New lipophilic isoniazid derivatives and their 1,3,4-oxadiazole analogues: Synthesis, antimycobacterial activity and investigation of their mechanism of action

Vosátka, Rudolf; Krátký, Martin; Švarcová, Markéta; Janoušek, Jiří; Stolaříková, Jiřina; Madacki, Jan; Huszár, Stanislav; Mikušová, Katarı́na; Korduláková, Jana; Trejtnar, František

doi:10.1016/j.ejmech.2018.04.017

Cited by 34 publications

(16 citation statements)

References 31 publications

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“…Similar structure: antibacterial activity against Escherichia coli (Wang et al 2018a, b, c), anticancer activity against bladder cancer T-24 cells (Wu et al 2017), involved in the synthesis of antimycobacterial agent (Vosátka et al 2018); anti-tubercular activity (de Castro et al 2018), anti-inflammatory activity (Wrasidlo and Natala 2018)…”

Section: Resultsmentioning

confidence: 99%

Biologically active metabolite(s) from haemolymph of red-headed centipede Scolopendra subspinipes possess broad spectrum antibacterial activity

et al. 2019

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The discovery of novel antimicrobials from animal species under pollution is an area untapped. Chinese red-headed centipede is one of the hardiest arthropod species commonly known for its therapeutic value in traditional Chinese medicine. Here we determined the antibacterial activity of haemolymph and tissue extracts of red-headed centipede, Scolopendra subspinipes against a panel of Gram-positive and Gram-negative bacteria. Lysates exhibited potent antibacterial activities against a broad range of bacteria tested. Chemical characterization of biologically active molecules was determined via liquid chromatography mass spectrometric analysis. From crude haemolymph extract, 12 compounds were identified including: (1) l -Homotyrosine, (2) 8-Acetoxy-4-acoren-3-one, (3) N -Undecylbenzenesulfonic acid, (4) 2-Dodecylbenzenesulfonic acid, (5) 3 H -1,2-Dithiole-3-thione, (6) Acetylenedicarboxylate, (7) Albuterol, (8) Tetradecylamine, (9) Curcumenol, (10) 3-Butylidene-7-hydroxyphthalide, (11) Oleoyl Ethanolamide and (12) Docosanedioic acid. Antimicrobial activities of the identified compounds were reported against Gram-positive and Gram-negative bacteria, fungi, viruses and parasites, that possibly explain centipede’s survival in harsh and polluted environments. Further research in characterization, molecular mechanism of action and in vivo testing of active molecules is needed for the development of novel antibacterials.

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Section: Resultsmentioning

confidence: 99%

Biologically active metabolite(s) from haemolymph of red-headed centipede Scolopendra subspinipes possess broad spectrum antibacterial activity

et al. 2019

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“…Analogously to our previous works [11,12], hydrazine-1-carboxamides were obtained using three synthetic approaches. Most of the derivatives (2b-2i, 2k, 2l, 2n, 2p-2q) were prepared from commercially available isocyanates and the hydrazide 1 in acetonitrile.…”

Section: Chemistrymentioning

confidence: 99%

“…What is more, N 2 -substituted derivatives of 4-(trifluoro-methyl) benzohydrazide (1) have been reported as antibacterial molecules effective against both Mycobacterium tuberculosis and nontuberculous mycobacteria [4][5][6], Gram-positive cocci including methicillin-resistant Staphylococcus aureus, yeasts and molds [4], anticonvulsants [7,8], cytostatic/antiproliferative and cytotoxic [9,10], metal-chelating [5,10] or anti-inflammatory agents [9]. That is why we applied this approach of also for biologically active N-alkyl-2-isonicotinoylhydrazine-1-carboxamides [11,12] using replacement of INH scaffold by isosteric 4-(trifluoromethyl)hydrazide 1 (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity

et al. 2020

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Based on the isosterism concept, we have designed and synthesized homologous N-alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (from C1 to C18) as potential antimicrobial agents and enzyme inhibitors. They were obtained from 4-(trifluoromethyl)benzohydrazide by three synthetic approaches and characterized by spectral methods. The derivatives were screened for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) via Ellman’s method. All the hydrazinecarboxamides revealed a moderate inhibition of both AChE and BuChE, with IC50 values of 27.04–106.75 µM and 58.01–277.48 µM, respectively. Some compounds exhibited lower IC50 for AChE than the clinically used drug rivastigmine. N-Tridecyl/pentadecyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides were identified as the most potent and selective inhibitors of AChE. For inhibition of BuChE, alkyl chain lengths from C5 to C7 are optimal substituents. Based on molecular docking study, the compounds may work as non-covalent inhibitors that are placed in a close proximity to the active site triad. The compounds were evaluated against Mycobacterium tuberculosis H37Rv and nontuberculous mycobacteria (M. avium, M. kansasii). Reflecting these results, we prepared additional analogues of the most active carboxamide (n-hexyl derivative 2f). N-Hexyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-amine (4) exhibited the lowest minimum inhibitory concentrations within this study (MIC ≥ 62.5 µM), however, this activity is mild. All the compounds avoided cytostatic properties on two eukaryotic cell lines (HepG2, MonoMac6).

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“…The active forms of INH shown different effects on the cell wall mycolic acids synthesis [ 18 ], on nucleic acids replication/transcription [ 19 ], and on bacterial respiratory metabolism, as well [ 20 ]. All this time, it never been completely discovered the complex mechanism of action of isoniazid as prodrug [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, for slow acetylators the risk for hepatotoxic effects occurrence is possible due to high concentrations of isoniazid metabolites [ 24 , 29 , 30 ]. Literature [ 22 , 31 , 32 ] revealed that the any change added to isoniazid molecule such as the inclusion of a functional group to the hydrazine structure could block the acetylation of the drug by NATs, therefore influencing its activity and toxicity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, and Biologic Activity of New Acyl Hydrazides and 1,3,4-Oxadiazole Derivatives

et al. 2020

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Starting from isoniazid and carboxylic acids as precursors, thirteen new hydrazides and 1,3,4-oxadiazoles of 2-(4-substituted-phenoxymethyl)-benzoic acids were synthesized and characterized by appropriate means. Their biological properties were evaluated in terms of apoptosis, cell cycle blocking, and drug metabolism gene expression on HCT-8 and HT-29 cell lines. In vitro antimicrobial tests were performed by the microplate Alamar Blue assay for the anti-mycobacterial activities and an adapted agar disk diffusion technique for other non-tubercular bacterial strains. The best antibacterial activity (anti-Mycobacterium tuberculosis effects) was proved by 9. Compounds 7, 8, and 9 determined blocking of G1 phase. Compound 7 proved to be toxic, inducing apoptosis in 54% of cells after 72 h, an effect that can be predicted by the increased expression of mRNA caspases 3 and 7 after 24 h. The influence of compounds on gene expression of enzymes implicated in drug metabolism indicates that synthesized compounds could be metabolized via other pathways than NAT2, spanning adverse effects of isoniazid. Compound 9 had the best antibacterial activity, being used as a disinfectant agent. Compounds 7, 8, and 9, seemed to have antitumor potential. Further studies on the action mechanism of these compounds on the cell cycle may bring new information regarding their biological activity.

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New lipophilic isoniazid derivatives and their 1,3,4-oxadiazole analogues: Synthesis, antimycobacterial activity and investigation of their mechanism of action

Cited by 34 publications

References 31 publications

Biologically active metabolite(s) from haemolymph of red-headed centipede Scolopendra subspinipes possess broad spectrum antibacterial activity

Biologically active metabolite(s) from haemolymph of red-headed centipede Scolopendra subspinipes possess broad spectrum antibacterial activity

N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity

Synthesis, Characterization, and Biologic Activity of New Acyl Hydrazides and 1,3,4-Oxadiazole Derivatives

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