Drug resistance is a growing problem for many pathogens, including mycobacteria. Small heterocyclic molecules are among the leading scaffolds for developing potential antimycobacterial agents. Therefore, based on the molecular hybridization approach, we have prepared an extensive series of N-substituted 5-(3,5-dinitrophenyl)-1,3,4-oxadiazol-2-amine derivatives. We also investigated their isosteres and acyclic synthetic precursors. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis (Mtb) H37Rv, a panel of multidrug- and extensively drug-resistant Mtb isolates and two nontuberculous mycobacterial strains (NTM; M. avium and M. kansasii). The ability to inhibit mycobacterial growth was quantified using minimum inhibitory concentration (MIC) values. Many compounds achieved MIC values ≤ 0.03 μM for NTM and Mtb, regardless of their resistance profile. The highest activity was associated with oxadiazole and thiadiazole scaffolds with benzylamino or C5-C9 alkylamino substitution. The experimentally confirmed mechanism of action of these compounds consists of disruption of mycobacterial cell wall biosynthesis via inhibition of decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1). In vitro toxicity evaluation was performed in a hepatocyte model (HepG2), while in vivo toxicity was evaluated using Danio rerio embryos. These findings identify a promising new chemotype with potent, broad-spectrum and selective antimycobacterial activity, including efficacy against resistant strains, and support its further development as a potential therapeutic candidate.

• MeSH
• antituberkulotika * farmakologie   chemická syntéza   chemie   toxicita   MeSH
• dánio pruhované MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• oxadiazoly * farmakologie   chemická syntéza   chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata 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

New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 μM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 μM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 μM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 μM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 μM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.

• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   toxicita   MeSH
• buňky 3T3 MeSH
• chalkonoidy chemická syntéza   chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   toxicita   MeSH
• screeningové testy protinádorových léčiv MeSH
• sulfonamidy chemická syntéza   chemie   farmakologie   toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 μM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.

• MeSH
• antifungální látky chemická syntéza   chemie   farmakologie   toxicita   MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   toxicita   MeSH
• buňky Hep G2 MeSH
• léková rezistence účinky léků   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• oxadiazoly chemie   MeSH
• racionální návrh léčiv * MeSH
• sulfhydrylové sloučeniny chemická syntéza   chemie   farmakologie   toxicita   MeSH
• tetrazoly chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Herein, we report the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (0.011-0.026 μg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest.

• MeSH
• antituberkulotika chemická syntéza   farmakologie   toxicita   MeSH
• Bacteria účinky léků   MeSH
• buněčné linie MeSH
• houby účinky léků   MeSH
• latentní tuberkulóza farmakoterapie   mikrobiologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mikrozomy metabolismus   MeSH
• mnohočetná bakteriální léková rezistence MeSH
• mutageny toxicita   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• oxazoly chemická syntéza   farmakologie   MeSH
• primární buněčná kultura MeSH
• racionální návrh léčiv MeSH
• rifampin farmakologie   MeSH
• thiadiazoly chemická syntéza   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

5-Chloropyrazinamide (5-Cl-PZA) is an inhibitor of mycobacterial fatty acid synthase I with a broad spectrum of antimycobacterial activity in vitro. Some N-phenylpyrazine-2-carboxamides with different substituents on both the pyrazine and phenyl core possess significant in vitro activity against Mycobacterium tuberculosis. To test the activity of structures combining both the 5-Cl-PZA and anilide motifs a series of thirty 5-chloro-N-phenylpyrazine-2-carboxamides with various substituents R on the phenyl ring were synthesized and screened against M. tuberculosis H37Rv, M. kansasii and two strains of M. avium. Most of the compounds exerted activity against M. tuberculosis H37Rv in the range of MIC = 1.56-6.25 µg/mL and only three derivatives were inactive. The phenyl part of the molecule tolerated many different substituents while maintaining the activity. In vitro cytotoxicity was decreased in compounds with hydroxyl substituents, preferably combined with other hydrophilic substituents. 5-Chloro-N-(5-chloro-2-hydroxyphenyl)pyrazine-2-carboxamide (21) inhibited all of the tested strains (MIC = 1.56 µg/mL for M. tuberculosis; 12.5 µg/mL for other strains). 4-(5-Chloropyrazine-2-carboxamido)-2-hydroxybenzoic acid (30) preserved good activity (MIC = 3.13 µg/mL M. tuberculosis) and was rated as non-toxic in two in vitro models (Chinese hamster ovary and renal cell adenocarcinoma cell lines; SI = 47 and 35, respectively).

• MeSH
• antifungální látky chemická syntéza   farmakologie   MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   toxicita   MeSH
• buněčné linie MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• hydrofobní a hydrofilní interakce MeSH
• inhibiční koncentrace 50 MeSH
• křečci praví MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium účinky léků   MeSH
• nádorové buněčné linie MeSH
• pyrazinamid analogy a deriváty   chemická syntéza   chemie   farmakologie   toxicita   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The increasing emergence especially of drug-resistant tuberculosis has led to a strong demand for new anti-tuberculosis drugs. Eighteen salicylanilide benzoates were evaluated for their inhibition potential against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii; minimum inhibitory concentration values ranged from 0.5 to 16 μmol/L. The most active esters underwent additional biological assays. Four benzoates inhibited effectively the growth of five multidrug-resistant strains and one extensively drug-resistant strain of M. tuberculosis at low concentrations (0.25–2 μmol/L) regardless of the resistance patterns. The highest rate of multidrug-resistant mycobacteria inhibition expressed 4-chloro-2-[4-(trifluoromethyl)-phenylcarbamoyl]phenyl benzoate (0.25–1 μmol/L). Unfortunately, the most potent esters were still considerably cytotoxic, although mostly less than their parent salicylanilides.

• MeSH
• antituberkulotika farmakologie   toxicita   MeSH
• benzoáty farmakologie   toxicita   MeSH
• buňky Hep G2 MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• mnohočetná bakteriální léková rezistence MeSH
• Mycobacterium avium účinky léků   MeSH
• Mycobacterium kansasii účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• salicylanilidy farmakologie   toxicita   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Autoři prezentují velmi vzácný případ mimoplicní tuberkulózy u 14leté pacientky ze Somálska. Dívka byla přijata na Pediatrickou kliniku IPVZ v těžkém stavu pro rozsáhlou multicystickou intraabdominální expanzi a výraznou kachexii s podezřením na tumor. Histologické vyšetření mezenteria s následným pozitivním kultivačním nálezem prokázaly tuberkulózní etiologii. Tomu odpovídal i silně pozitivní tuberkulinový test. Jednalo se o TBC mezenteriálních uzlin a mezenteria s ohraničeným peritoneálním výpotkem. Zdroj onemocnění se nepodařilo prokázat. Při léčbě čtyřkombinací antituberkulotik spolu s kortikoidy vznikla přechodně toxická hepatopatie a porucha koagulace, které ustoupily po dočasném přerušení léčby. Po znovunasazení antituberkulotik již dívka léčbu snášela dobře. Po dvou měsících se klinický stav výrazně zlepšil a nitrobřišní nález ustupoval, což prokázala kontrolní magnetická rezonance. Dívka byla převedena na ambulantní léčbu, kterou i nadále snášela dobře. Léčba trvala celkem devět měsíců. Nyní žije v Nigérii, dle sdělení otce se cítí dobře. Při kontrolní sonografii břicha tam měla již normální nález.

Authors present a rare case of extrapulmonary tuberculosis in a 14 years old girl from Somalia. She was admitted to the Pediatric department of Thomayer Teaching Hospital in a serious status for large multicystic intraabdominal expansion suspicious from tumor. Histological and microbiological findings confirmed tuberculous etiology, which corresponded with positive tuberculin test. The diagnosis of tuberculosis of mesenterial lymphnodes with peritoneal ascites was set down. Reservoir of the infection was not found. The treatment with combination of four antituberculous drugs was complicated by transient hepatopathy and coagulopathy. The treatment was therefore temporary stopped. Its renewal proved after two months of duration an ameliorated clinical status and an improved result of NMR. The treatment was finished after nine month. This girl actually lives in Nigeria. As for report of her father she feels good and her abdomen sonography is physiological.

• Klíčová slova
• mimoplicní tuberkulóza, TBC mezenteriálních uzlin, TBC peritonitis, léčba TBC,
• MeSH
• antituberkulotika škodlivé účinky   terapeutické užití   toxicita   MeSH
• břišní dutina chirurgie   mikrobiologie   patologie   MeSH
• diferenciální diagnóza MeSH
• lidé MeSH
• mezenterium mikrobiologie   patologie   MeSH
• mladiství MeSH
• tuberkulóza epidemiologie   klasifikace   mikrobiologie   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• antifungální látky farmakologie   imunologie   toxicita   MeSH
• antituberkulotika farmakologie   imunologie   toxicita   MeSH
• Candida albicans účinky léků   MeSH
• farmaceutická technologie MeSH
• financování organizované MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie metody   přístrojové vybavení   MeSH
• mikrovlny MeSH
• Mycobacterium avium účinky léků   MeSH
• Mycobacterium kansasii účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• statistika jako téma MeSH
• thioamidy farmakologie   MeSH
• thioketony farmakologie   MeSH
• triaziny farmakologie   MeSH
• Trichophyton účinky léků   MeSH
• Check Tag
• lidé MeSH

• MeSH
• alkany farmakologie   MeSH
• antifungální látky farmakologie   imunologie   toxicita   MeSH
• antituberkulotika farmakologie   imunologie   toxicita   MeSH
• azetidiny farmakologie   MeSH
• benzothiazoly farmakologie   MeSH
• cyklohexany farmakologie   MeSH
• financování organizované MeSH
• ketony farmakologie   MeSH
• lidé MeSH
• Mycobacterium avium účinky léků   MeSH
• Mycobacterium kansasii účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• objevování léků metody   MeSH
• skvalen analogy a deriváty   farmakologie   MeSH
• statistika jako téma MeSH
• Check Tag
• lidé MeSH