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Investigations into Simplified Analogues of the Herbicidal Natural Product (+)-Cornexistin.

ABSTRACT: We report the design, synthesis and biological evaluation of simplified analogues of the herbicidal natural product (+)-cornexistin. Guided by an X-Ray co-crystal structure of cornexistin bound to transketolase from Zea mays, we attempted to identify the key interactions that are necessary for cornexistin to maintain its herbicidal profile. This resulted in the preparation of three novel analogues investigating the importance of substituents that are located on the nine-membered ring of cornexistin. One analogue maintained a good level of biological activity and could provide researchers insights in how to further optimize the structure of cornexistin for commercialization in the future.

SUBMITTER: Steinborn C

PROVIDER: S-EPMC7614749 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Investigations into Simplified Analogues of the Herbicidal Natural Product (+)-Cornexistin.

Steinborn Christian C Tancredi Aldo A Habiger Christoph C Diederich Christina C Kramer Jan J Reingruber Anna M AM Laber Bernd B Freigang Jörg J Lange Gudrun G Schmutzler Dirk D Machettira Anu A Besong Gilbert G Magauer Thomas T Barber David M DM

Chemistry (Weinheim an der Bergstrasse, Germany) 20230523 39

We report the design, synthesis and biological evaluation of simplified analogues of the herbicidal natural product (+)-cornexistin. Guided by an X-Ray co-crystal structure of cornexistin bound to transketolase from Zea mays, we attempted to identify the key interactions that are necessary for cornexistin to maintain its herbicidal profile. This resulted in the preparation of three novel analogues investigating the importance of substituents that are located on the nine-membered ring of cornexis ...[more]

PMID: 36807428

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Project description:Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1, a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation. We used compound 3, a diazirine- and alkyne-containing bi-functional photo-affinity probe analogue of our lead B-THP-T, compound 1, to identify potential targets of our lead compound in the procyclic form T. brucei. Bi-functional compound 3 was UV cross-linked to its target(s) in vivo and biotin affinity or Cy5.5 reporter tags were subsequently appended by Cu(II)-catalysed azide-alkyne cycloaddition. The biotinylated protein adducts were isolated with streptavidin affinity beads and subsequent LC-MSMS identified the FoF1-ATP synthase (mitochondrial complex V) as a potential target. This target identification was confirmed using various different approaches. We show that (i) compound 1 decreases cellular ATP levels (ii) by inhibiting oxidative phosphorylation (iii) at the FoF1-ATP synthase. Furthermore, the use of GFP-PTP-tagged subunits of the FoF1-ATP synthase, shows that our compounds bind specifically to both the α- and β-subunits of the ATP synthase. The FoF1-ATP synthase is a target of our simplified acetogenin-type analogues. This mitochondrial complex is essential in both procyclic and bloodstream forms of T. brucei and its identification as our target will enable further inhibitor optimisation towards future drug discovery. Furthermore, the photo-affinity labeling technique described here can be readily applied to other drugs of unknown targets to identify their modes of action and facilitate more broadly therapeutic drug design in any pathogen or disease model.

Project description:Despite the vast availability of antibiotics, bacterial infections remain a leading cause of death worldwide. In an effort to enhance the armamentarium against resistant bacterial strains, 1,2,3-triazole (5a-x) and sulfonate (7a-j) analogues of natural bioactive precursors were designed and synthesized. Preliminary screening against two Gram-positive (Streptococcus pneumoniae and Enterococcus faecalis) and four Gram-negative bacterial strains (Pseudomonas aeruginosa, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli) was performed to assess the potency of these analogues as antibacterial agents. Among all triazole analogues, 5e (derived from carvacrol) and 5u (derived from 2-hydroxy 1,4-naphthoquinone) bearing carboxylic acid functionality emerged as potent antibacterial agents against S. pneumoniae (IC50: 62.53 and 39.33 μg/mL), E. faecalis (IC50: 36.66 and 61.09 μg/mL), and E. coli (IC50: 15.28 and 22.57 μg/mL). Furthermore, 5e and 5u also demonstrated moderate efficacy against multidrug-resistant E. coli strains and were therefore selected for further biological studies. Compound 5e in combination with ciprofloxacin displayed a synergistic effect on multidrug-resistant E. coli MRA11 and MRC17 strains, whereas compound 5u was selective against E. coli MRA11 strain. Growth kinetic studies on S. pneumoniae and E. coli treated with 5e and 5u showed an extended lag phase. 5e and 5u did not show significant cytotoxicity up to 100 μg/mL concentration on human embryonic kidney (HEK293) cells. Transmission electron microscopic (TEM) analysis of bacterial cells (S. pneumoniae and E. coli) exposed to 5e and 5u clearly showed morphological changes and damaged cell walls. Moreover, these compounds also significantly inhibited biofilm formation in S. pneumoniae and E. coli strains, which was visualized by scanning electron microscopic (SEM) analysis. Treatment of larvae of Galleria mellonella (an in vivo model for antimicrobial studies) with 5e and 5u did not cause an alteration in the hemocyte density, thereby indicating lack of an immune response, and were nontoxic up to a concentration of 2.5 mg/mL.

Dataset Information

Investigations into Simplified Analogues of the Herbicidal Natural Product (+)-Cornexistin.

Publications

Investigations into Simplified Analogues of the Herbicidal Natural Product (+)-Cornexistin.

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