This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring. This series brought two new compounds (21: R = 2-F, 4-Cl and 22: R = 2-F, 4-Br) with in vitro activity against Mycobacterium tuberculosis H37Rv as well as multidrug-resistant clinical isolates, with minimum inhibitory concentration ranging from 6.25 to 25 μg/mL. The lactone-type derivatives 4H-pyrazino[2,3-d][1,3]oxazin-4-ones (Series-3) were inactive, but solvent stability studies of compound 29 indicated that they might be developed to usable lactone prodrugs of inhibitors of mycobacterial aspartate decarboxylase (PanD).

• MeSH
• aminoacyl-tRNA-synthetasy antagonisté a inhibitory   metabolismus   MeSH
• antituberkulotika * farmakologie   chemie   chemická syntéza   MeSH
• inhibitory enzymů farmakologie   chemie   chemická syntéza   MeSH
• mikrobiální testy citlivosti * MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis * účinky léků   enzymologie   MeSH
• pyraziny farmakologie   chemie   chemická syntéza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH

A series of N-pyridinylbenzamides was designed and prepared to investigate the influence of isosterism and positional isomerism on antimycobacterial activity. Comparison to previously published isosteric N-pyrazinylbenzamides was made as an attempt to draw structure-activity relationships in such type of compounds. In total, we prepared 44 different compounds, out of which fourteen had minimum inhibitory concentration (MIC) values against Mycobacterium tuberculosis H37Ra below 31.25 μg/ml, most promising being N-(5-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (23) and N-(6-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (24) with MIC = 7.81 μg/ml (26 μm). Five compounds showed broad-spectrum antimycobacterial activity against M. tuberculosis H37Ra, M. smegmatis and M. aurum. N-(pyridin-2-yl)benzamides were generally more active than N-(pyridin-3-yl)benzamides, indicating that N-1 in the parental structure of N-pyrazinylbenzamides might be more important for antimycobacterial activity than N-4. Marginal antibacterial and antifungal activity was observed for title compounds. The hepatotoxicity of title compounds was assessed in vitro on hepatocellular carcinoma cell line HepG2, and they may be considered non-toxic (22 compounds with IC50 over 200 μm).

• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• Aspergillus účinky léků   MeSH
• benzamidy chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• Candida albicans účinky léků   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium smegmatis účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Based on successful antitubercular isoniazid scaffold we have designed its "mee-too" analogues by a combination of this drug linked with substituted anilines through pyruvic acid as a bridge. Lipophilicity important for passive diffusion through impenetrable mycobacterial cell wall was increased by halogen substitution on the aniline. We prepared twenty new 2-(2-isonicotinoylhydrazineylidene)propanamides that were assayed against susceptible Mycobacterium tuberculosis H37Rv, nontuberculous mycobacteria, and also multidrug-resistant tuberculous strains (MDR-TB). All the compounds showed excellent activity not only against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.03 μM), but also against M. kansasii (MIC ≥2 μM). The most active molecules have CF3 and OCF3 substituent in the position 4 on the aniline ring. MIC against MDR-TB were from 8 μM. The most effective derivatives were used for the mechanism of action investigation. The treatment of Mtb. H37Ra with tested compounds led to decreased production of mycolic acids and the strains overproducing InhA were more resistant to them. These results confirm that studied compounds inhibit the enoyl-acyl carrier protein reductase (InhA) in mycobacteria. The compounds did not show any cytotoxic and cytostatic activity for HepG2 cells. The amides can be considered as a promising scaffold for antitubercular drug discovery having better antimicrobial properties than original isoniazid together with a significantly improved pharmaco-toxicological profile.

• MeSH
• amidy chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• aniliny chemie   MeSH
• antituberkulotika chemická syntéza   metabolismus   farmakologie   terapeutické užití   MeSH
• bakteriální léková rezistence účinky léků   MeSH
• bakteriální proteiny antagonisté a inhibitory   metabolismus   MeSH
• buňky Hep G2 MeSH
• kyselina pyrohroznová chemie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis účinky léků   metabolismus   MeSH
• oxidoreduktasy antagonisté a inhibitory   metabolismus   MeSH
• racionální návrh léčiv * MeSH
• tuberkulóza farmakoterapie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Zinc metalloprotease 1 (Zmp1) is an extracellular enzyme, which has been found essential for the intracellular survival and pathogenesis of Mycobacterium tuberculosis. In this work, we designed and synthesized a series of novel thiazolidinedione-hydroxamates and evaluated in silico their drug-likeness behavior. Then, their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis were analyzed by MALDI-TOF MS. Nine of the tested compounds were found to inhibit the enzymatic reaction more effectively than the generic metalloprotease inhibitor phosphoramidon. Furthermore, the synthesized thiazolidinedione-hydroxamate hybrids were evaluated for their in vitro antimycobacterial activity and acute cytotoxicity using whole-cell assays. Results showed that none of the hybrids exhibited acute cytotoxicity against RAW264.7 macrophages. Whereas extracellular antimycobacterial activity was limited, RAW264.7 macrophage infection results showed that a majority of the hybrids inhibited the intracellular growth of Mycobacterium tuberculosis at a concentration of 100 and 10 μM. The thiazolidinedione-hydroxamate compound 2n was considered to be the best candidate of the evaluated library.

• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• bakteriální proteiny antagonisté a inhibitory   metabolismus   MeSH
• kyseliny hydroxamové chemie   farmakologie   MeSH
• lidé MeSH
• metaloproteasy antagonisté a inhibitory   metabolismus   MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   enzymologie   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• thiazolidindiony chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.

• MeSH
• antituberkulotika chemická syntéza   metabolismus   farmakologie   toxicita   MeSH
• Cercopithecus aethiops MeSH
• fenothiaziny chemická syntéza   metabolismus   farmakologie   toxicita   MeSH
• HEK293 buňky MeSH
• inhibitory enzymů chemická syntéza   metabolismus   farmakologie   toxicita   MeSH
• jaterní mikrozomy metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• Mycobacterium smegmatis účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• NADH-dehydrogenasa antagonisté a inhibitory   MeSH
• organoselenové sloučeniny chemická syntéza   metabolismus   farmakologie   toxicita   MeSH
• parazitické testy citlivosti MeSH
• receptory dopaminu D2 metabolismus   MeSH
• receptory serotoninové metabolismus   MeSH
• synergismus léků MeSH
• vazba proteinů MeSH
• Vero buňky MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

By understanding the rampant infections of Mycobacterium tuberculosis (Mtb) and inflammations caused due to the generation of radical species during the Mtb infection, a series of (E)-2-(2-allylidenehydrazinyl)thiazole derivatives, with dual-action properties, was designed. The molecules were designed with a considerable variation in LogP, one of the critical parameters in physicochemical properties, and analyzed for their drug-likeness. For the synthesis, a simple, green, and multicomponent one-pot synthesis method was developed. The in vitro inhibition potentials were evaluated against Mtb H37 Rv by the microplate Alamar Blue assay. The results reveal that compound 6 was potent, with a MIC value of 6.5 µg/ml, and showed better interactions with the KasA protein with binding free energy (ΔG) of -9.4 kcal/mol. Also, the radical scavenging properties were studied to establish the dual-action properties of the molecules. Compound 9 exhibited promising antioxidant and nitric oxide radical scavenging activities, with 81.7% and 81.0%, respectively, at 1,000-μg/ml concentration.

• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• racionální návrh léčiv * MeSH
• scavengery volných radikálů chemická syntéza   chemie   farmakologie   MeSH
• thiazoly chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH

According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by Mycobacterium tuberculosis against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino-N-phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. smegmatis, M. kansasii, M. avium) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against M. tuberculosis H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, N-(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (3c, MIC = 3.91 μg/mL or 13.02 μM, SI > 38) and 5-(heptylamino)-N-(p-tolyl)pyrazine-2-carboxamide (4e, MIC = 0.78 μg/mL or 2.39 μM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the Candida genus.

• MeSH
• antituberkulotika chemická syntéza   chemie   izolace a purifikace   farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• pyrazinamid chemie   MeSH
• pyraziny chemie   MeSH
• racionální návrh léčiv MeSH
• vyvíjení léků MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

We prepared a series of substituted N-(pyrazin-2-yl)benzenesulfonamides as an attempt to investigate the effect of different linkers connecting pyrazine to benzene cores on antimicrobial activity when compared to our previous compounds of amide or retro-amide linker type. Only two compounds, 4-amino-N-(pyrazin-2-yl)benzenesulfonamide (MIC = 6.25 μg/mL, 25 μM) and 4-amino-N-(6-chloropyrazin-2-yl)benzenesulfonamide (MIC = 6.25 μg/mL, 22 μM) exerted good antitubercular activity against M. tuberculosis H37Rv. However, they were excluded from the comparison as they-unlike the other compounds-possessed the pharmacophore for the inhibition of folate pathway, which was proven by docking studies. We performed target fishing, where we identified matrix metalloproteinase-8 as a promising target for our title compounds that is worth future exploration.

• MeSH
• antiinfekční látky chemická syntéza   chemie   farmakologie   MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• chemické jevy MeSH
• mikrobiální testy citlivosti MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• sulfonamidy chemická syntéza   chemie   farmakologie   MeSH
• techniky syntetické chemie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH

We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.

• MeSH
• alkoholoxidoreduktasy antagonisté a inhibitory   metabolismus   MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• bakteriální proteiny antagonisté a inhibitory   metabolismus   MeSH
• dinitrobenzeny chemická syntéza   chemie   farmakologie   MeSH
• fluorované uhlovodíky chemická syntéza   chemie   farmakologie   MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   enzymologie   MeSH
• triazoly chemická syntéza   chemie   farmakologie   MeSH
• vyvíjení léků * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H37Ra, H37Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 μM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 μM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 μM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.

• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• fenoly chemická syntéza   chemie   farmakologie   MeSH
• isocitrátlyasa antagonisté a inhibitory   metabolismus   MeSH
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• Mycobacterium tuberculosis účinky léků   enzymologie   MeSH
• salicylanilidy chemická syntéza   chemie   farmakologie   MeSH
• tuberkulóza farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH