4-Chloroisocoumarins As Chlamydial Protease Inhibitors and Anti-Chlamydial Agents

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Apr 13

PMID 38611800

Authors

Matthew J A Phillips

Wilhelmina M Huston

Andrew M McDonagh

Tristan Rawling

Affiliations

Soon will be listed here.

Abstract

4-Chloroisocoumarin compounds have broad inhibitory properties against serine proteases. Here, we show that selected 3-alkoxy-4-chloroisocoumarins preferentially inhibit the activity of the conserved serine protease High-temperature requirement A of . The synthesis of a new series of isocoumarin-based scaffolds has been developed, and their anti-chlamydial properties were investigated. The structure of the alkoxy substituent was found to influence the potency of the compounds against High-temperature requirement A, and modifications to the C-7 position of the 3-alkoxy-4-chloroisocoumarin structure attenuate anti-chlamydial properties.

References

POWERS J, Kam C, Narasimhan L, Oleksyszyn J, Hernandez M, Ueda T . Mechanism-based isocoumarin inhibitors for serine proteases: use of active site structure and substrate specificity in inhibitor design. J Cell Biochem. 1989; 39(1):33-46. DOI: 10.1002/jcb.240390105. View

Hwang J, Strange N, Mazraani R, Phillips M, Gamble A, Huston W . Design, synthesis and biological evaluation of P2-modified proline analogues targeting the HtrA serine protease in Chlamydia. Eur J Med Chem. 2022; 230:114064. DOI: 10.1016/j.ejmech.2021.114064. View

Suchland R, Geisler W, Stamm W . Methodologies and cell lines used for antimicrobial susceptibility testing of Chlamydia spp. Antimicrob Agents Chemother. 2003; 47(2):636-42. PMC: 151736. DOI: 10.1128/AAC.47.2.636-642.2003. View

Zhou Y, Lu X, Huang D, Lu Y, Zhang H, Zhang L . A novel protease inhibitor causes inclusion vacuole reduction and disrupts the intracellular growth of Chlamydia trachomatis. Biochem Biophys Res Commun. 2019; 516(1):157-162. DOI: 10.1016/j.bbrc.2019.05.184. View

Gloeckl S, Ong V, Patel P, Tyndall J, Timms P, Beagley K . Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis. Mol Microbiol. 2013; 89(4):676-89. DOI: 10.1111/mmi.12306. View

Hwang J, Strange N, Phillips M, Krause A, Heywood A, Gamble A . Optimization of peptide-based inhibitors targeting the HtrA serine protease in Chlamydia: Design, synthesis and biological evaluation of pyridone-based and N-Capping group-modified analogues. Eur J Med Chem. 2021; 224:113692. DOI: 10.1016/j.ejmech.2021.113692. View

Zhao Q, Xu X, Xie Z, Liu X, You Q, Guo Q . Design, synthesis and biological evaluation of 3-substituted indenoisoquinoline derivatives as topoisomerase I inhibitors. Bioorg Med Chem Lett. 2016; 26(3):1068-1072. DOI: 10.1016/j.bmcl.2015.12.014. View

Peuchmaur M, Lacour M, Sevalle J, Lisowski V, Touati-Jallabe Y, Rodier F . Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein. Bioorg Med Chem. 2013; 21(4):1018-29. DOI: 10.1016/j.bmc.2012.11.045. View

Harper J, POWERS J . Reaction of serine proteases with substituted 3-alkoxy-4-chloroisocoumarins and 3-alkoxy-7-amino-4-chloroisocoumarins: new reactive mechanism-based inhibitors. Biochemistry. 1985; 24(25):7200-13. DOI: 10.1021/bi00346a028. View

10.

Billamboz M, Bailly F, Letizia Barreca M, De Luca L, Mouscadet J, Calmels C . Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain. J Med Chem. 2008; 51(24):7717-30. DOI: 10.1021/jm8007085. View

11.

Cross R, Ling C, Day N, McGready R, Paris D . Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation?. Expert Opin Drug Saf. 2015; 15(3):367-82. PMC: 4898140. DOI: 10.1517/14740338.2016.1133584. View

12.

Menon S, Timms P, Allan J, Alexander K, Rombauts L, Horner P . Human and Pathogen Factors Associated with Chlamydia trachomatis-Related Infertility in Women. Clin Microbiol Rev. 2015; 28(4):969-85. PMC: 4548260. DOI: 10.1128/CMR.00035-15. View

13.

HANSCH C, Leo A, Unger S, Kim K, Nikaitani D, Lien E . "Aromatic" substituent constants for structure-activity correlations. J Med Chem. 1973; 16(11):1207-16. DOI: 10.1021/jm00269a003. View

14.

Huston W, Swedberg J, Harris J, Walsh T, Mathews S, Timms P . The temperature activated HtrA protease from pathogen Chlamydia trachomatis acts as both a chaperone and protease at 37 degrees C. FEBS Lett. 2007; 581(18):3382-6. DOI: 10.1016/j.febslet.2007.06.039. View

15.

Huston W, Theodoropoulos C, Mathews S, Timms P . Chlamydia trachomatis responds to heat shock, penicillin induced persistence, and IFN-gamma persistence by altering levels of the extracytoplasmic stress response protease HtrA. BMC Microbiol. 2008; 8:190. PMC: 2585093. DOI: 10.1186/1471-2180-8-190. View

16.

St Cyr S, Barbee L, Workowski K, Bachmann L, Pham C, Schlanger K . Update to CDC's Treatment Guidelines for Gonococcal Infection, 2020. MMWR Morb Mortal Wkly Rep. 2020; 69(50):1911-1916. PMC: 7745960. DOI: 10.15585/mmwr.mm6950a6. View

17.

Heynekamp J, Hunsaker L, Vander Jagt T, Royer R, Deck L, Vander Jagt D . Isocoumarin-based inhibitors of pancreatic cholesterol esterase. Bioorg Med Chem. 2008; 16(9):5285-94. PMC: 2474762. DOI: 10.1016/j.bmc.2008.03.016. View

18.

Hoy B, Lower M, Weydig C, Carra G, Tegtmeyer N, Geppert T . Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep. 2010; 11(10):798-804. PMC: 2948180. DOI: 10.1038/embor.2010.114. View

19.

Bongard J, Schmitz A, Wolf A, Zischinsky G, Pieren M, Schellhorn B . Chemical Validation of DegS As a Target for the Development of Antibiotics with a Novel Mode of Action. ChemMedChem. 2019; 14(11):1074-1078. DOI: 10.1002/cmdc.201900193. View

20.

Gopinath P, Nilaya S, Muraleedharan K . Highly chemoselective esterification reactions and Boc/THP/TBDMS discriminating deprotections under samarium(III) catalysis. Org Lett. 2011; 13(8):1932-5. DOI: 10.1021/ol200247c. View