• Something wrong with this record ?

Design and Synthesis of Pyrano[3,2-b]indolones Showing Antimycobacterial Activity

N. Monakhova, J. Korduláková, A. Vocat, A. Egorova, A. Lepioshkin, EG. Salina, J. Nosek, E. Repková, J. Zemanová, H. Jurdáková, R. Górová, J. Roh, G. Degiacomi, JC. Sammartino, MR. Pasca, ST. Cole, K. Mikušová, V. Makarov

. 2021 ; 7 (1) : 88-100. [pub] 20201222

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21019463

Latent Mycobacterium tuberculosis infection presents one of the largest challenges for tuberculosis control and novel antimycobacterial drug development. A series of pyrano[3,2-b]indolone-based compounds was designed and synthesized via an original eight-step scheme. The synthesized compounds were evaluated for their in vitro activity against M. tuberculosis strains H37Rv and streptomycin-starved 18b (SS18b), representing models for replicating and nonreplicating mycobacteria, respectively. Compound 10a exhibited good activity with MIC99 values of 0.3 and 0.4 μg/mL against H37Rv and SS18b, respectively, as well as low toxicity, acceptable intracellular activity, and satisfactory metabolic stability and was selected as the lead compound for further studies. An analysis of 10a-resistant M. bovis mutants disclosed a cross-resistance with pretomanid and altered relative amounts of different forms of cofactor F420 in these strains. Complementation experiments showed that F420-dependent glucose-6-phosphate dehydrogenase and the synthesis of mature F420 were important for 10a activity. Overall these studies revealed 10a to be a prodrug that is activated by an unknown F420-dependent enzyme in mycobacteria.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc21019463
003      
CZ-PrNML
005      
20210830101030.0
007      
ta
008      
210728s2021 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1021/acsinfecdis.0c00622 $2 doi
035    __
$a (PubMed)33352041
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Monakhova, Natalia $u Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russian Federation
245    10
$a Design and Synthesis of Pyrano[3,2-b]indolones Showing Antimycobacterial Activity / $c N. Monakhova, J. Korduláková, A. Vocat, A. Egorova, A. Lepioshkin, EG. Salina, J. Nosek, E. Repková, J. Zemanová, H. Jurdáková, R. Górová, J. Roh, G. Degiacomi, JC. Sammartino, MR. Pasca, ST. Cole, K. Mikušová, V. Makarov
520    9_
$a Latent Mycobacterium tuberculosis infection presents one of the largest challenges for tuberculosis control and novel antimycobacterial drug development. A series of pyrano[3,2-b]indolone-based compounds was designed and synthesized via an original eight-step scheme. The synthesized compounds were evaluated for their in vitro activity against M. tuberculosis strains H37Rv and streptomycin-starved 18b (SS18b), representing models for replicating and nonreplicating mycobacteria, respectively. Compound 10a exhibited good activity with MIC99 values of 0.3 and 0.4 μg/mL against H37Rv and SS18b, respectively, as well as low toxicity, acceptable intracellular activity, and satisfactory metabolic stability and was selected as the lead compound for further studies. An analysis of 10a-resistant M. bovis mutants disclosed a cross-resistance with pretomanid and altered relative amounts of different forms of cofactor F420 in these strains. Complementation experiments showed that F420-dependent glucose-6-phosphate dehydrogenase and the synthesis of mature F420 were important for 10a activity. Overall these studies revealed 10a to be a prodrug that is activated by an unknown F420-dependent enzyme in mycobacteria.
650    _2
$a antituberkulotika $x farmakologie $7 D000995
650    _2
$a lidé $7 D006801
650    12
$a latentní tuberkulóza $7 D055985
650    12
$a Mycobacterium tuberculosis $x genetika $7 D009169
650    12
$a tuberkulóza $7 D014376
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Korduláková, Jana
700    1_
$a Vocat, Anthony $u Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland
700    1_
$a Egorova, Anna $u Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russian Federation
700    1_
$a Lepioshkin, Alexander $u Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russian Federation
700    1_
$a Salina, Elena G $u Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russian Federation
700    1_
$a Nosek, Jozef
700    1_
$a Repková, Eva
700    1_
$a Zemanová, Júlia
700    1_
$a Jurdáková, Helena
700    1_
$a Górová, Renáta
700    1_
$a Roh, Jaroslav $u Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové 50005, Czech Republic
700    1_
$a Degiacomi, Giulia $u Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia 27100, Italy
700    1_
$a Sammartino, José Camilla $u Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia 27100, Italy
700    1_
$a Pasca, Maria Rosalia $u Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia 27100, Italy
700    1_
$a Cole, Stewart T $u Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland
700    1_
$a Mikušová, Katarína
700    1_
$a Makarov, Vadim $u Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow 119071, Russian Federation
773    0_
$w MED00205751 $t ACS infectious diseases $x 2373-8227 $g Roč. 7, č. 1 (2021), s. 88-100
856    41
$u https://pubmed.ncbi.nlm.nih.gov/33352041 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20210728 $b ABA008
991    __
$a 20210830101030 $b ABA008
999    __
$a ok $b bmc $g 1690312 $s 1139909
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 7 $c 1 $d 88-100 $e 20201222 $i 2373-8227 $m ACS infectious diseases $n ACS infect. dis. $x MED00205751
LZP    __
$a Pubmed-20210728
Back

Find record

Citation metrics

Archiving options