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A new acyl derivative of sulfadimethoxine inhibits phagocyte oxidative burst and ameliorates inflammation in a mice model of zymosan-induced generalised inflammation

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Abstract

Chronic inflammation and oxidative stress play a pivotal role in the pathophysiology of most challenging illnesses, including cancer, Alzheimer’s, cardiovascular and autoimmune diseases. The present study aimed to investigate the anti-inflammatory potential of a new sulfadimethoxine derivative N-(4-(N-(2,6-dimethoxypyrimidin-4-yl) sulfamoyl) phenyl) dodecanamide (MHH-II-32). The compound was characterised by applying 1H-, 13C-NMR, EI–MS and HRFAB–MS spectroscopic techniques. The compound inhibited zymosan-induced oxidative bursts from whole blood phagocytes and isolated polymorphonuclear cells with an IC50 value of (2.5 ± 0.4 and 3.4 ± 0.3 µg/mL), respectively. Furthermore, the inhibition of nitric oxide with an IC50 (3.6 ± 2.2 µg/mL) from lipopolysaccharide-induced J774.2 macrophages indicates its in vitro anti-inflammatory efficacy. The compound did not show toxicity towards normal fibroblast cells. The observational findings, gross anatomical analysis of visceral organs and serological tests revealed the non-toxicity of the compound at the highest tested intraperitoneal (IP) dose of 100 mg/kg in acute toxicological studies in Balb/c mice. The compound treatment (100 mg/kg) (SC) significantly (P < 0.001) downregulated the mRNA expression of inflammatory markers TNF-α, IL-1β, IL-2, IL-13, and NF-κB, which were elevated in zymosan-induced generalised inflammation (IP) in Balb/c mice while upregulated the expression of anti-inflammatory cytokine IL-10, which was reduced in zymosan-treated mice. No suppressive effect was observed at the dose of 25 mg/kg. Ibuprofen was taken as a standard drug. The results revealed that the new acyl derivative of sulfadimethoxine has an immunomodulatory effect against generalised inflammatory response with non-toxicity both in vitro and in vivo, and has therapeutic potential for various chronic inflammatory illnesses.

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Data availability

The data will be available from the corresponding author upon reasonable request.

Abbreviations

ANOVA:

Analysis of variance

BME:

β-mercaptoethanol

cDNA:

Complementary deoxyribonucleic acid

CVDs:

Cardiovascular diseases

DMEM:

Dulbecco’s-modified eagle’s medium

DNA:

Deoxyribonucleic acid

dNTPs:

Deoxynucleotide triphosphate

EDTA:

Ethylene diamine tetra acetic acid

FBS:

Fetal bovine serum

ESRD:

End-stage renal disease

GPx:

Glutathione peroxidase

HBSS:

Hank’s balance salt solution

IBD:

Inflammatory bowel disease

IC50:

Inhibitory concentration 50

IL:

Interleukin

IP:

Intraperitoneal

L-NMMA:

NG-monomethyl-l-arginine acetate

LPS:

Lipopolysaccharide

LSM:

Lymphocyte separation medium

MTT:

Methyl thiazolyl tetrazolium

MAPK:

Mitogen-activated protein kinase

NADPH:

Nicotinamide adenine dinucleotide phosphate (reduced)

NF-кB:

Nuclear factor kappa B

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PBS:

Phosphate buffer saline

PCR:

Polymerase chain reaction

PMNs:

Polymorphonuclear leukocytes

RA:

Rheumatoid arthritis

RBCs:

Red blood cells

RLU:

Relative light unit

RNA:

Ribonucleic acid

ROS:

Reactive oxygen species

SC:

Subcutaneous

SLE:

Systematic lupus erythematosus

ZIGI:

Zymosan-induced generalised inflammation

SD:

Standard deviation

SEM:

Standard error of mean

SOZ:

Serum opsonized zymosan

SPSS:

Statistical package for social sciences

TNF-α:

Tumor necrosis factor alpha

NS:

Nephrotic syndrome

NSAIDs:

Nonsteroidal anti-inflammatory drugs

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Acknowledgements

We are thankful to Animal house facility of PCMD, ICCBS, University of Karachi for providing desired strain of mice and proper work station. Biobank facility of PCMD, ICCBS, University of Karachi provided us cell lines. HMH is thankful to the International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Pakistan for the 1-year doctoral fellowship under supervision of HS.

Funding

The work is financially supported by Higher Education commission (HEC), Pakistan (Project No. 8263 NRPU 2017–18).

Author information

Authors and Affiliations

  1. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Tariq Ahmad Baig, Syeda Farah Shah & Almas Jabeen

  2. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Haroon M. Haniffa & Hina Siddiqui

  3. Department of Chemical Sciences, Faculty of Applied Sciences, South Eastern University, Sammanthurai, 32200, Sri Lanka

    Haroon M. Haniffa

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  1. Tariq Ahmad Baig
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  4. Syeda Farah Shah
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  5. Almas Jabeen
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Contributions

TA conducted biology experiments, collected and analysed the underlying data, provide statistical analysis. TA and SFS drafted the manuscript. HMH performed chemistry experiments synthesize and provide compound for biological studies and analysed data under the supervision of HS. AJ contributed to the concept and design of the current study, analysed the biological data and interpreted the results together with TA. AJ supervised the biology experiments, responsible for fund support and revised and finalized the manuscript. All authors read and approved the submitted version of this article.

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Correspondence to Almas Jabeen.

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Ethical approval

The in vitro studies on human blood cells was conducted as per approval of the Independent Ethics Committee, UoK No: ICCBS/IEC-008-BC-2015. The blood was collected from healthy volunteers with their informed consent, for in vivo studies animal study protocol was approved by the local ethical committee of research animals, PCMD, ICCBS, UK (ASP No. 2018–0010).

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Baig, T.A., Haniffa, H.M., Siddiqui, H. et al. A new acyl derivative of sulfadimethoxine inhibits phagocyte oxidative burst and ameliorates inflammation in a mice model of zymosan-induced generalised inflammation. Inflammopharmacol 31, 3303–3316 (2023). https://doi.org/10.1007/s10787-023-01372-0

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  • DOI: https://doi.org/10.1007/s10787-023-01372-0

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