• Je něco špatně v tomto záznamu ?

Phenotypic screening of the 'Kurz-box' of chemicals identifies two compounds (BLK127 and HBK4) with anthelmintic activity in vitro against parasitic larval stages of Haemonchus contortus

LT. Nguyen, T. Kurz, S. Preston, H. Brueckmann, B. Lungerich, HMPD. Herath, AV. Koehler, T. Wang, L. Skálová, A. Jabbar, RB. Gasser,

. 2019 ; 12 (1) : 191. [pub] 20190430

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc19027637

Grantová podpora
SVV260416 Charles University
EFSA-CDN Charles University

BACKGROUND: Due to anthelmintic resistance problems, there is a need to discover and develop new drugs for the treatment and control of economically important and pathogenic nematodes of livestock animals. With this focus in mind, we screened 236 compounds from a library (called the 'Kurz-box') representing chemically diverse classes such as heterocyclic compounds (e.g. thiazoles, pyrroles, quinolines, pyrimidines, benzo[1,4]diazepines), hydoxamic acid-based metalloenzyme inhibitors, peptidomimetics (bis- and tris-pyrimidoneamides, alkoxyamides) and various intermediates on Haemonchus contortus, one of the most important parasitic nematodes of ruminants. METHODS: In the present study, we tested these compounds, and measured the inhibition of larval motility and development of exsheathed third-stage (xL3) and fourth-stage (L4) larvae of H. contortus using an optimised, whole-organism phenotypic screening assay. RESULTS: Of the 236 compounds, we identified two active compounds (called BLK127 and HBK4) that induced marked phenotypic changes in the worm in vitro. Compound BLK127 induced an 'eviscerated' phenotype in the xL3 stage and also inhibited L4 development. Compound HBK4 exerted a 'curved' phenotype in both xL3s and L4s. CONCLUSIONS: The findings from this study provide a basis for future work on the chemical optimisation of these compounds, on assessing the activity of optimised compounds on adult stages of H. contortus both in vitro and in vivo (in the host animal) and against other parasitic worms of veterinary and medical importance.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc19027637
003      
CZ-PrNML
005      
20190815105528.0
007      
ta
008      
190813s2019 enk f 000 0|eng||
009      
AR
024    7_
$a 10.1186/s13071-019-3426-7 $2 doi
035    __
$a (PubMed)31039802
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a enk
100    1_
$a Nguyen, Linh Thuy $u Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia. Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Hradec Králové, Czech Republic.
245    10
$a Phenotypic screening of the 'Kurz-box' of chemicals identifies two compounds (BLK127 and HBK4) with anthelmintic activity in vitro against parasitic larval stages of Haemonchus contortus / $c LT. Nguyen, T. Kurz, S. Preston, H. Brueckmann, B. Lungerich, HMPD. Herath, AV. Koehler, T. Wang, L. Skálová, A. Jabbar, RB. Gasser,
520    9_
$a BACKGROUND: Due to anthelmintic resistance problems, there is a need to discover and develop new drugs for the treatment and control of economically important and pathogenic nematodes of livestock animals. With this focus in mind, we screened 236 compounds from a library (called the 'Kurz-box') representing chemically diverse classes such as heterocyclic compounds (e.g. thiazoles, pyrroles, quinolines, pyrimidines, benzo[1,4]diazepines), hydoxamic acid-based metalloenzyme inhibitors, peptidomimetics (bis- and tris-pyrimidoneamides, alkoxyamides) and various intermediates on Haemonchus contortus, one of the most important parasitic nematodes of ruminants. METHODS: In the present study, we tested these compounds, and measured the inhibition of larval motility and development of exsheathed third-stage (xL3) and fourth-stage (L4) larvae of H. contortus using an optimised, whole-organism phenotypic screening assay. RESULTS: Of the 236 compounds, we identified two active compounds (called BLK127 and HBK4) that induced marked phenotypic changes in the worm in vitro. Compound BLK127 induced an 'eviscerated' phenotype in the xL3 stage and also inhibited L4 development. Compound HBK4 exerted a 'curved' phenotype in both xL3s and L4s. CONCLUSIONS: The findings from this study provide a basis for future work on the chemical optimisation of these compounds, on assessing the activity of optimised compounds on adult stages of H. contortus both in vitro and in vivo (in the host animal) and against other parasitic worms of veterinary and medical importance.
650    _2
$a zvířata $7 D000818
650    _2
$a anthelmintika $x chemie $x farmakologie $7 D000871
650    _2
$a preklinické hodnocení léčiv $7 D004353
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a Haemonchus $x účinky léků $x růst a vývoj $7 D006189
650    _2
$a inhibiční koncentrace 50 $7 D020128
650    _2
$a larva $x účinky léků $x růst a vývoj $7 D007814
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a fenotyp $7 D010641
655    _2
$a časopisecké články $7 D016428
700    1_
$a Kurz, Thomas $u Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
700    1_
$a Preston, Sarah $u Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia. Faculty of Science and Technology, Federation University, Ballarat, VIC, Australia.
700    1_
$a Brueckmann, Hjoerdis $u Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
700    1_
$a Lungerich, Beate $u Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
700    1_
$a Herath, H M P Dilrukshi $u Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia.
700    1_
$a Koehler, Anson V $u Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia.
700    1_
$a Wang, Tao $u Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia.
700    1_
$a Skálová, Lenka $u Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Hradec Králové, Czech Republic.
700    1_
$a Jabbar, Abdul $u Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia.
700    1_
$a Gasser, Robin B $u Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia. robinbg@unimelb.edu.au.
773    0_
$w MED00165371 $t Parasites & vectors $x 1756-3305 $g Roč. 12, č. 1 (2019), s. 191
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31039802 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20190813 $b ABA008
991    __
$a 20190815105756 $b ABA008
999    __
$a ok $b bmc $g 1432786 $s 1066097
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 12 $c 1 $d 191 $e 20190430 $i 1756-3305 $m Parasites & vectors $n Parasit Vectors $x MED00165371
GRA    __
$a SVV260416 $p Charles University
GRA    __
$a EFSA-CDN $p Charles University
LZP    __
$a Pubmed-20190813

Najít záznam

Citační ukazatele

Možnosti archivace