Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

Abstract

A series of analogues of Pseudonocardia sp. natural products were synthesized, which have been reported to possess potent antibacterial activity against Helicobacter pylori and induce growth defects in Escherichia coli and Staphylococcus aureus. Taking inspiration from a methodology used in our total synthesis of natural products, we applied this methodology to access analogues possessing bulky N-substituents, traditionally considered to be challenging scaffolds. Screening of the library provided valuable insights into the structure–activity relationship of the bacterial growth defects, and suggested that selectivity between bacterial species should be attainable. Furthermore, a structurally related series of analogues was observed to inhibit production of the virulence factor pyocyanin in the human pathogen Pseudomonas aeruginosa, which may be a result of their similarity to the Pseudomonas quinolone signal (PQS) quorum sensing autoinducer. This provided new insights regarding the effect of N-substitution in PQS analogues, which has been hitherto underexplored.

16S rDNA analysis of osteoporotic rats treated with osteoking

“…The actinomycete Pseudonocardia sp. CL38489 can produce a family of quinolones and is active against Helicobacter pylori , which is responsible for the generation of numerous digestive disorders [26–28]. In addition, it has been reported that Pseudonocardia can convert vitamin D 3 to calcifediol and calcitriol by using resting cells [29, 30].…”

Highlights on quinolonic compounds with changes on the basic structure as promising molecules to new drugs

“…Changes in position 2 were, recently, also explored because PQS (Pseudomonas quinolone signal) and HHQ (2-heptyl-4(1H)-quinolone), compounds responsible for the quorum sensing (QS) of Pseudomonas aeruginosa (Figure 12), these molecules regulate the expression of genes that code virulence factors in this bacteria (GEDDIS et al, 2018;Li & Clark, 2020;RAMOS et al, 2020). So, Geddis et al (2018) reported synthetic compounds, we will focus on the compounds 21a, 21b and 21c (Figure 14), and tested the growth of Staphylococcus aureus 25923 in the presence of 200 μM of each compound using gentamicin as positive control. They observed a strong effect comparable to the standard when the optical density 600 (OD600) was measured.…”

Biological Effects of Quinolones: A Family of Broad-Spectrum Antimicrobial Agents

“…These naturally occurring quinolones present a geranyl or oxidized geranyl side chain at position C-2 compared to fatty acid-derived alkyl or alkenyl chains usually found in microbial quinolones. Although these compounds have been described over twenty years ago, no therapy has been developed based on these quinolones; however, some advances have been made in the synthesis of those structures [ 62 ]. We will be watchful for the development of new therapies based on the structures of naturally occurring quinolones.…”