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
• Názvy látek
• antituberkulotika * MeSH
• oxadiazoly * MeSH

Tuberculosis remains a leading global health threat, exacerbated by the emergence of multi-drug-resistant strains. The search for novel therapeutic agents is critical in addressing this challenge. This review systematically summarizes the potential of oxadiazole derivatives as promising candidates in antimycobacterial drug discovery. We focus on various classes of oxadiazoles, especially 1,2,3-oxadiazoles, 1,2,4-oxadiazoles, and 1,2,5-s in structure-activity relationship studies are discussed, emphasizing the mechanisms of antimycobacterial action. Additionally, the synergistic potential of 1,2,4-oxadiazoles in enhancing the efficacy of existing tuberculosis treatment with ethionamide is also discussed. By integrating insights from recent research, this review aims to provide a comprehensive overview of the role of oxadiazoles in the fight against tuberculosis, paving the way for future investigations and the development of effective therapeutic strategies.

• Klíčová slova
• 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, Mycobacterium tuberculosis, ethionamide-boosting effect,
• MeSH
• antituberkulotika * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis * účinky léků   MeSH
• objevování léků * MeSH
• oxadiazoly * chemie   farmakologie   chemická syntéza   MeSH
• tuberkulóza * farmakoterapie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH
• Názvy látek
• antituberkulotika * MeSH
• oxadiazoly * MeSH

A small library of 2-[(1H-indol-3-yl)methyl]-5-(alkylthio)-1,3,4-oxadiazoles was prepared, starting from indole-3-acetic acid methyl ester and its 5-methyl-substituted derivative. The synthetic route involved the formation of intermediate hydrazides, their condensation with carbon disulfide, and intramolecular cyclization to corresponding 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones. The latter were then S-alkylated, and in case of ester derivatives, they were further hydrolyzed into corresponding carboxylic acids. All 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones and their S-alkylated derivatives were then screened for their protective effects in vitro and in vivo. Methyl substitution on the indole ring and propyl, butyl, or benzyl substitution on sulfhydryl group-possessing compounds were revealed to protect Friedreich's ataxia fibroblasts against the effects of glutathione depletion induced by the γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine. Two of the active compounds also reproducibly increased the survival of Caenorhabditis elegans exposed to juglone-induced oxidative stress.

• Klíčová slova
• Caenorhabditis elegans, Friedreich's ataxia, indole, oxadiazole, oxidative stress,
• MeSH
• acetáty chemická syntéza   MeSH
• antioxidancia * chemická syntéza   chemie   farmakologie   MeSH
• Caenorhabditis elegans MeSH
• Friedreichova ataxie farmakoterapie   metabolismus   patologie   MeSH
• indoly * chemie   farmakologie   MeSH
• kultivované buňky MeSH
• kyseliny indoloctové chemie   MeSH
• lidé MeSH
• oxadiazoly * chemická syntéza   chemie   farmakologie   MeSH
• oxidační stres účinky léků   MeSH
• thioketony * chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetáty MeSH
• antioxidancia * MeSH
• indole MeSH Prohlížeč
• indoleacetic acid MeSH Prohlížeč
• indoly * MeSH
• kyseliny indoloctové MeSH
• oxadiazoly * MeSH
• thioketony * MeSH

The development of novel drugs is essential for the treatment of tuberculosis and other mycobacterial infections in future. A series of N-alkyl-2-isonicotinoylhydrazine-1-carboxamides was synthesized from isoniazid (INH) and then cyclized to N-alkyl-5-(pyridin-4-yl)-1,3,4-oxadiazole-2-amines. All derivatives were characterised spectroscopically. The compounds were screened for their in vitro antimycobacterial activity against susceptible and multidrug-resistant Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM; M. avium, M. kansasii). The most active carboxamides were substituted by a short n-alkyl, their activity was comparable to INH with minimum inhibitory concentrations (MICs) against Mtb. of 0.5-2 μM. Moreover, they are non-toxic for HepG2, and some of them are highly active against INH-resistant NTM (MICs ≥4 μM). Their cyclization to 1,3,4-oxadiazoles did not increase the activity. The experimentally proved mechanism of action of 2-isonicotinoylhydrazine-1-carboxamides consists of the inhibition of enoyl-ACP reductase (InhA) in a way similar to INH, which is blocking the biosynthesis of mycolic acids. N-Dodecyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amine as the most efficacious oxadiazole inhibits growth of both susceptible and drug-resistant Mtb. strains with uniform MIC values of 4-8 μM with no cross-resistance to antitubercular drugs including INH. The mechanism of action is not elucidated but it is different from INH. Obtained results qualify these promising derivatives for further investigation.

• Klíčová slova
• 1,3,4-oxadiazole, 2-isonicotinoylhydrazine-1-carboxamide, Antimycobacterial activity, Isoniazid, Mycobacterium tuberculosis, Tuberculosis,
• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• bakteriální léková rezistence MeSH
• buňky Hep G2 MeSH
• isoniazid analogy a deriváty   chemická syntéza   farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• oxadiazoly chemická syntéza   chemie   farmakologie   MeSH
• tuberkulóza farmakoterapie   mikrobiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,3,4-oxadiazole MeSH Prohlížeč
• antituberkulotika MeSH
• isoniazid MeSH
• oxadiazoly MeSH

In this work, four series of tertiary amine-containing derivatives of 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. We found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. The N-benzylpiperazine derivatives, which had the highest lipophilicity among all of the series, showed the highest in vitro antimycobacterial activities against Mycobacterium tuberculosis CNCTC My 331/88 (H37Rv), comparable to those of the first-line drugs isoniazid and rifampicin. The presence of two tertiary amines in these N-benzylpiperazine derivatives enabled us to prepare water-soluble dihydrochloride salts, overcoming the serious drawback of previously described 3,5-dinitrophenyl tetrazole and oxadiazole lead compounds. The water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents described in this work are good candidates for further in vitro and in vivo pharmacokinetic and pharmacodynamic studies.

• Klíčová slova
• Antitubercular agent, Lipophilicity, Mycobacterium tuberculosis, Solubility, Structure-activity relationships, Tuberculosis,
• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• buňky Hep G2 MeSH
• Caco-2 buňky MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• oxadiazoly chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk MeSH
• rozpustnost MeSH
• tetrazoly chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk MeSH
• voda chemie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antituberkulotika MeSH
• oxadiazoly MeSH
• tetrazoly MeSH
• voda MeSH