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.
- 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
BACKGROUND: Despite of the globally positive trends in the epidemiology of tuberculosis, the increasing rates of drug-resistant strains are urging to introduce new antituberculars into clinical practice. Development of a new chemical entity from hit to marketed drug is an extremely time and resources consuming process with uncertain outcome. Repurposing of clinically used drugs can be a cheaper alternative to develop new drugs effective in the treatment of tuberculosis. OBJECTIVE: To extract the latest information on new mechanisms of action described or proposed for clinically used antitubercular drugs. To identify drugs from various pharmacodynamic groups as candidates for repurposing to become effective in combatting tuberculosis. Attention will be paid to elucidate the connection between repurposed drugs and new antituberculars in clinical practice or in clinical trials. METHODS: Scientific databases were searched for the keywords. RESULTS: We reviewed the latest aspects of usage and new mechanisms of action for both first-line and second-line antitubercular drugs in clinical practice. Further, we found that surprisingly large number of clinically used drugs from various pharmacodynamic groups have potential to be used in the treatment of tuberculosis, including antimicrobial drugs not typically used against tuberculosis, statins, CNS drugs (tricyclic phenothiazines, antidepressants, anticonvulsants), non-steroidal anti-inflammatory drugs, kinase inhibitors, and others (metformin, disulfiram, verapamil, lansoprazole). Repurposed drugs may become effective antituberculars, acting either by direct effects on mycobacteria or as adjunct, host-directed therapy. CONCLUSION: In this review, we showed that proper research of old drugs is a very efficient tool to develop new antituberculars.
- MeSH
- antituberkulotika terapeutické užití MeSH
- bakteriální léková rezistence účinky léků MeSH
- lidé MeSH
- přehodnocení terapeutických indikací léčivého přípravku metody MeSH
- tuberkulóza farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
INTRODUCTION: Enoyl-(acyl-carrier-protein) reductase (ENR) is a limiting step enzyme in the Fatty Acid Synthase II system. In mammals, there is no homologue to ENR, which makes it an optimal candidate target for selective anti-infective drugs. Up-to-date, only two ENR inhibitors are used in clinical practice. AREA COVERED: This review is a survey on important patents on low molecular weight compounds with ENR inhibiting activity published in 2011-2015. Common patent databases (SciFinder, esp@cenet, WIPO) were used to locate patent applications on the proposed topic and in the timespan of 2011-2015. EXPERT OPINION: In 2011-2015, we have observed patents in previously known structural groups of diphenyl ethers and acrylamides as well as new structural classes, often identified by high-throughput screening campaigns. The spectrum of activity of applied derivatives covers significant bacteria, mycobacteria, and apicomplexan parasites (Plasmodia and Toxoplasma). Good news from research of ENR inhibitors: a) four selective anti-staphylococcal compounds applied in 2011-2015 or earlier were pushed to Phase I or Phase II clinical trials and some of them proved safety and tolerability after peroral and/or intravenous administration; b) big pharma companies have renewed their interest in the development of new anti-infective compounds against resistant strains of clinical relevance.
- MeSH
- antibiotická rezistence MeSH
- antiinfekční látky škodlivé účinky farmakologie terapeutické užití MeSH
- enoyl-ACP-reduktasa (NADH) antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů škodlivé účinky farmakologie terapeutické užití MeSH
- lidé MeSH
- patenty jako téma MeSH
- racionální návrh léčiv MeSH
- rychlé screeningové testy MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Substitution of chlorine in 5-chloro-N-phenylpyrazine-2-carboxamide (1) with simple n-alkylamines yielded a series of 5-alkylamino-N-phenylpyrazine-2-carboxamides (propylamino to octylamino derivatives), which possessed similar or increased activity against Mycobacterium tuberculosis H37Rv compared to parent 5-chloro derivative (1), with MIC ranging from 2.5 to 12.2 μM. 5-Butylamino to 5-heptylamino derivatives exerted similar activity also against Mycobacterium kansasii. Importantly, the substitution led also to significant decrease of in vitro cytotoxicity in HepG2 cell line. 5-Heptylamino-N-phenylpyrazine-2-carboxamide (1e) exerted MIC=2.5 μM (M.tbc) and IC50 >250 μM (HepG2). Further modification of alkylamino chain with terminal methoxy or hydroxy group lead to compounds with decreased or none activity, the decrease was proportional to the decrease of lipophilicity. 5-(2-Phenylethylamino) and 5-(3-phenylpropylamino) derivatives were also of decreased activity. On contrary to alkylamino derivatives derived from 1, alkylamino derivatives derived from 5-chloro-N-2-chlorophenylpyrazine-2-carboxamide (2) possessed substantially decreased or none activity. None of the prepared compounds was active against Mycobacterium avium.
- MeSH
- amidy chemická syntéza chemie farmakologie MeSH
- antibakteriální látky chemická syntéza farmakologie MeSH
- antituberkulotika chemická syntéza farmakologie MeSH
- lidé MeSH
- pyrazinamid chemická syntéza chemie farmakologie MeSH
- tuberkulóza farmakoterapie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
INTRODUCTION: Hippocampal neurogenesis in adults is a new and attractive target for the treatment and prevention of neurodegenerative and neuro-psychiatric diseases. Recently, neurogenesis stimulating activity was observed in some of the commonly used small molecule drugs such as antidepressants and atypical antipsychotics. Stimulation of neurogenesis is attractive mainly due to its wide scope of application, ranging from depressions, schizophrenia, dementia, Parkinson`s and Alzheimer`s Disease to various brain injuries. AREAS COVERED: New compounds based on 7-phenyl or 7-pyridinyl-1H-indole-2-carboxamide showed interesting neural stem cell proliferation inducing activity in vitro and were claimed as potential therapeutics for various neurodegenerative and neuropsychiatric diseases as well as brain injuries. The potential of the presented compounds is evaluated with respect to other small molecule neurogenesis inducers in literature. EXPERT OPINION: Nanomolar in vitro activities of presented compounds and their favorable physico-chemical properties, giving a fair chance of good oral bioavailability and sufficient CNS penetration, make these compounds promising drug candidates. The biggest drawback of the presented application is the absence of pharmacokinetics, toxicity and in vivo activity data. On the other hand, the high number of applications in this area (seven published in last two years) indicates that Hoffmann-La Roche takes it seriously.
- MeSH
- biologická dostupnost MeSH
- dospělí MeSH
- duševní poruchy farmakoterapie patofyziologie prevence a kontrola MeSH
- hipokampus účinky léků patofyziologie MeSH
- indoly chemie farmakokinetika farmakologie MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- nervové kmenové buňky účinky léků metabolismus MeSH
- neurodegenerativní nemoci farmakoterapie patofyziologie prevence a kontrola MeSH
- neurogeneze účinky léků MeSH
- patenty jako téma MeSH
- poranění mozku farmakoterapie patofyziologie MeSH
- proliferace buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- zvířata 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
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
A series of 19 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro whole cell antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two types of Mycobacterium avium. The series consisted of 3-(benzylamino)-5-cyanopyrazine-2-carboxamides and 3-(benzylamino)pyrazine-2,5-dicarbonitriles with various substituents on the phenyl ring. RP-HPLC method was used to determine the lipophilicity of the prepared compounds. Nine compounds exerted similar or better activity against Mycobacterium tuberculosis compared to pyrazinamide (MIC=6.25-12.5 μg/mL). 3-(Benzylamino)pyrazine-2,5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12.5-25 μg/mL. Although not the most active, 4-NH(2) substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI=5.5 and SI >21.
- MeSH
- antituberkulotika chemická syntéza farmakologie MeSH
- benzylaminy chemie MeSH
- inhibiční koncentrace 50 MeSH
- kultivované buňky MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Mycobacterium účinky léků MeSH
- pyrazinamid chemická syntéza farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
