Synthesis, Inhibition of Mycobacterium tuberculosis Enoyl-acyl Carrier Protein Reductase and Antimycobacterial Activity of Novel Pentacyanoferrate(II)-isonicotinoylhydrazones (original) (raw)
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New one-pot synthesis of anti-tuberculosis compounds inspired on isoniazid
European journal of medicinal chemistry, 2020
A library of thirty N-substituted tosyl N'-acryl-hydrazones was prepared with p-toluenesulfonyl hydrazide, methyl propiolate and different aldehydes in a one-pot synthesis via an aza-Michael reaction. The scope of the reaction was studied, including aliphatic, isoprenylic, aromatic and carbocyclic aldehydes. The prepared collection was tested against Mycobacterium tuberculosis H37Rv. Nine analogs of the collection showed Minimum Inhibitory Concentration 10 mM, of which the most active members (MIC of 1.25 mM) were exclusively E isomers. In order to validate the mechanism of action of the most active acrylates, we tested their activity on a M. tuberculosis InhA over-expressing strain obtaining MIC that consistently doubled those obtained on the wild type strain. Additionally, the binding mode of those analogs on M. tuberculosis InhA was investigated by docking simulations. The results displayed a hydrogen bond interaction between the sulfonamide and Ile194 and the carbonyl of the methyl ester with Tyr 158 (both critical residues in the interaction with the fatty acyl chain substrate), where the main differences on the binding mode relays on the hydrophobicity of the nitrogen substituent. Additionally, chemoinformatic analysis was performed to evaluate in silico possible cytotoxicity risk and ADME-Tox profile. Based on their simple preparation and interesting antimycobacterial activity profile, the newly prepared aza-acrylates are promising candidates for antitubercular drug development.
Current Pharmaceutical Design, 2006
Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant strains have created a need for the development of new antimycobacterial agents. Mycolic acids, the hallmark of mycobacteria, are high-molecularweight α-alkyl, β-hydroxy fatty acids, which appear mostly as bound esters in the mycobacterial cell wall. The product of the M. tuberculosis inhA structural gene (InhA) has been shown to be the primary target for isoniazid (INH), the most prescribed drug for active TB and prophylaxis. InhA was identified as an NADH-dependent enoyl-ACP reductase specific for long-chain enoyl thioesters. InhA is a member of the mycobacterial Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. Although the history of chemotherapeutic agent development demonstrates the remarkably successful tinkering of a few structural scaffolds, it also emphasizes the ongoing, cyclical need for innovation. The main focus of our contribution is on new data describing the rationale for the design of a pentacyano(isoniazid)ferrateII compound that requires no KatG-activation, its chemical characterization, in vitro activity studies against WT and INH-resistant I21V M. tuberculosis enoyl reductases, the slow-onset inhibition mechanism of WT InhA by the inorganic complex, and molecular modeling of its interaction with WT InhA. This inorganic complex represents a new class of lead compounds to the development of anti-tubercular agents aiming at inhibition of a validated target.
9 New Isoniazid Complexes, Promising Agents Against Mycobacterium
Tuberculosis (TB) is a public health disease that produces several million deaths annually worldwide. Due to this critical situation and the appearance of drug-resistant microbial strains, innovation in TB drug discovery is a research priority. In this work, the synthesis and characterization by elemental analysis, thermogravimetry, conductimetric measurements and spectroscopies UV-Vis, IR and EPR of [Cu(INH)(H 2 O)]SO 4 ⋅2H 2 O (Cu-INH) and [CoCl(INH) 2 (H 2 O)] Cl⋅2.5H 2 O (Co-INH) complexes with isoniazid (INH) are reported. Besides, the lipophilicity, the activity against Mycobacterium tuberculosis (MIC Cu-INH = 0.78 µg/mL and MIC Co-INH = 0.19 µg/mL) and the cytotoxicity (IC 50 = 48.8 and 625 µg/mL for the copper and cobalt complexes, respectively) were measured and the selectivity index (62.5 for Cu-INH and 3205 for Co-INH) was calculated. These results indicate that these complexes are good candidates for further studies.
Synthesis and molecular docking of isonicotinohydrazide derivatives as anti-tuberculosis candidates
Malaysian Journal of Fundamental and Applied Sciences
Tuberculosis (TB) is a chronic disease as a result of Mycobacterium tuberculosis. It can affect all age groups, and hence, is a global health problem that causes the death of millions of people every year. One of the drugs used in tuberculosis treatment is isonicotinohydrazide (Isoniazid). In this study, N'-benzoylisonicotinohydrazide derivative compounds (a-l) were prepared using acylation reactions between isonicotinohydrazide and benzoyl chloride derivatives, employing the reflux method. Molecular docking studies suggested that all of the compounds had better interaction with Mycobactarium tuberculosis enoyl-acyl carrier protein reductase (InhA) than isonicotinohydrazide. It can be concluded that N'-benzoylisonicotinohydrazide derivatives (a-l) can be used as anti-tuberculosis candidates. The docking results obtained revealed that all of the compounds were interacted well with InhA, with compound g exhibiting the best interaction.
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.
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.
Synthesis and Antimycobacterial Activity of a Novel Series of Isonicotinylhydrazide Derivatives
Archiv der Pharmazie, 2009
A series of eight N'-[(E)-(disubstituted-phenyl)methylidene]isonicotino-hydrazide derivatives were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory concentration (MIC) in µg/mL. Four compounds 2b-d and 2f exhibited a significant activity (0.6 µg/mL), when compared with first line drugs such as isoniazid (INH) and rifampin (RIP) and could be a good starting point to develop new lead compounds in the fight against multidrug resistant tuberculosis.