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

Mohammed A S Abourehab,Dana M Zaher,Faisal A Almalki,Alaa M Alqahtani,Ashraf N Abdalla,Ahmed M Gouda,Eman A M Beshr

doi:10.3390/molecules26216582

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.

Highlights

More than 150 anticancer drugs approved by the FDA for the treatment of different types of cancer are available in the market [1]
The design of anticancer-NSAID hybrids could be used to avoid some of the problems encountered in combination therapy
The new hybrids were evaluated for their antiproliferative activities against three (MCF-7, A549, and HT-29) cancer cell lines using a quick screening assay

Summary

Introduction

More than 150 anticancer drugs approved by the FDA for the treatment of different types of cancer are available in the market [1]. Weninger et al [22] have reported a series of acetylsalicylic acid derivatives with Zeise’s Salt (IIa–d) These derivatives exhibited growth-inhibitory activities against HT-29 and MCF-7 cancer cells at IC50 values in the range of 30-50 μM. The new conjugate exhibited much higher cytotoxic activity compared to the parent components It inhibited the growth of HCT15 and HCT116 cancer cell lines at IC50 of 0.45 and 0.26 μM, respectively. We reported compound VIIIa–c (Figure 2) with in vivo anti-inflammatory activities comparable with that of ibuprofen [28,29] Two of these hybrids (VIIIb,c) were investigated for their cytotoxic activity against three cancer cell lines (IC50 = 0.406o-f02.487 μM). An additional investigation will be performed to evaluate the potential mechanism of their action of the most active compounds

Chemistry

Conclusions

Drug-Likeness and ADME Studies