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.

• 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

A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N-benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N-(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) and N-(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 μg·mL(-1). Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) against Staphylococcus aureus with MIC = 7.81 μM, and Staphylococcus epidermidis with MIC = 15.62 μM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis. In some cases, it was capable of H-bond interactions, typical for most of the known inhibitors.

• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• buňky Hep G2 MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   MeSH
• pyraziny chemická syntéza   chemie   farmakologie   MeSH
• simulace molekulového dockingu MeSH
• Staphylococcus aureus účinky léků   MeSH
• Staphylococcus epidermidis účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Byla připravena série jedenácti nových 5-amino-N-fenylpyrazin-2-karboxamidů, které byly hodnoceny jako potenciální antiinfektiva. Připravené sloučeniny byly popsány IČ, 1H NMR a 13C NMR spektry, prvkovou analýzou a teplotami tání. Byly vypočteny parametry lipofility Log P a ClogP. Žádný z připravených derivátů nebyl účinný proti testovaným mykobakteriálním kmenům (Mycobacterium tuberculosis H37Rv, M. kansasii, M. avium) ani v nejvyšší testované koncentraci 100 μg/ml. 5-Amino-N-(2,5-dimethylfenyl)pyrazin-2-karboxamid (3) vykázal antibakteriální aktivitu vůči kmenu Staphylococcus aureus (MIC = 62.5μmol/l). U testovaných látek nebyla zjištěna žádná antifungální aktivita. Několik sloučenin vykázalo mírnou aktivitu (v řádu desítekμmol/l) proti virům chřipky A.

A series of eleven novel 5-amino-N-phenylpyrazine-2-carboxamides were synthesized and evaluated for in vitro anti-infective properties. Prepared compounds were characterized by IR, 1H NMR and 13C NMR spectra, elementary analysis and melting points. Lipophilicity parameters Log P and ClogP were calculated. None of the compounds was effective against any of tested mycobacterial strains (Mycobacterium tuberculosis H37Rv, M. kansasii, M. avium) up to concentration of 100 μg/mL. 5-amino-N-(2,5-dimethylphenyl) pyrazine-2-carboxamide (3) exerted moderate antibacterial activity against Staphylococcus aureus (MIC = 62.5 μM). No antifungal activity was detected. Several compounds exerted moderate antiviral activity against influenza A viruses at the level of tens of μM.

• Klíčová slova
• 5-chloro-N-phenylpyrazine-2-carboxamide, karboxamidy,
• MeSH
• antibakteriální látky MeSH
• antiinfekční látky MeSH
• farmaceutická chemie * MeSH
• lidé MeSH
• mykobakteriózy farmakoterapie   MeSH
• pyraziny chemie   metabolismus   MeSH
• Staphylococcus aureus účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH