylacetone. The rates of reaction are measured at different concentrations of Thioamides at a constant concentration of 3-chloroacetylacetone. The plot of log (dc/dt) against log [3-chloroacetylacetone] and log [Thioamides] is also a straight line and the slope of the plot is nearly one with respect to both. At five different temperatures, second order rate constants are determined. The energy of activation (Ea) is determined by plotting a graph of logk versus 1/T, and other thermodynamic parameters are calculated. The negative entropy of activation (ΔS* ) of this reaction specifies the rigid nature of the transition state. The entropy of activation (ΔS* ) is negative and specifies that less stable noncyclic reactants convert into stable cyclic products. Free energy of activation (ΔG* ) is calculated. Reacting species are oppositely charged according to the salt effect. In the water-isopropyl, alcohol system reaction is fast than water-ethanol system. Conclusion: Using Van’t Hoff’s differential method, the rate of reaction between 3- chloroacetylacetone and Thioamides is found to be one with respect to both components; The proposed rate law also shows that the order of the reaction is two; Negative entropy (ΔS* ) shows that from open chain compound, cyclic compound is formed. Nucleophilic addition and addition– elimination reactions take place; Oppositely charged species are present in the reaction; Rate increases with an increase in dielectric constant. Isopropyl alcohol-water system shows a high-rate constant as compared to that ethanol-water system.

Background: Anticancer activity of 9-anilinoacridine derivatives has been well reported. Although, the DNA-drug sequence-specific binding of these compounds may be affected by the substituent(s) on the aniline ring, it is still unclear which substituent (NH2 or CH2–OH) on the anilino ring of the compound is the critical element. A good understanding of chemical properties such as steric, lipophilic and electronic properties at the molecular level may provide important background for mutagenic and carcinogenic properties. Objectives: The present study is an attempt to understand the reactive nature of some selected 9-anilinoacridine derivatives in both gas and solvent phases and to predict their anticancer activity by QSAR analysis. Methods: Full geometry optimizations of all derivatives were carried out at gradient corrected DFT using DMol³ program. We used DNP basis set in combination with BLYP to study all the derivatives. The molecular mechanics parameters used for QSAR analysis were calculated using Hyperchem software. Results: We found Compound (31) (R=COOC6H5) as the most stable compound and compound (6) (R1= NO2) as the most reactive one in both gas and solvent phases. Fukui function (f+) values of all the atoms showed that N10 is the most reactive atom in each of the molecule which indicates that N10 is the preferred site for nucleophilic attack. The final QSAR model with four parameters (electrophilicity, hardness, surface area, and molar refractivity) is capable of predicting anticancer activity of the compounds against leukemic HL-60 cell lines with r² = 0.91 and 0.88 in both gas and solvent phases, respectively. Conclusion: The global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity were calculated to understand the reactive nature and reactive sites of the compounds. The comparative QSAR study with the help of DFT and MM + techniques provides the importance of the selected descriptors in predicting the activity of the selected derivatives.

Background: Oxalate ligand-based metal complexes have long been used for the thermal synthesis of metal oxides. Polymeric homo/heterometallic oxalate-based molecular materials of the general formula, {A]M^IIM^III[C2O4]3]}∞, [A = organic cation, M^II/M^III: di/trivalent transition metal ion; C2O4: oxalate ligand] provides a molecular source to prepare metal oxides through solid state thermal decomposition primarily due to the potential to tune the materials’ outcome by adjusting the molecular stoichiometry and composition. Objective: The study aims to explore the effect of mixing at the di- and trivalent metal sites of {N[n-C4H9]4]Fe^IIFe^III[C2O4]3]}∞ which decomposes to hematite, on the nature of thermal decomposition reaction as well as the nature of the obtained decomposed materials. Methods: Two series of materials {N[n-C4H9]4]Fe^II1-xZn^IIxFe^III[C2O4]3]}∞ and {N[n- C4H9]4]Fe^IIFe^III1-xCr^IIIx[C2O4]3]}∞ were prepared as precursors for non-isothermal thermogravimetry [TG] study. Model-free integral isoconversional method is employed to calculate the activation energy of decomposition, and hence the most probable reaction mechanism, as well as the reaction rate of thermal decomposition, was determined. Based on the kinetic parameters, the important thermodynamic parameters such as the changes of entropy, enthalpy, and Gibbs free energy are estimated for the activated complex formation from the precursors. Powder X-ray diffraction studies were made to identify the decomposed materials. Results: For materials with 0 < x ≤ 1 well-defined two-step and one-step decomposition process were observed for {N[n-C4H9]4]Fe^II1-xZn^IIxFe^III[C2O4]3]}∞ and {N[n- C4H9]4]Fe^IIFe^III1-xCr^IIIx[C2O4]3]}∞, respectively. For each series of materials, a systematic dependence of the activation energy on the extent of conversion indicates a systematic change in the reactivity. The thermal decomposition strongly depends on the extent of mixing at the di- and trivalent sites and proceeds through different reaction mechanisms at different rates. On the decomposition of these series of materials, a range of metal oxides was obtained. Possibly, during such extent of mixing dependent reactions, the reactant particles go through modifications in their reactivity by several factors. Conclusion: Present work may invoke interest in solid state synthesis of different metal oxides under controlled thermal decomposition by identifying the rate controlling the process through reaction kinetics study for better synthesis and manoeuvring.

Background: Pyridinium and imidazolium-based compounds show diverse applications with basic skeleton designs in order to achieve improved optical and thermal behavior. Aim: The aim of the study was to design and develop a greener, efficient protocol towards newer pyridinium and imidazolium compounds, and investigate optical, solvatochromic, thermal, and theoretical properties. Objectives: The purpose is to study the optical properties of pyridinium and imidazolium compounds, for which we illustrate the solvent polarity effect on the absorption and emission behavior as a function of orientation polarizability and ET(30) solvent parameters. The study focuses on thermal stability and computes the molecular orbital orientation and HOMO- LUMO energies using theoretical simulation by the DFT approach. Methods: The structures were confirmed by FT-IR, Mass, ¹H NMR and ¹³C NMR, and optical properties were investigated using a UV-Visible spectrophotometer and fluorometer. The thermal behavior was investigated using thermal gravimetric analysis, and molecular orbital orientation and energies were determined using GAUSSIAN 16 software. Results: The newer compounds with good thermal stability and optical behavior have been synthesized and characterized. The study interprets the intermolecular electron transfer amongst the molecules and the effect of solvents on their excitation and emission properties. The experimental and theoretical study illustrates the optical, thermal, and electronic properties of both compounds. Conclusion: The present work describes the solvatochromic optical behavior of pyridinium bromide and imidazolium bromide synthesized by a microwave-assisted, greener and efficient strategy. The solvatochromic study interprets the presence of non-specific solutesolvent interactions. The photophysical, thermal, and DFT study revealed that both pyridinium and imidazolium compounds are used for optoelectronic applications. Moreover, the work could be helpful to researchers for developing new skeletons for optoelectronic applications.

Background: Alzheimer’s disease (AD) has been characterized by a progressive loss of cognitive functions, especially memory, impacting the daily life and personality of the elderly. In the present study, we performed molecular modeling of methylxanthines and tannins, with pharmacologic actions as stimulants of the Central Nervous System (CNS) and antioxidant, respectively, present in Paullinia cupana Kunth (guarana), evaluating the theoretical viability of these molecules as an alternative for the treatment of Alzheimer's disease, specifically to act by inhibiting the β-secretase enzyme (BACE-1). Methods: It has been accomplished optimization of selected chemical structures, derivation of the pharmacophore, docking simulation, as well as prediction of physicochemical, pharmacokinetic (ADME) and toxicological (TOX) properties, ending with the activity prediction and synthetic viability of the selected molecules. For the physicochemical properties, evaluated according to Lipinski’s Rule of Five, only methylxanthines, catechin and epicatechin remained within the parameters evaluated. Results: In the molecular docking, caffeine, theobromine, theophylline, catechin, epicatechin, and proanthocyanidin, respectively, interacted with 57.14%, 42.86%, 28.57%, 57.14%, 28.57% e 57.14% of the active site amino acid residues of BACE-1. The ADME properties indicated the average permeability of the blood-brain barrier to the molecules caffeine, theobromine, theophylline, catechin and epicatechin, and caffeine, theobromine and theophylline showed high intestinal absorption and low aggregation to plasma proteins. The TOX properties showed only proanthocyanidin as a safer molecule. Only catechin and epicatechin were related to the action of BACE-1 in predicting activity. The synthetic viability of methylxanthine has been evaluated as high, while catechin and epicatechin were median and proanthocyanidin has been evaluated as difficult. Conclusion: Catechin and epicatechin tannins presented more favorable results indicating the interaction of suppression of the Aβ aggregation, potential BACE-1 inhibitors.