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Methyl sulfonamide substituents improve the pharmacokinetic properties of bicyclic 2-pyridone based Chlamydia trachomatis inhibitors
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.ORCID iD: 0000-0001-7680-0918
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2019 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 10, no 11, p. 1966-1987Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg(-1) showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2019. Vol. 10, no 11, p. 1966-1987
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-166479DOI: 10.1039/c9md00405jISI: 000498725400013Scopus ID: 2-s2.0-85075072755OAI: oai:DiVA.org:umu-166479DiVA, id: diva2:1382129
Funder
Swedish Cancer SocietyKnut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe FoundationsSwedish Foundation for Strategic Research Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2023-08-25Bibliographically approved
In thesis
1. Novel inhibitors of Chlamydia trachomatis virulence
Open this publication in new window or tab >>Novel inhibitors of Chlamydia trachomatis virulence
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chlamydia trachomatis is an obligate intracellular bacterium that infects over 100 million people globally every year. Chlamydia infections can be persistent, cause infertility and blindness, adding an economical burden in the healthcare systems. Moreover, Chlamydia infections are treated with broad-spectrum antibiotics that contribute to the selection of antibiotic resistant bacteria in the commensal flora. For this reason, novel compounds with specificity against C. trachomatis would be important for treatment of Chlamydia infections.

We have developed a new class of substituted 2-pyridone amides that inhibited development of C. trachomatis. While bacterial growth was only affected to a limited extent, the produced progeny bacteria had impaired capacity to infect new cells. The compounds presented no toxicity in human or mouse cell lines and they did not inhibit growth of bacteria from the normal flora. Structure activity relationship (SAR) development of 2-pyridones lead to compounds with effect at nanomolar concentrations. Further modifications of the C3 part of the molecules resulted in isostere compounds with even a higher potency. By exploring the C8 position, we observed that methylsulfonamide substituents improved the pharmacokinetic properties and enabled oral uptake in mice. This discovery opens the door for oral treatment.

Among 2-pyridone amides, KSK213 was one of the most potent and we investigated the mode of action on the life cycle of C. trachomatis. KSK213 reduced transcription by the end of the developmental cycle and upon infection of new host cells. Mutations in RNA helicase and RNAse III genes, involved in transcription, mediated resistance to KSK213. It also attenuated the infectivity in a mouse vaginal infection model. To further explore the molecular target for 2-pyridone amides in Chlamydia, we used a custom synthesized probe for affinity chromatography approaches.

Here we show that 2-pyridones are potent non-toxic inhibitors of C. trachomatis that can be chemically modified to increase potency and enable oral bioavailability. These molecules have the potential to treat and prevent Chlamydia infections without affecting the normal flora.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2020. p. 48
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2092
Keywords
Chlamydia trachomatis, 2-pyridone, small molecules, KSK213, Structure-Activity Relationships (SAR), antibiotic resistance, target identification, transcription, RNA, progeny, infectivity
National Category
Infectious Medicine Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medicinal Chemistry Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-174666 (URN)978-91-7855-340-2 (ISBN)978-91-7855-339-6 (ISBN)
Public defence
2020-09-25, Triple Helix, University management building, Umeå, 13:00 (English)
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Supervisors
Note

Additional appendix only available in printed version, as it contains specific methods that we want to publish in the future. 

Available from: 2020-09-04 Created: 2020-09-01 Last updated: 2020-09-02Bibliographically approved

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Kulén, MartinaNúñez-Otero, CarlosCairns, Andrew G.Silver, JimLindgren, Anders E. G.Andersson, Emma K.Singh, PardeepVielfort, KatarinaBahnan, WaelGood, James A. D.Bergström, SvenGylfe, ÅsaAlmqvist, Fredrik

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Kulén, MartinaNúñez-Otero, CarlosCairns, Andrew G.Silver, JimLindgren, Anders E. G.Andersson, Emma K.Singh, PardeepVielfort, KatarinaBahnan, WaelGood, James A. D.Bergström, SvenGylfe, ÅsaAlmqvist, Fredrik
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Molecular Infection Medicine Sweden (MIMS)Department of Clinical MicrobiologyDepartment of Molecular Biology (Faculty of Medicine)
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