Pyrrolizine/Indolizine-NSAID Hybrids: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies

Abstract

In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5 μM) was investigated against MCF-7, A549, and HT-29 cancer cell lines using the cell viability assay, MTT assay. The results revealed 4–71% inhibition of the growth of the three cancer cell lines, where 8a,e,f were the most active. In addition, an investigation of the antiproliferative activity of 8a,e,f against MCF-7 cells revealed IC50 values of 7.61, 1.07, and 3.16 μM, respectively. Cell cycle analysis of MCF-7 cells treated with the three hybrids at 5 μM revealed a pro-apoptotic increase in cells at preG1 and cell cycle arrest at the G1 and S phases. In addition, the three hybrids induced early apoptotic events in MCF-7 cells. The results of the molecular docking of the three hybrids into COX-1/2 revealed higher binding free energies than their parent compounds 5a,c and the co-crystallized ligands, ibuprofen and SC-558. The results also indicated higher binding free energies toward COX-2 over COX-1. Moreover, analysis of the binding modes of 8a,e,f into COX-2 revealed partial superposition with the co-crystallized ligand, SC-558 with the formation of essential hydrogen bonds, electrostatic, or hydrophobic interactions with the key amino acid His90 and Arg513. The new hybrids also showed drug-likeness scores in the range of 1.06–2.03 compared to ibuprofen (0.65) and ketoprofen (0.57). These results above indicated that compounds 8a,e,f deserve additional investigation as potential anticancer candidates.

Synthesis and Biological Activities of Acetaminophen and Ibuprofen Metal Complexes or Derivatives: A Review

“…Even though ibuprofen was not evaluated in this study, previous research has shown that it provides limited inhibitory effect against MCF-7 (Pedro-Hernández et al, 2017). Several amide derivatives of ibuprofen have shown enhanced antiproliferative effects when compared to the parent drug (Abourehab et al, 2021). This supports that dexibuprofen-amide derivatives are more effective in inhibiting MCF-7 than the parent drug, ibuprofen (He et al, 2021).…”

Design and synthesis of hybrid compounds as novel drugs and medicines

“… 32 Encouraged by the above findings, Abourehab et al designed and synthesised a new series of hybrids by linking the pyrrolizine/indolizine derivatives with ibuprofen or ketoprofen NSAIDs. 33 These two scaffolds were selected based on their promising cytotoxic activity. The antiproliferative activities of these compounds/hybrids were investigated and showed 4–71% inhibition of the growth of three cancer cell lines, MCF-7, A549, and HT-29.…”

“…7, the most active compounds, revealed IC 50 values of 7.6, 1.1, and 3.2 mM, respectively, against MCF-7 cells. 33 Non-viral gene therapy (NVGT)…”

A Comprehensive Overview of Globally Approved JAK Inhibitors

“…In this work, the crystal structures of JAK kinases were visualized using the Discovery Studio Visualizer [ 47 ]. The crystals were prepared by removing water molecules following the previous reports [ 48 , 49 ]. Moreover, 2/3D binding modes of the JAK inhibitors into the co-crystallized kinases were visualized according to the previous report [ 50 ].…”