Pyrrole-Based Hydrazones Synthesized and Evaluated In Vitro as Potential Tuberculostatics (original) (raw)
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Turk. J. …, 2011
The difficulty in managing tuberculosis includes the prolonged duration of the treatment, the emergence of drug resistance, and coinfection with HIV/AIDS. Tuberculosis control requires new drugs that act on novel drug targets to help in combating resistant forms of Mycobacterium tuberculosis and reduce the treatment duration. For this purpose, 6-substituted-3(2 H) -pyridazinone-2-acetyl-2-(substituted/nonsubstituted acetophenone) hydrazone derivatives were synthesized and their structures were elucidated by elemental analyses, IR, and 1 H-NMR. The in vitro antimycobacterial activities of synthesized compounds 5a-l were determined by the agar proportion method against Mycobacterium tuberculosis H37Rv. Among the target compounds, 5b and 5f exhibited the best antimycobacterial activity, with a MIC value of 5 μ g/mL.
Novel 2-(2-(4-Aryloxybenzylidene)-Hydrazinyl)-Benzothiazole derivatives were studied using molecular modeling techniques including 3D-QSAR (three-dimensional quantitative structure–activity relationship), CoMFA, CoMSIA, and molecular docking. In the present study 3D-QSAR for 25 derivatives possessing a wide variety of bioactivity against mycobacterium tuberculosis H37Rv strain. The results of the CoMFA model has q2 = 0.767 and r2 = 0.938, the best CoMSIA model has q2 = 0.806 and r2 = 0.945. The models were graphically interpreted by using contour plots, which gave more accuracy into the structural requirements for increasing the biological activity of compounds and proved a strong basis for future rational drug design of more active inhibitors for tuberculosis. The results indicated the steric, electrostatic, and hydrophobic, H-acceptor fields play key roles in models. The results of the CoMSIA model show better results than CoMFA model. Molecular docking shows the binding relationship of the ligand and the receptor protein.
Antibiotics
Fifteen 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives 3a–d and sulfonyl hydrazones 5a–k were synthesized. They were characterized by 1H-NMR, 13C NMR, and HRMS. Mycobacterium tuberculosis strain H37Rv was used to assess their antimycobacterial activity. All compounds demonstrated significant minimum inhibitory concentrations (MIC) from 0.07 to 0.32 µM, comparable to those of isoniazid. The cytotoxicity was evaluated using the standard MTT-dye reduction test against human embryonic kidney cells HEK-293T and mouse fibroblast cell line CCL-1. 4-Hydroxy-3-methoxyphenyl substituted 1,2,3-thiadiazole-based hydrazone derivative 3d demonstrated the highest antimycobacterial activity (MIC = 0.0730 µM) and minimal associated cytotoxicity against two normal cell lines (selectivity index SI = 3516, HEK-293, and SI = 2979, CCL-1). The next in order were sulfonyl hydrazones 5g and 5k with MIC 0.0763 and 0.0716 µM, respectively, which demonstrated comparable minimal cytotoxicity. All compo...
QSAR Modeling of Antimicrobial Activity of some p-substituted Aromatic Hydrazones
2017
QSAR analysis of a series of previously synthesized p-substituted aromatic hydrazones tested for growth inhibitory activity against Bacillus subtilis, was performed using several physicochemical descriptors: Surface tension (ST), Molar Refraction (MR), Molar Volume (MV), Parachor (Pc), Index of Refractivity (); Density (D) and Polarizability (). Twoparameter models were obtained and validated by using several statistical parameters: R; Radj; F-test; Sd; Rped; PRESS/SSY; Q2; SPRESS; PSE and Q. Both the parameters (D and ) contributing to statistically best model (model 16) have positive input to the modeling of biological activity of selected hydrazones.
Antimycobacterial pyrroles: synthesis, anti-Mycobacterium tuberculosis activity and QSAR studies
Bioorganic & Medicinal Chemistry, 2000
AbstractÐA number of known antifungal pyrrole derivatives and some newly synthesized compounds (5±33) were tested in vitro against Mycobacterium tuberculosis CIP 103471. The majority of tested compounds were ecient antimycobacterial agents showing MIC values ranging from 0.5 to 32 mg/mL. A 3-D-QSAR study has been performed on these pyrrole derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. Due to the absence of information on a putative receptor responsible for this activity, classical quantitative structure±activity relationships (QSAR) and comparative molecular ®eld analysis (CoMFA) have been applied. A model able to well correlate the antimycobacterial activity with the chemical structures of pyrrole derivatives 5±33 has been developed which is potentially helpful in the design of novel and more potent antituberculosis agents. The combination of CoMFA with classical QSAR descriptors led to a better hybrid 3-D-QSAR model, that successfully explains the structure±activity relationships (r 2 =0.86) of the training set. A comparison between the QSAR, CoMFA and mixed QSAR±CoMFA models is also presented. The hybrid model is to be preferred, however, because of its lowest values of the average absolute error of prediction toward a limited external test set. #
Synthesis and anti-mycobacterial evaluation of some pyrazine-2-carboxylic acid hydrazide derivatives
European Journal of Medicinal Chemistry, 2010
A series of pyrazine-2-carboxylic acid hydrazide derivatives were synthesized and screened for their activity against Mycobacterium tuberculosis. The results show that pyrazine-2-carboxylic acid hydrazide–hydrazone derivatives 3a–l were less active than pyrazinamide. In contrast, the N4-ethyl-N1-pyrazinoyl-thiosemicarbazide 4 showed the highest activity against M. tuberculosis H37Rv (IC90 = 16.87 μg/mL). Details of the structure–activity and structure–cytotoxicity relationships are discussed.
European Journal of Medicinal Chemistry, 2020
Tuberculosis, caused by Mycobacterium tuberculosis, is a serious infectious disease and remains a global health problem. There is an increasing need for the discovery of novel therapeutic agents for its treatment due to the emerging multi-drug resistance. Herein, we present the rational design and the synthesis of eighteen new thiadiazolylhidrazones (TDHs) which were synthesized by intramolecular oxidative N-S bond formation reaction of 2-benzylidene-N-(phenylcarbamothioyl)hydrazine-1-carboximidamide derivatives by phenyliodine(III) bis(trifluoroacetate) (PIFA) under mild conditions. The compounds were characterized by various spectral techniques including FTIR, 1 H NMR, 13 C NMR and HRMS. Furthermore, the proposed structure of TDH12 was resolved by single-crystal X-ray analysis. The compounds were evaluated for their in vitro antitubercular activity against M. tuberculosis H37Rv. Among them, some compounds exhibited remarkable antimycobacterial activity, MIC=0.78-6.25 µg/mL, with low cytotoxicity. Additionally, the most active compounds were screened for their biological activities against M. tuberculosis in the nutrient starvation model. Enzyme inhibition assays and molecular docking studies revealed enoyl acyl carrier protein reductase (InhA) as the possible target enzyme for the compounds to possess their antitubercular activities.