Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra, M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strains, including Candida albicans and Aspergillus flavus. Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 µM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing ʟ-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-ᴅ/ʟ-Pgl-Me, MIC < 1.95 µg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the ᴅ- and ʟ-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.

• Klíčová slova
• amino acids, antibacterial, antimycobacterial, cytotoxicity, pyrazinamide, tuberculosis,
• MeSH
• aminokyseliny chemie   farmakologie   MeSH
• antibakteriální látky farmakologie   MeSH
• antituberkulotika farmakologie   MeSH
• Aspergillus flavus účinky léků   MeSH
• buňky Hep G2 MeSH
• Candida albicans účinky léků   MeSH
• chromatografie kapalinová MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium smegmatis účinky léků   MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• optická otáčivost MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• Pseudomonas aeruginosa účinky léků   MeSH
• pyrazinamid chemie   farmakologie   MeSH
• Staphylococcus aureus účinky léků   MeSH
• tuberkulóza farmakoterapie   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminokyseliny MeSH
• antibakteriální látky MeSH
• antituberkulotika MeSH
• pyrazinamid MeSH

We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 µg/mL, 46 µM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.

• Klíčová slova
• aminopyrazine, antibacterial activity, antifungal activity, antimycobacterial activity, cytotoxicity, pyrazinamide derivatives,
• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• antifungální látky farmakologie   MeSH
• Bacteria účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• buňky Hep G2 MeSH
• houby účinky léků   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární konformace MeSH
• pyraziny chemická syntéza   chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• antifungální látky MeSH
• pyraziny MeSH

Three series of N-(pyrazin-2-yl)benzamides were designed as retro-amide analogues of previously published N-phenylpyrazine-2-carboxamides with in vitro antimycobacterial activity. The synthesized retro-amides were evaluated for in vitro growth inhibiting activity against Mycobacterium tuberculosis H37Rv (Mtb), three non-tuberculous mycobacterial strains (M. avium, M. kansasii, M. smegmatis) and selected bacterial and fungal strains of clinical importance. Regarding activity against Mtb, most N-pyrazinylbenzamides (retro-amides) possessed lower or no activity compared to the corresponding N-phenylpyrazine-2-carboxamides with the same substitution pattern. However, the active retro-amides tended to have lower HepG2 cytotoxicity and better selectivity. Derivatives with 5-chloro substitution on the pyrazine ring were generally more active compared to their 6-cloro positional isomers or non-chlorinated analogues. The best antimycobacterial activity against Mtb was found in N-(5-chloropyrazin-2-yl)benzamides with short alkyl (2h: R² = Me; 2i: R² = Et) in position 4 of the benzene ring (MIC = 6.25 and 3.13 µg/mL, respectively, with SI > 10). N-(5-Chloropyrazin-2-ylbenzamides with hydroxy substitution (2b: R² = 2-OH; 2d: R² = 4-OH) on the benzene ring or their acetylated synthetic precursors possessed the broadest spectrum of activity, being active in all three groups of mycobacterial, bacterial and fungal strains. The substantial differences in in silico calculated properties (hydrogen-bond pattern analysis, molecular electrostatic potential, HOMO and LUMO) can justify the differences in biological activities between N-pyrazinylbenzamides and N-phenylpyrazine-2-carboxamides.

• Klíčová slova
• antibacterial, antifungal, antimycobacterial, cytotoxicity, linker, pyrazinamide, retro-amide, tuberculosis,
• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• benzamidy chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• racionální návrh léčiv * MeSH
• techniky syntetické chemie * MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• benzamide MeSH Prohlížeč
• benzamidy MeSH

Hybrid compounds based on a combination of the first-line antitubercular pyrazinamide (PZA) and a formerly identified antimycobacterial scaffold of 4-arylthiazol-2-amine were designed. Eighteen compounds were prepared, characterized and tested for in vitro growth inhibition activity against M. tuberculosis H37Rv, M. kansasii, M. avium and M. smegmatis by Microplate Alamar Blue Assay at neutral pH. Active compounds were tested for in vitro cytotoxicity in the human hepatocellular carcinoma cell line (HepG2). The most active 6-chloro-N-[4-(4-fluorophenyl)thiazol-2-yl]pyrazine-2-carboxamide (9b) also had the broadest spectrum of activity and inhibited M. tuberculosis, M. kansasii, and M. avium with MIC = 0.78 μg mL-1 (2.3 μM) and a selectivity index related to HepG2 cells of SI > 20. Structure-activity relationships within the series are discussed. Based on its structural similarity to known inhibitors and the results of a molecular docking study, we suggest mycobacterial beta-ketoacyl-(acyl-carrier-protein) synthase III (FabH) as a potential target.

• Publikační typ
• časopisecké články MeSH

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, "Drug Synthesis and Analysis," meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.

• Klíčová slova
• chemical biology, drug design and development, medicinal chemistry, natural compounds, new small entities, organic synthesis, pharmaceutical analysis, therapeutic proteins,
• MeSH
• chemie farmaceutická MeSH
• farmaceuti MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• lidé MeSH
• mezisektorová spolupráce MeSH
• příprava léků * MeSH
• výzkumní pracovníci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• kongresy MeSH
• Geografické názvy
• Slovenská republika MeSH

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation of pyrazinamide derivatives as potential anti-TB drugs. In this paper we report the synthesis and biological evaluations of a series of ureidopyrazines. Compounds were synthesized by reacting alkyl/aryl isocyanates with aminopyrazine or with propyl 5-aminopyrazine-2-carboxylate. Reactions were performed in pressurized vials using a CEM Discover microwave reactor with a focused field. Purity and chemical structures of products were assessed, and the final compounds were tested in vitro for their antimycobacterial, antibacterial, and antifungal activities. Propyl 5-(3-phenylureido)pyrazine-2-carboxylate (compound 4, MICMtb = 1.56 μg/mL, 5.19 μM) and propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate (compound 6, MICMtb = 6.25 μg/mL, 18.91 μM) had high antimycobacterial activity against Mtb H37Rv with no in vitro cytotoxicity on HepG2 cell line. Therefore 4 and 6 are suitable for further structural modifications that might improve their biological activity and physicochemical properties. Based on the structural similarity to 1-(2-chloropyridin-4-yl)-3-phenylurea, a known plant growth regulator, two selected compounds were evaluated for similar activity as abiotic elicitors.

• Klíčová slova
• Mycobacterium tuberculosis, abiotic elicitors, anti-infectives, callus culture, ester, pyrazinoic acid, ureidopyrazine,
• MeSH
• antituberkulotika chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• Fagopyrum chemie   MeSH
• fyziologický stres účinky léků   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• pyrazinamid chemie   farmakologie   MeSH
• pyraziny chemická syntéza   chemie   farmakologie   MeSH
• regulátory růstu rostlin chemická syntéza   chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antituberkulotika MeSH
• propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate MeSH Prohlížeč
• propyl 5-(3-phenylureido)pyrazine-2-carboxylate MeSH Prohlížeč
• pyrazinamid MeSH
• pyraziny MeSH
• regulátory růstu rostlin MeSH