Exploring the 5-substituted 2-aminobenzothiazole-based DNA gyrase B inhibitors active against ESKAPE pathogens
Povzetek
We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound E showed low nanomolar inhibition of DNA gyrase (IC50 < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.03 μg/mL for most Gram-positive strains and 4–16 μg/mL against Gram-negative E. coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, a combination of docking calculations, molecular dynamics (MD) simulations, and MD-derived structure-based pharmacophore modeling was performed. The computational analysis has revealed that the substitution at position C5 can be used to modify the physicochemical properties and antibacterial spectrum and enhance the inhibitory potency of the compounds. Additionally, a discussion of challenges associated with the synthesis of 5-substituted 2-aminobenzothiazoles is presented.
Ključne besede
inhibitorji;organske kisline;proteini;bacteria;genetics;inhibitors;organic acids;peptides;proteins;
Podatki
| Jezik: | Angleški jezik |
|---|---|
| Leto izida: | 2023 |
| Tipologija: | 1.01 - Izvirni znanstveni članek |
| Organizacija: | UL FFA - Fakulteta za farmacijo |
| UDK: | 579.8:615.2 |
| COBISS: |
157232131
|
| ISSN: | 2470-1343 |
| Št. ogledov: | 18 |
| Št. prenosov: | 4 |
| Ocena: | 0 (0 glasov) |
| Metapodatki: |
|
Ostali podatki
| Sekundarni jezik: | Slovenski jezik |
|---|---|
| Sekundarne ključne besede: | Bakterije;Genetika;Peptidi; |
| Vrsta dela (COBISS): | Članek v reviji |
| Strani: | str. 24387-24395 |
| Letnik: | ǂVol. ǂ8 |
| Zvezek: | ǂiss. ǂ27 |
| Čas izdaje: | 2023 |
| DOI: | 10.1021/acsomega.3c01930 |
| ID: | 21372097 |
Priporočena dela:
Exploring the 5-substituted 2-aminobenzothiazole-based DNA gyrase B inhibitors active against ESKAPE pathogens
2023,
ni podatka o podnaslovu
Discovery and Hit-to-Lead Optimization of Benzothiazole scaffold-based DNA gyrase inhibitors with potent activity against Acinetobacter baumannii and Pseudomonas aeruginosa
2023,
ni podatka o podnaslovu
Synthesis and evaluation of N-phenylpyrrolamides as DNA gyrase B inhibitors
2018,
ni podatka o podnaslovu
Sinteza konjugatov benzotiazolpirolamidnih zaviralcev DNA-giraze B s siderofori
2019,
ni podatka o podnaslovu
Sinteza zaviralcev DNA giraze B z aminopiperidinskim osnovnim skeletom
2016,
diplomska naloga