Novel β-lactam antibiotic derivative and its complexes: DFT, frontier energy levels, DNA interaction, docking, physicochemical and antimicrobial properties

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Highlights

  • New ampicillin Schiff base and its nano-particle size complexes synthesized and characterized.

  • New drug derivative and its Cu and Co complexes gave antimicrobial activity exceeded the parent market drug.

  • Docking and DNA interaction clearly prove the potency of the prepared compounds.

  • In silico treatments gave excellent comparable result with the in vitro results.

Abstract

Ampicillin

acetylacetone Schiff base (HAA) and its complexes with Co(II), Ni(II), Cu(II), Eu(III) and Gd(III) obtained in pure form. The obtained compounds characterized by CHNM%, FTIR, UV–Vis, Fluorescence, 1HNMR, Mass spectra, DTA, TGA, Magnetic susceptibility, X-ray, AAS, melting point, solubility in different solvents and the conductivity of 0.001 M in DMSO. The obtained data indicate the formation of the target complexes in the form [Co(AA)(H2O)2]NO3.2H2O, [Ni(AA)(H2O)2]Cl.4H2O, [Cu(AA)]Cl.2.5H2O, [Eu(AA)(H2O)Cl]Cl.6H2O and [Gd(AA)(H2O)(NO3)]NO3.2H2O. Co and Ni gave Oh structure while Cu gave square planar form. The Crystal field parameters calculated and discussed for the target complexes. Molecular modelling, molecular mechanics and DFT calculation carried out to the synthesized compounds. The x-ray analysis indicates the nanoparticle behaviour for the Cu-AA complex with an orthorhombic structure. The interactions of the synthesized complexes with DNA moiety investigated with means of spectrometric titration (UV–vis. spectra) and by using fluorescence spectroscopy. Antimicrobial activities of the synthesized compounds screened using the disc diffusion method. HAA and Cu-AA gave activity exceeded the Ampicillin. The docking work carried using the targeting protein of Escherichia coli FabH (PDB code: 1HNJ). The obtained binding energy compared and discussed in terms of the in vitro studies.

Introduction

Ampicillin shows complete resistance to certain microorganisms such as Klebsiella sp, Enterobacter sp, Proteus Vulgaris, Pseudomonas Aeruginosa and no activity is recorded with beta-lactamase creating Staphylococci. Pathogens such as Streptococcus Pyogenes, Bacillus subtilis, Escherichia coli, and Salmonella typhi [[1], [2], [3]] known to be susceptible to ampicillin. Treatment still shows lower minimum inhibition concentration when compared to other prevailing antibiotics from ampicillin. Ampicillin derivatives exhibit improved antibacterial action towards susceptible bacteria and some effects on high resistance ones [4].

Reports showed that the complexes derived from some ligands have wide applications in industrial, medicinal, agricultural, or pharmaceutical fields, sometimes gave activity and efficiency larger than its components (ligands and the central metal ions) [[5], [6], [7]]. So, the scientists went in this direction, which they prepared and characterized some of these complexes.

Orabi, studied the synthesis of some divalent metals (Mg, Ca, Zn, Cu, Ni, Co) and Ce(III), Nd(III), UO2(VI) and Th(IV) complex with ampicillin and amoxicillin. As an antibacterial agent, the synthesized compounds were tested. The formed complexes had enhanced activity [5].

Alabdali et al., reported the preparation of new ligands to result from the interaction of terephthaldehyde and glyoxal with the antibacterial 6-amino penicillanic acid (6- APA) and their complexes with cobalt, copper, and zinc. The evaluation of the synthesized compounds showed higher activity and sensitivity both Gram-positive and Gram-negative organisms [8].

Also, Chaudhary, et al., also mentioned the antibacterial activity and molecular modelling of Co+2, Ni+2, Cu+2, and Zn+2 complexes derived from amoxicillin trihydrate and nicotinaldehyde Schiff base. All compounds were screened, in vitro, against four bacterial pathogens, namely, E. coli, P. Vulgaris, K. pneumonia, and S. aureus, and showed better activity compared to parent drug and control drug [9]. Recent research showed the bioactivity of some divalent Co, Ni, Cu, and Zn synthesized from Schiff base derived from amoxicillin and picolinaldehyde, which showed promising antibacterial activity against four human pathogenic clinical strains of bacteria [10].

DNA is the pharmacological target of several of the drugs that are in medical use or in advanced clinical tests. Targeting DNA to modify cell functions. Small ligand molecules join to DNA and synthetically change and/or inhibit the functioning of it. These ligand molecules work as a drug when modification of DNA function is needed to treat or control disease [11].

Metal ions stabilize a specific nucleic acid structure and can cause the denaturation of the native conformation, forming other structural motifs such as triple-strand formation, condensation, and nucleic acid aggregation. In fact, most of these structural changes influence the in vivo nucleic acid functions [12]. Several recent accounts highlight the growing interest in the interactions of metal ions and metal complexes with nucleic acids in specific for therapeutic applications [[13], [14], [15], [16]].

Transition metals can induce or suppress cellular interactions related to DNA as they manipulate the function of cells to produce the desired result, thereby allowing the diagnosis or treatment of disease [[17], [18], [19], [20]]. They are ideal for these purposes, as their great diversity in structures, as well as their electrochemical and photophysical unique properties, can allow for specific interactions between DNA and other biomolecules [21], while their spectroscopic characteristics facilitate use as probes for biophysical studies [22]. Consequently, there is extraordinary interest in the development of transition metal complexes given the extensive array of readily available ligands for coordination and the different geometries, coordination numbers, redox potentials, kinetic and thermodynamic characteristics of the metals [23].

Transition metal complexes are known to bind to DNA via both covalent and non-covalent interactions. In covalent binding, the labile ligand of the complexes is replaced by a nitrogen base of DNA. On the other hand, the non-covalent DNA interactions include intercalative, electrostatic, and groove (surface) binding of cationic metal complexes outside of the DNA helix, major or minor groove [24].

After the development of the initial algorithms in the 1980s, molecular docking became an important tool in structure-based drug discovery and drug design [25,26]. The molecular docking approach is very critical to model the interaction between ligand molecule, small molecule, which would form a complex and a protein at the atomic level and to find the best orientation with overall minimum energy, which allows us to determine the binding mode and affinity between the constituent molecules in molecular recognition to understand the interaction mechanisms and to designing therapeutic interventions proteins as well as to elucidate fundamental biochemical processes [27].

In the present work, a new Ampicillin derivative was prepared by condensation of the Ampicillin with acetylacetone. Cobalt(II), Nickel(II), Copper(II), Europium(III), and Gadolinium(III) complexes were synthesized by the reaction of the target metal nitrates or chlorides, with the prepared ligand. The synthesized ligand and its complexes were characterized using different tools. The physicochemical properties were evaluated in silico and experimental levels. The in vitro bioactivity behaviour was tested on the Gram +ve, Gram –ve bacteria, and fungi. The docking and DNA interaction results indicate the promising data which strongly advice to use the newly synthesized compounds as a new drug.

Section snippets

Materials

All chemical reagents and solvents employed for the synthesis were of analytical grade and obtained from Aldrich. Ampicillin trihydrate in its pure form was obtained from a Pharmaceutical Corporation and was used without additional purification. The extra pure form of acetylacetone purchased from Aldrich used as received. Cupric chloride dihydrate (CuCl2.2H2O), nickel chloride hexahydrate (NiCl2.6H2O), cobalt nitrate hexahydrate (Co(NO3)2.6H2O), europium chloride hexahydrate (EuCl3.6H2O) and

Characterization of the drug derivative HAA

The purity of the formed compound and the progress of the reaction were tested using thin-layer chromatography, which performed on the silica gel plates with a suitable solvent system (90% Chloroform:10% Ethanol). The ligand HAA has the molecular formula C21H25N3O5S (M.wt = 431.505). HAA was formed as a canary yellow crystalline form with a melting point = 200 °C. The solubility of the ligand under consideration was investigated in some polar and non-polar solvents, it was soluble in common

Conclusion

The new Ampicillin derivative HAA was synthesized and obtained in pure form. The obtained HAA reacted with Co(II), Ni(II), Cu(II), Eu(III) and Gd(III) gave the target complexes. Generally, HAA and its metal complexes gave bio-activity larger than the market drug Ampicillin. The new Cu-AA complex has a square planar structure. The newly HAA ligand and Cu-AA complex gave a wide spectra effect towards the target microorganism exceeded the parent Ampicillin. Co complex gave antimicrobial activity

CRediT authorship contribution statement

Abbas M. Abbas: Conceptualization, Methodology, Funding acquisition, Formal analysis, Writing - review & editing, Writing - original draft. Sara R. Fisal: Conceptualization, Methodology, Funding acquisition, Formal analysis, Writing - review & editing, Writing - original draft. Adel S. Orabi: Conceptualization, Methodology, Funding acquisition, Formal analysis, Writing - review & editing, Writing - original draft.

Acknowledgments

We would like to thank Dr. Salah Abo-Bakr, Geology Department, Faculty of Science, Suez Canal University, Egypt, for his generous support by x-ray analysis.

References (70)

  • W.J. Geary

    The use of conductivity measurements in organic solvents for the characterisation of coordination compounds

    Coord. Chem. Rev.

    (1971)
  • R. Di Stefano et al.

    Organometallic complexes with biological molecules: XVII. Triorganotin (IV) complexes with amoxicillin and ampicillin

    J. Inorg. Biochem.

    (2002)
  • S. Sallam et al.

    DNA interaction with octahedral and square planar Ni (II) complexes of aspartic-acid Schiff-bases

    J. Mol. Struct.

    (2011)
  • A. El-Bindary et al.

    Geometrical structure, potentiometric, molecular docking and thermodynamic studies of azo dye ligand and its metal complexes

    J. Mol. Liq.

    (2016)
  • M. Ghoneim et al.

    Polymer complexes. LX. Supramolecular coordination and structures of N (4-(acrylamido)-2-hydroxybenzoic acid) polymer complexes

    Spectrochim. Acta Mol. Biomol. Spectrosc.

    (2015)
  • S. Shahzad et al.

    Synthesis of 99mTc-gemifloxacin freeze dried kits and their biodistribution in Salmonella typhi, Pseudomonas aeruginosa and Klebsiella pneumoniae

    Arabian Journal of Chemistry

    (2019)
  • S. Hisaindee et al.

    Antipathogenic effects of structurally-related Schiff base derivatives: structure–activity relationship

    Arabian Journal of Chemistry

    (2015)
  • P. Tyagi et al.

    Synthesis, characterization of 1, 2, 4-triazole Schiff base derived 3d-metal complexes: induces cytotoxicity in HepG2, MCF-7 cell line, BSA binding fluorescence and DFT study

    Spectrochim. Acta Mol. Biomol. Spectrosc.

    (2017)
  • A. Rauf et al.

    Synthesis, spectroscopic characterization, DFT optimization and biological activities of Schiff bases and their metal (II) complexes

    J. Mol. Struct.

    (2017)
  • L. Shi et al.

    Design and synthesis of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III (FabH) as potential antibacterial agents

    Eur. J. Med. Chem.

    (2010)
  • K. Cheng et al.

    Synthesis, antibacterial activities and molecular docking studies of peptide and Schiff bases as targeted antibiotics

    Bioorg. Med. Chem.

    (2009)
  • P.-C. Lv et al.

    Design, synthesis, and structure–activity relationships of pyrazole derivatives as potential FabH inhibitors

    Bioorg. Med. Chem. Lett

    (2010)
  • X.-L. Wang et al.

    Design, synthesis and antibacterial activities of vanillic acylhydrazone derivatives as potential β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors

    Eur. J. Med. Chem.

    (2012)
  • F. Arjmand et al.

    Synthesis, antibacterial, antifungal activity and interaction of CT-DNA with a new benzimidazole derived Cu (II) complex

    Eur. J. Med. Chem.

    (2005)
  • N. Raman et al.

    Design, synthesis, DNA binding ability, chemical nuclease activity and antimicrobial evaluation of Cu (II), Co (II), Ni (II) and Zn (II) metal complexes containing tridentate Schiff base

    Journal of Saudi Chemical Society

    (2013)
  • P. Jayaseelan et al.

    Synthesis, characterization, anti-microbial, DNA binding and cleavage studies of Schiff base metal complexes

    Arabian Journal of Chemistry

    (2016)
  • R. Sutherland et al.

    Activity of ampicillin in vitro compared with other antibiotics

    J. Clin. Pathol.

    (1964)
  • J. Davies et al.

    Origins and evolution of antibiotic resistance

    Microbiol. Mol. Biol. Rev.

    (2010)
  • A.S. Orabi

    Complexes derived from some biologically active ligands

    J. Coord. Chem.

    (2008)
  • N. Naz et al.

    Synthesis, spectral characterization and biological evaluation of schiff base transition metal complexes derived from ampicillin with D-glucose

    Asian J. Chem.

    (2013)
  • I. Bukhari et al.

    Synthesis, characterization and biological evaluation of Schiff base transition metal complexes with ampicillin

    Sci. Int.

    (2005)
  • A.J. Alabdali et al.

    Synthesis, characterization and biological evaluation of penicillin derivatives complexes with some transition metal ions

    Int. J. Curr. Microbiol. App. Sci

    (2016)
  • V.V. Andrushchenko, VCD and IR Spectroscopic Study of Metal Ion Induced Structural Changes of Synthetic and Natural...
  • N.V. Hud, Nucleic Acid-Metal Ion Interactions, Royal Society of...
  • N. Hadjiliadis et al.

    Metal Complex-DNA Interactions

    (2009)
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