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Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platform.

Abstract：

AIM AND OBJECTIVE:Antibiotic resistance is a serious constraint to the development of new effective antibacterials. Therefore, the discovery of the new antibacterials remains one of the main challenges in modern medicinal chemistry. This study was undertaken to identify novel molecules with antibacterial activity. MATERIALS AND METHODS:Using our unique double-reporter system, in-house large-scale HTS campaign was conducted for the identification of antibacterial potency of small-molecule compounds. The construction allows us to visually assess the underlying mechanism of action. After the initial HTS and rescreen procedure, luciferase assay, C14-test, determination of MIC value and PrestoBlue test were carried out. RESULTS:HTS rounds and rescreen campaign have revealed the antibacterial activity of a series of Nsubstituted triazolo-azetidines and their isosteric derivatives that has not been reported previously. Primary hit-molecule demonstrated a MIC value of 12.5 µg/mL against E. coli Δ tolC with signs of translation blockage and no SOS-response. Translation inhibition (26%, luciferase assay) was achieved at high concentrations up to 160 µg/mL, while no activity was found using C14-test. The compound did not demonstrate cytotoxicity in the PrestoBlue assay against a panel of eukaryotic cells. Within a series of direct structural analogues bearing the same or bioisosteric scaffold, compound 2 was found to have an improved antibacterial potency (MIC=6.25 µg/mL) close to Erythromycin (MIC=2.5-5 µg/mL) against the same strain. In contrast to the parent hit, this compound was more active and selective, and provided a robust IP position. CONCLUSION:N-substituted triazolo-azetidine scaffold may be used as a versatile starting point for the development of novel active and selective antibacterial compounds.

journal_name

Comb Chem High Throughput Screen

journal_title

Combinatorial chemistry & high throughput screening

authors

Ivanenkov YA,Yamidanov RS,Osterman IA,Sergiev PV,Aladinskiy VA,Aladinskaya AV,Terentiev VA,Veselov MS,Ayginin AA,Skvortsov DA,Komarova KS,Chemeris AV,Baimiev AK,Sofronova AA,Malyshev AS,Machulkin AE,Petrov RA,Bezrukov D

doi

10.2174/1386207322666190412165316

subject

Has Abstract

pub_date

2019-08-08 00:00:00

pages

346-354

issue

eissn

1386-2073

issn

1875-5402

pii

CCHTS-EPUB-98053

journal_volume

pub_type

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Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platform.