Synthesis,bioevaluation and molecular docking study of new piperazine and amide linked dimeric 1,2,3-triazoles

Abstract

In search of more potent new antitubercular agents, a library of novel piperazine tethered dimeric 1,2,3-triazoles were designed by assembling 1,2,3-triazoles and piperazine in a single molecular architectural framework. The titled compounds (3a–m) were synthesized by 1,3-dipolar cycloaddition of 1,4-di(prop-2-yn-1-yl)piperazine (1) and various azides (2a–m) using click chemistry approach with good yields. All the synthesized compounds (3a–m) have been screened for their in vitro antitubercular, antifungal and antioxidant activities against their respective strains. Among them, 3b, 3d, and 3i have revealed promising antitubercular activity against Mycobacterium tuberculosis (Mtb) H37Rv with MIC 12.5?µg/mL. Molecular docking results provided well-clustered solutions to the mode of binding for these molecules into the active site of Mtb enoyl reductase (InhA). In addition to this, most of synthesized compounds were found to have potential antifungal as well as antioxidant activity.     

呋喃西林水溶液在光和热作用下的稳定性

The influence of both light and heat on the stability of nitrofurazone aqueous solution was studied. Results show that in either heating experiments or the exposure to light at high temperatures, the degradation rate obeyed zero-order kinetics. The total rate constant ktotal caused by both light and heat can be divided into two parts: ktotal =kdark klight, where kdark and klight are the degradation rate constants caused by heat and light, respectively. The klight can be expressed as klight=Alight*exp(-Ea,light/RT)*E, where E is the illuminance of light, and Alight and Ea,light both are experimental constants. The values of these kinetic parameters were determined based on the experiments in the dark and upon exposure to three different light sources. Results show that the values of Alight and Ea, light varied with the light source. To save time, labor, and drugs, exponential heating experiments were employed and compared with the isothermal experiments. Results indicated that kinetic parameters obtained by exponential heating experiments are comparable to those obtained by isothermal experiments either in the dark or upon exposure to light.     

A novel PI index and its applications to QSPR/QSAR studies

A novel topological index, PI (Padmakar-Ivan index), is derived in this paper. The index is very simple to calculate and has disseminating power similar to that of the Wiener (W) and the Szeged (Sz) indices. The comprehensive studies show that the proposed PI index correlates highly with W and Sz as well as with physicochemical properties and biological activities of a large number of diversified and complex compounds. The proposed PI index promises to be a useful parameter in the QSPR/QSAR studies. The stability of each model is demonstrated by applying cross-validation test. Furthermore, more favorable comparison with other representative indices such as the Randic index is also made in order to establish the predictive ability of the PI index. The results have shown that in several cases the PI index gave better results.     

Oxidative Cyclization of Isoniazid with Fluoroquinolones: Synthesis,Antibacterial and Antitubercular Activity of New 2,5‐disubstituted‐1,3,4‐Oxadiazoles

We report herein one‐pot synthesis and the antibacterial and antitubercular activities of 2,5‐disubstituted‐1,3,4‐oxadiazole compounds obtained by hybridization of a well‐known antitubercular agent isoniazid (INH ) with four broad‐spectrum antibiotics belonging to fluoroquinolone (FQ ) class. The work is aimed at designing and developing potential antimicrobial agents having synergistic action due to the coupling of INH and FQ through the biologically active 1,3,4‐oxadiazole nucleus. The synthesized compounds are expected to have low toxicity as compared to INH due to the absence of free hydrazide group in the chemical structure of the prepared derivatives. The antibacterial activities of the 1,3,4 oxadiazole derivatives were also tested against several Gram‐positive and Gram‐negative pathogenic bacterial strains. The antitubercular activity was evaluated against M. tuberculosis H₃₇Rv strain, and the results were compared with that of the positive control INH . The title compounds showed excellent antimicrobial and promising antitubercular activity in comparison to the parent fluoroquinolones and INH , respectively.     

Synthesis,antitubercular evaluation and molecular docking studies of phthalimide bearing 1,2,3-triazoles

In a search for safer and potent antitubercular agents, here a library of newly substituted dioxoisoindolinylmethyl-triazolyl-N-phenylacetamide derivatives (5a–l) has been synthesized via click chemistry approach. All synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB). Among the screened compounds, 5d, 5e, 5h, and 5l showed good antitubercular activity. The compounds 5d and 5l have shown very effective antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB) with MIC 12.5?μg/mL. All the newly synthesized compounds were thoroughly characterized by ¹H NMR, ¹³C NMR, and HRMS spectral data. We further performed exploratory docking studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase to demonstrate the mechanism of antitubercular activity.     

AM1 studies on methyl radical additions to C=N and N=N double bonds in aza and azo compounds

The addition reactions of CH₃ to C_sp ² and N_sp ² inE-but-2-ene,E-2-azabut-2-ene andE-azomethane were studied theoretically at the level of a semiempirical quantum-chemical method. Similar reactions withE-azoethane andE-azoisopropane were also studied. The activation enthalpies were calculated by means of the Austin Model 1 (AM1) unrestricted Hartree-Fock (UHF) approximation. The calculated data qualitatively support those available in the literature: the activation enthalpies of the additions to N_sp ² are larger than those to C_sp ². The results further support the validity of the Hammond postulate.     

A comparative QSAR study using Wiener, Szeged, and molecular connectivity indices

In this study we have investigated the relative correlation potential of Wiener (W), Szeged (Sz), and molecular connectivity indices (0chiR, 1chiR and 2chiR) in developing quantitative structure-activity relationships, QSAR; log P values of benzoic acid and its nuclear-substituted derivatives were used for this purpose. The statistical analyses for univariate and multivariate correlations had indicated that both W and Sz are closely related to the connectivity indices (mchiR) and that the W, the Sz, and the 1chiR indices have similar modeling potentials. 1chiR gives slightly better results than both W and Sz. Other connectivity indices 0chiR and 2chiR correlate poorly with log P.     

Electrochemical Elucidation of the Facilitated Ion Transport Across a Bilayer Lipid Membrane in the Presence of Neutral Carrier Compounds

The ion transport facilitated by neutral carrier compounds (valinomycin, nonactin) has been investigated by cyclic voltammetry in the several electrolyte solutions (KF, KCl, KBr, KNO₃, KSCN, KClO₄), and we demonstrated the effect of the counter anions on the facilitated transport of K⁺ from the viewpoint of electroneutrality. Voltammograms for the ion transport were generated at steady state and the current density between W1 and W2, j_W1–W2, increased with the absolute value of the applied membrane potential, E_W1–W2. Then, the magnitude of j_W1–W2 at a certain E_W1–W2 increased with the hydrophobicity of the counter anion. It was proved that the logarithm of |j_W1–W2|at a certain E_W1–W2 is almost proportional to the hydration energy of the counter anion. This indicates that not only K⁺ but also the counter anion distributes into the BLM. Therefore, the magnitude of j_W1–W2 at a certain E_W1–W2 increased with an increase of pH, because the hydroxide ion was served as a counter anion. Based on the variation of the zero‐current potential in case of various asymmetrical ionic compositions, it is found that the amount of cation transport is much larger than that of anion transport.     

Dicationic liquid mediated synthesis of tetrazoloquinolinyl methoxy phenyl 4-thiazolidinones and their antibacterial and antitubercular evaluation

In a search of new potentially active antitubercular agents here we have synthesized 3-substituted phenyl-2-(4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)phenyl)thiazolidin-4-ones (8a–l) and evaluated their antibacterial, particularly antitubercular activity. These have been conveniently synthesized by performing one–pot cyclocondensation of 4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)benzaldehyde, anilines and mercaptoacetic acid in dicationic ionic liquid, (3-methyl-1-[3-(methyl-1H-imidazolium-1-yl)propyl]-1H-imidazolium dibromide [C₃(MIM)₂–2Br]) and obtained excellent yields of (8a–l). 4-Thiazolidinones (8a–l) were thoroughly characterized by their spectral analyses. These compounds have been screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra and Mycobacterium bovis (BCG). The compounds 8a, 8c, and 8e exhibited notable in vitro antitubercular activity compare to the reference, Rifampicin. Molecular docking study has also been performed to know the binding mode of these analogs in to the active site of DprE1 enzyme. The synthesized compounds were also evaluated for their in vitro antibacterial activity and amongst them compound 8k has shown moderate activity against both gram-negative and gram-positive bacterial strains.     

Antifungal,anti-inflamatory and neuritogenic activity of newly-isolated compounds from Disporopsis aspersa

Abstract

A new ester (1) and a terpenoid (2) were isolated from the dried whole plant of Disporopsis aspersa (H_UA) E_NGL. ex D_IELS for the first time and their structures were elucidated, as well as their biological activities are described. The two compounds all showed good antifungal activities, especially furanone (2) exhibited better antifungal activity against Pseudoperonospora cubensis and Phytophthora infestans with EC₅₀ value of 22.82, 18.90?μg/mL, respectively. Compound 1 exhibited a significant promotion on the neurite outgrowth in NGF-induced PC-12 cells, and moderate inhibition on the NO production induced by lipopolysaccharide (LPS) in BV-2 microglial cells.