Žiga Skok (Avtor), Michaela Barančokova (Avtor), Ondřej Benek (Avtor), Cristina Durante Cruz (Avtor), Päivi Tammela (Avtor), Tihomir Tomašić (Avtor), Nace Zidar (Avtor), Lucija Peterlin-Mašič (Avtor), Anamarija Zega (Avtor), Danijel Kikelj (Avtor), Janez Ilaš (Avtor)

Povzetek

We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 [micro]M), and efflux impaired E. coli strain (MIC = 0.78 [micro]M), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.

Ključne besede

DNA gyrase;topoisomerase IV;GyrB;ParE;antibacterial benzothiazole;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 615.4:54
COBISS: 32932099 Povezava se bo odprla v novem oknu
ISSN: 1948-5875
Št. ogledov: 9
Št. prenosov: 0
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: topoizomeraza IV;giraza DNA;antibakterijski benzotiazol;inibitorji giraze B;Farmacevtska kemija;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 2433-2440
Letnik: ǂVol. ǂ11
Zvezek: ǂiss. ǂ12
Čas izdaje: 2020
DOI: 10.1021/acsmedchemlett.0c00416
ID: 16716415