BACKGROUND: There is an urgent need for new antitubercular compounds. Modification of antimycobacterial isonicotinohydrazide at hydrazide N2 provided antimycobacterial active compounds. OBJECTIVE: Combining this scaffold with various aliphatic amines that are also frequently present in antitubercular compounds, we have designed, synthesized, and evaluated twenty-three N- (cyclo)alkyl-2-(2-isonicotinoylhydrazineylidene)propanamides and their analogues as potential antimycobacterial compounds. By increasing lipophilicity, we intended to facilitate the penetration of mycobacteria's highly impermeable cell wall. METHODS: The target amides were prepared via condensation of isoniazid and pyruvic acid, followed by carbodiimide-mediated coupling with yields from 35 to 98 %. The compounds were screened against Mycobacterium tuberculosis H37Rv and two nontuberculous mycobacteria (M. avium, M. kansasii). RESULTS: All the derivatives exhibited low minimum inhibitory concentrations (MIC) from ≤0.125 and 2 μM against M. tuberculosis and nontuberculous mycobacteria, respectively. The most active molecules were substituted by a longer n-alkyl from C8 to C14. Importantly, the compounds showed comparable or even several-fold lower MIC than parent isonicotinohydrazide. Based on in silico predictions, a vast majority of the derivatives share suitable physicochemical properties and structural features for drug-likeness. CONCLUSION: Presented amides are promising antimycobacterial agents.

• Keywords
• Amides, Antimycobacterial activity, Hydrazides, Hydrazones, Isoniazid, Pyruvic acid, Tuberculosis.,
• MeSH
• Amides pharmacology   MeSH
• Amines pharmacology   MeSH
• Antitubercular Agents chemistry   MeSH
• Isoniazid * pharmacology   chemistry   MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium tuberculosis * MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amides MeSH
• Amines MeSH
• Antitubercular Agents MeSH
• Isoniazid * MeSH

The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H37Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.125 μM), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.

• Keywords
• InhA, antimycobacterial activity, enzyme inhibition, esters, isoniazid, mechanism of action, mutual prodrugs,
• Publication type
• Journal Article MeSH

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).

• Keywords
• 4-(trifluoromethyl)benzohydrazide, acetylcholinesterase inhibition, antimycobacterial activity, butyrylcholinesterase inhibition, cytostatic properties, hydrazides,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Anti-Infective Agents * chemical synthesis   chemistry   pharmacology   MeSH
• Hep G2 Cells MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors * chemical synthesis   chemistry   pharmacology   MeSH
• GPI-Linked Proteins metabolism   MeSH
• Imidazoles * chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Mycobacterium avium growth & development   MeSH
• Mycobacterium kansasii growth & development   MeSH
• Mycobacterium tuberculosis growth & development   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• ACHE protein, human MeSH Browser
• Anti-Infective Agents * MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors * MeSH
• GPI-Linked Proteins MeSH
• Imidazoles * MeSH

Infections caused by Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of 4-(3-heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulfonamide against NTM, we designed a series of homologous sulfamethoxazole-based n-alkyl ureas (C₁-C12), as well as several related ureas and an oxalamide. Fifteen ureas and one oxalamide were synthesized by five synthetic procedures and characterized. They were screened for their activity against Mtb. and three NTM strains (M. avium, M. kansasii). All of them share antimycobacterial properties with minimum inhibitory concentration (MIC) values starting from 2 µM. The highest activity showed 4,4'-[carbonylbis(azanediyl)]bis[N-(5-methylisoxazol-3-yl)benzenesulfonamide] with MIC of 2-62.5 µM (i.e., 1.07-33.28 µg/mL). Among n-alkyl ureas, methyl group is optimal for the inhibition of both Mtb. and NTM. Generally, longer alkyls led to increased MIC values, heptyl being an exception for NTM. Some of the novel derivatives are superior to parent sulfamethoxazole. Several urea and oxalamide derivatives are promising antimycobacterial agents with low micromolar MIC values.

• Keywords
• antimycobacterial activity, in vitro activity, oxalamide, sulfamethoxazole, sulfonamides, tuberculosis, ureas,
• MeSH
• Anti-Bacterial Agents chemical synthesis   chemistry   pharmacology   MeSH
• Microbial Sensitivity Tests MeSH
• Urea chemical synthesis   chemistry   pharmacology   MeSH
• Molecular Structure MeSH
• Mycobacterium drug effects   MeSH
• Sulfamethoxazole chemical synthesis   chemistry   pharmacology   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Urea MeSH
• Sulfamethoxazole MeSH

A series of N-alkyl-3-(alkylamino)pyrazine-2-carboxamides and their N-alkyl-3-chloropyrazine-2-carboxamide precursors were prepared. All compounds were characterized by analytical methods and tested for antimicrobial and antiviral activity. The antimycobacterial MIC values against Mycobacterium tuberculosis H37Rv of the most effective compounds, 3-(hexylamino)-, 3-(heptylamino)- and 3-(octylamino)-N-methyl-pyrazine-2-carboxamides 14‒16, was 25 μg/mL. The compounds inhibited photosystem 2 photosynthetic electron transport (PET) in spinach chloroplasts. This activity was strongly connected with the lipophilicity of the compounds. For effective PET inhibition longer alkyl chains in the 3-(alkylamino) substituent in the N-alkyl-3-(alkylamino)pyrazine-2-carboxamide molecule were more favourable than two shorter alkyl chains.

• Keywords
• alkylation, aminodehalogenation, antimycobacterial activity, inhibition of photosynthetic electron transport, pyrazinamide, pyrazine, structure-activity relationships,
• MeSH
• Antitubercular Agents chemical synthesis   pharmacology   MeSH
• Bacterial Proteins antagonists & inhibitors   metabolism   MeSH
• Chloroplasts metabolism   MeSH
• Microbial Sensitivity Tests MeSH
• Mycobacterium tuberculosis drug effects   metabolism   MeSH
• Pyrazinamide chemical synthesis   chemistry   pharmacology   MeSH
• Pyrazines chemical synthesis   pharmacology   MeSH
• Spinacia oleracea metabolism   MeSH
• Fatty Acid Synthases antagonists & inhibitors   metabolism   MeSH
• Electron Transport drug effects   MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antitubercular Agents MeSH
• Bacterial Proteins MeSH
• fatty acid synthase I, mycobacteria MeSH Browser
• Pyrazinamide MeSH
• Pyrazines MeSH
• Fatty Acid Synthases MeSH