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  3. Design, synthesis and evaluation of novel pyrrole-hydroxybutenolide hybrids as promising antiplasmodial and anti-inflammatory agents

Design, synthesis and evaluation of novel pyrrole-hydroxybutenolide hybrids as promising antiplasmodial and anti-inflammatory agents

  • Eur J Med Chem. 2023 Jun 5;254:115340. doi: 10.1016/j.ejmech.2023.115340.
Alka Raj Pandey 1,  Suriya Pratap Singh 2,  Prince Joshi 3,  Kunwar Satyadeep Srivastav 4,  Smriti Srivastava 5,  Kanchan Yadav 3,  Ramesh Chandra 5,  Amol Chhatrapati Bisen 6,  Sristi Agrawal 6,  Sachin Nashik Sanap 6,  Rabi Sankar Bhatta 6,  Renu Tripathi 3,  Manoj Kumar Barthwal 4,  Koneni V Sashidhara 7
Affiliations

Affiliations

  • 1 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P, India.
  • 2 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 3 Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P, India.
  • 4 Division of Pharmacology, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P, India.
  • 5 Division of Pharmacology, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
  • 6 Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P, India.
  • 7 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India; Sophisticated Analytical Instrument Facility & Research, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, U.P, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P, India. Electronic address: kv_sashidhara@cdri.res.in.
PMID: 37054559 DOI: 10.1016/j.ejmech.2023.115340
Abstract

In the pursuance of novel scaffolds with promising antiplasmodial and anti-inflammatory activity, a series of twenty-one compounds embraced with most promising penta-substituted pyrrole and biodynamic hydroxybutenolide in single skeleton was designed and synthesized. These pyrrole-hydroxybutenolide hybrids were evaluated against Plasmodium falciparum Parasite. Four hybrids 5b, 5d, 5t and 5u exhibited good activity with IC50 of 0.60, 0.88, 0.97 and 0.96 μM for chloroquine sensitive (Pf3D7) strain and 3.92, 4.31, 4.21 and 1.67 μM for chloroquine resistant (PfK1) strain, respectively. In vivo efficacy of 5b, 5d, 5t and 5u was studied against the P. yoelii nigeriensis N67 (a chloroquine-resistant) Parasite in Swiss mice at a dose of 100 mg/kg/day for 4 days via oral route. 5u was found to show maximum 100% Parasite inhibition with considerably increased mean survival time. Simultaneously, the series of compounds was screened for anti-inflammatory potential. In preliminary assays, nine compounds showed more than 85% inhibition in hu-TNFα cytokine levels in LPS stimulated THP-1 monocytes and seven compounds showed more than 40% decrease in fold induction in reporter gene activity analyzed via Luciferase assay. 5p and 5t were found to be most promising amongst the series, thus were taken up for further in vivo studies. Wherein, mice pre-treated with them showed a dose dependent inhibition in carrageenan induced paw swelling. Moreover, the results of in vitro and in vivo pharmacokinetic parameters indicated that the synthesized pyrrole-hydroxybutenolide conjugates abide by the required criteria for the development of orally active drug and thus this scaffold can be used as pharmacologically active framework that should be considered for the development of potential antiplasmodial and anti-inflammatory agents.

Keywords

Antiinflammatory activity; Antimalarial activity; CQ-Resistant; CQ-Sensitive; Carrageenan; Hu-TNFα; Luciferase assay; Plasmodium falciparum; Plasmodium yoelli; Pyrrole-hydroxybutenolides.

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