Novel β-lactam antibiotic derivative and its complexes: DFT, frontier energy levels, DNA interaction, docking, physicochemical and antimicrobial properties
Graphical abstract
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)
- et al.
Early transmissible ampicillin resistance in zoonotic Salmonella enterica serotype Typhimurium in the late 1950s: a retrospective, whole-genome sequencing study
Lancet Infect. Dis.
(2018) - et al.
Schiff bases: a short review of their antimicrobial activities
J. Adv. Res.
(2011) - et al.
Synthesis, physicochemical elucidation, biological screening and molecular docking studies of a Schiff base and its metal (II) complexes
Arabian Journal of Chemistry
(January 2020) - et al.
Bioactivity of some divalent M (II) complexes of penicillin based Schiff base ligand: synthesis, spectroscopic characterization, and thermal study
Journal of Saudi Chemical Society
(2018) - et al.
Targeting the nucleolus for cancer intervention
Biochim. Biophys. Acta (BBA) - Mol. Basis Dis.
(2014) Exploring biologically relevant chemical space with metal complexes
Curr. Opin. Chem. Biol.
(2007)- et al.
New trends for metal complexes with anticancer activity
Curr. Opin. Chem. Biol.
(2008) - et al.
The interaction of native DNA with iron (III)-N, N′-ethylene-bis (salicylideneiminato)-chloride
J. Inorg. Biochem.
(2004) - et al.
Spectrophotometric determination of ampicillin and its dosage forms
Talanta
(1992) - et al.
Synthesis, spectral, crystal structure, thermal behavior, antimicrobial and DNA cleavage potential of two octahedral cadmium complexes: a supramolecular structure
Spectrochim. Acta Mol. Biomol. Spectrosc.
(2015)
The use of conductivity measurements in organic solvents for the characterisation of coordination compounds
Coord. Chem. Rev.
Organometallic complexes with biological molecules: XVII. Triorganotin (IV) complexes with amoxicillin and ampicillin
J. Inorg. Biochem.
DNA interaction with octahedral and square planar Ni (II) complexes of aspartic-acid Schiff-bases
J. Mol. Struct.
Geometrical structure, potentiometric, molecular docking and thermodynamic studies of azo dye ligand and its metal complexes
J. Mol. Liq.
Polymer complexes. LX. Supramolecular coordination and structures of N (4-(acrylamido)-2-hydroxybenzoic acid) polymer complexes
Spectrochim. Acta Mol. Biomol. Spectrosc.
Synthesis of 99mTc-gemifloxacin freeze dried kits and their biodistribution in Salmonella typhi, Pseudomonas aeruginosa and Klebsiella pneumoniae
Arabian Journal of Chemistry
Antipathogenic effects of structurally-related Schiff base derivatives: structure–activity relationship
Arabian Journal of Chemistry
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.
Synthesis, spectroscopic characterization, DFT optimization and biological activities of Schiff bases and their metal (II) complexes
J. Mol. Struct.
Design and synthesis of potent inhibitors of β-ketoacyl-acyl carrier protein synthase III (FabH) as potential antibacterial agents
Eur. J. Med. Chem.
Synthesis, antibacterial activities and molecular docking studies of peptide and Schiff bases as targeted antibiotics
Bioorg. Med. Chem.
Design, synthesis, and structure–activity relationships of pyrazole derivatives as potential FabH inhibitors
Bioorg. Med. Chem. Lett
Design, synthesis and antibacterial activities of vanillic acylhydrazone derivatives as potential β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors
Eur. J. Med. Chem.
Synthesis, antibacterial, antifungal activity and interaction of CT-DNA with a new benzimidazole derived Cu (II) complex
Eur. J. Med. Chem.
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
Synthesis, characterization, anti-microbial, DNA binding and cleavage studies of Schiff base metal complexes
Arabian Journal of Chemistry
Activity of ampicillin in vitro compared with other antibiotics
J. Clin. Pathol.
Origins and evolution of antibiotic resistance
Microbiol. Mol. Biol. Rev.
Complexes derived from some biologically active ligands
J. Coord. Chem.
Synthesis, spectral characterization and biological evaluation of schiff base transition metal complexes derived from ampicillin with D-glucose
Asian J. Chem.
Synthesis, characterization and biological evaluation of Schiff base transition metal complexes with ampicillin
Sci. Int.
Synthesis, characterization and biological evaluation of penicillin derivatives complexes with some transition metal ions
Int. J. Curr. Microbiol. App. Sci
Metal Complex-DNA Interactions
Cited by (9)
Complexes of β-lactam antibiotics and their Schiff-base derivatives as a weapon in the fight against bacterial resistance
2023, Coordination Chemistry ReviewsRecent advances in medicinal chemistry of ampicillin: Derivatives, metal complexes, and sensing approaches
2022, TrAC - Trends in Analytical ChemistryCitation Excerpt :Compounds 71 and 72 were more potent against methicillin-resistant Staphylococcus aureus strain than AMP. Schiff bases of AMP were also synthesized in Naz's group (73 – with glucose) [159] and Abbas' group (74 – with acetylacetone) [160] (Fig. 10). Then, the complexes with appropriate metal ions were obtained.
Novel action for ampicillin derivative and its complexes: Physicochemical, thermal analysis, DNA interaction, docking with FabH protein, in silico, and in vitro studies
2022, Journal of Molecular LiquidsCitation Excerpt :The absorption bands were prominent at 354, 267, and 240 nm due to the 2B1 g→2A1 g, n → π*, and π → π* transitions [25]. The obtained magnetic moment for [Eu(HAS)(H2O)Cl]Cl·2H2O (1.97 BM) and [Gd(HAS)(H2O)(NO3)]NO3·3H2O (7.56 BM) matched with those noted for high spin octahedral/pentagonal bi-pyramidal structures [28,31]. The UV–Vis spectra of those complexes showed an absorption band at 358 and 272 nm as n → π* and π → π* transitions, 456, 324, and 274 nm as π → π*, n → π*, and CT transitions, respectively.
Mixed-ligand complexes of ampicillin derived Schiff base ligand and Nicotinamide: Synthesis, physico-chemical studies, DFT calculation, antibacterial study and molecular docking analysis
2021, Journal of Molecular StructureCitation Excerpt :The β-lactams, characterized by the presence of β-lactam nuclei, an important species in the preparation of pharmacologically active compounds, are a diverse family of most commonly used antibiotics such as the penicillin, cephalosporin and carbapenem [13,14]. The Schiff base derivatives of ampicillin are multi-dentate ligands and forms several stable metal complexes with significant antibacterial activity [14–17]. Over the years, the penicillin based Schiff bases are tremendously used in medicinal chemistry due to their role in in treatment of bacterial diseases [18].
Four-membered ring systems
2021, Progress in Heterocyclic Chemistry