Dorzolamide intermediates with potential anti-inflammatory activity.

Autor: Atre R; Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India., Obukhov AG; Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA., Majmudar CY; Bakul Finechem Research Centre, Mumbai, India., Nair K; Bakul Finechem Research Centre, Mumbai, India., White FA; Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, USA., Sharma R; Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India., Siddiqi F; Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India., Faisal SM; Laboratory of Vaccine Immunology, National Institute of Animal Biotechnology (NIAB), Hyderabad, Telangana, India., Varma VP; Laboratory of Vaccine Immunology, National Institute of Animal Biotechnology (NIAB), Hyderabad, Telangana, India., Hassan MI; Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India., Mohammad T; Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India., Darwhekar GN; Acropolis Institute of Pharmaceutical Education and Research (AIPER), Indore, MP, 453771, India., Baig MS; Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India. Electronic address: msb.iit@iiti.ac.in.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Dec 02; Vol. 987, pp. 177160. Date of Electronic Publication: 2024 Dec 02.
DOI: 10.1016/j.ejphar.2024.177160
Abstrakt: Dorzolamide (DZD), a Carbonic anhydrase (CA) inhibitor clinically used to lower intraocular pressure, exhibits anti-inflammatory effects owing to the drug's ability to inhibit the TIR domain-containing adaptor protein (TIRAP)-mediated signalling in macrophages. Here, we investigated whether DZD intermediates also demonstrate any anti-inflammatory property like DZD but with a reduced inhibition of CA. We found that several intermediates of DZD show increased binding to TIRAP at the common interface of kinases, such as Protein kinase C-delta (PKCδ) and Bruton's tyrosine kinase (BTK). Such binding results in a decreased activity of TIRAP, p38 Mitogen-activating protein kinases (MAPK), and p65, which are essential for major inflammatory signaling pathways. Remarkably, the DZD intermediates were more effective than DZD in decreasing the mRNA expression levels of pro-inflammatory cytokines in Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The DZD intermediates also exhibit a reduced binding energy to CA II and CA IV, highlighting their improved specificity as anti-inflammatory compounds with decreased unwanted biological effects. Furthermore, we validated the anti-inflammatory effect of the most efficient DZD intermediate, DRZ V, in a model of mouse sepsis. DRZ V-treated septic mice exhibited improved survival compared to DZD-treated septic mice. Our data indicate that the tested DZD intermediates are more effectual in dampening TIRAP-mediated inflammatory signaling as compared to DZD. Thus, DZD intermediates may be a promising option for developing novel anti-inflammatory therapeutics.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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