Molecular modeling and antioxidant evaluation of new di-2-thienyl ketones festooned with thiazole or pyridine moiety

https://doi.org/10.1016/j.molstruc.2021.131287Get rights and content

Highlights

  • Synthesis of new functionalized dithienyl ketones linked thiazole and/or pyridine.

  • The DFT study was conducted to determine the HOMO-LUMO energies and Fukui's indices.

  • The local relative electrophilicity and nucleophilicity descriptors were calculated.

  • Antioxidant activity of the synthesized dithienyl ketone derivatives was explored.

  • The computational docking processes were examined toward (PDB Code: 2AS1).

ABSTRACT

Different novel derivatives of 5-(5-bromothiophen-2-oyl)-2-(phenylamino)thiophen-3-yl) ethylidene-hydrazinylthiazole and 2-(5-bromothiophen-2-oyl)thieno[2,3-b]pyridine were prepared by utilizing the synthesized (5-bromothien-2-yl) (4-acetyl-3-methyl-5-phenylaminothien-2-yl) ketone (3) as a precursor. The electronic and chemical reactivity of the derivatives toward nucleophilic, electrophilic, and radical attacks were evaluated based on quantum chemical calculations; the highest occupied molecular orbital (HOMO)-lowest occupied molecular orbital (LUMO) energies and Fukui indices were determined using the density functional theory (DFT) at Becke, 3-parameter, Lee–Yang–Parr (B3LYP) level. Compound 6 possessed the lowest HOMO energy value (EH), LUMO energy value (EL), and energy gap (ΔEH-L). Significant inhibition percentage was observed while evaluating the antioxidant activities of the synthesized di-2-thienyl ketones 3–8 using vitamin C as a reference drug. The highest antioxidant activity with an IC50 value of 39.85 and 34.37 µM was observed for the di-2-thienyl ketones 5 and 6 incorporating thiazole ring. Meanwhile, the rest of the di-2-thienyl ketone derivatives displayed reasonable IC50 values from 51.60 to 68.88 µM. This experimental data was supported by molecular docking analysis of the interactions between di-2-thienyl ketone compounds and cytochrome c peroxidase (PDB Code: 2AS1) applied through Molecular Operating Environment (MOE) v10.2015.10.

Introduction

Heterocyclic compounds are highly abundant organic compounds and are of great significance in the pharmaceutical and healthcare industry. Thiophene and its analogs are considered the most important heterocyclic compounds [1], [2], [3]. They are popular among chemists and biologists owing to their biological efficacies and implementation in the synthetic routes [4,5]. A lot of compounds containing thiophene rings demonstrated substantial pharmacological and physiological properties like anti-psychotic [6], anti-mitotic [7], anti-arrhythmic [8], kinases inhibiting [9], anti-anxiety [10], antioxidant [11], and anticancer [12]. The existence of polar functional moieties, hydrophobic groups, and the lack of steric hindrance are the factors contributing to thiophene's biological activities, including the antioxidant activity [13]. Thienyl ketones have significant clinical applications; various thienyl ketone hybrids, for example, Suprofen (2-[4-(2-thienyl-carbonyl)phenyl]propanoic acid) and Tiaprofenic (2-[5-benzoyl-2-thienyl]propanoic acid) are classified as anti-inflammatory drugs with analgesic and antipyretic properties (Fig. 1) [14]. They inhibit the formation of malondialdehyde (MDA), which is a marker of oxidative stress, in human platelets stimulated by arachidonic acid [15]. Thiazoles are additionally interesting class of heterocyclic compounds, they have attracted continuing interest over the years due to numerous pharmacological applications and varied biological activities [16], [17], [18]. Thiazole derivatives are also known to possess several anticancer activities through diverse mechanisms [19], [20], [21], [22], [23], [24].

As the world population is increasing day by day, health problems are also growing exponentially. Therefore, the synthesis of novel drug molecules, especially with antioxidant properties, has become a research necessity because antioxidants are known to defend the cells from free radical attack and inhibit various conditions like cancer, Alzheimer's disease‏, cell destruction, and heart attack [25,26]. Antioxidants play a major role in protecting the biological function of cytochrome c, which stimulates automated cell death (apoptosis) when liberated from mitochondria to cytosol [27]. Based on the above, the strategy of this research article includes gathering the bioactive di-2-thienyl ketone with thiazole and/or pyridine in one structure and explored the prepared hybrids as antioxidant agents. The HOMO-LUMO energies and Fukui's indices of the synthesized compounds were determined using the DFT study. The antioxidant potential of the synthesized dithienyl ketone hybrids was examined using the DPPH assay and the results showed compounds 9 and 9 have promising activity. Furthermore, a docking study was carried out for all synthesized hybrids to predict their binding mode with cytochrome c peroxidase (PDB Code: 2AS1).

Section snippets

Synthesis of the targeted functionalized dithienyl ketones

Melting points of the compounds were measured in degree centigrade using Gallenkamp apparatus, and the infrared (IR) spectroscopic analysis (using potassium bromide [KBr]) was carried out using Thermo Scientific Nicolet iS10 FTIR spectrometer. The proton nuclear magnetic resonance (1H NMR) and Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded on JEOL's NMR 500 MHz spectrometer using hexadeuterodimethyl sulfoxide (DMSO-d6) as solvent. The mass analyses were performed on

Synthesis of functionalized dithienyl ketones

The reaction of 2-acetyl-3-oxo-N-phenylbutanethioamide (2) [36] with 5-bromo-2-(bromoacetyl)-thiophene (1) in the presence of triethylamine was achieved in boiling ethyl alcohol, resulting in 3-acetyl-5-(5-bromothiophen-2-oyl)-4-methyl-2-(phenylamino)thiophene (3) (Scheme 1). Displacement of the bromine atom from 5-bromo-2-(bromoacetyl)-thiophene (1) with nucleophilic sulfur of thiol form 2′ resulted in the non-isolable thioether intermediate A, which underwent intramolecular elimination of

Conclusion

The core functionalized (5-bromothien-2-yl) (4-acetyl-3-methyl-5-phenylaminothien-2-yl) ketone (3) was prepared by cyclization of 2-acetyl-3-oxo-N-phenylbutanethioamide with 5-bromo-2-(bromoacetyl)-thiophene. The di-2-thienyl ketones 5 and 6 incorporating thiazole moiety were produced based on Hantzsch methodology, which involved the reaction of di-2-thienyl ketone thiosemicarbazone 4 with chloroacetic acid and chloroacetone, respectively. The reactions of d-2-ithienyl ketone 3 with DMF-DMA and

Declaration of Competing Interest

The author declares that there is no conflict of interest.

References (64)

  • S.S. Korshunov et al.

    The antioxidant functions of cytochrome c

    FEBS Lett.

    (1999)
  • I.I. Althagafi et al.

    Synthesis, molecular modeling and antioxidant activity of new phenolic bis-azobenzene derivatives

    J. Mol. Struct.

    (2019)
  • R. Brenk et al.

    Probing molecular docking in a charged model binding site

    J. Mol. Biol.

    (2006)
  • M. Bakir et al.

    Novel κ2-Nim, S-and κ4-C, Nim,(μ-S),(μ-S)-coordination of di-2-thienyl ketone thiosemicarbazone (dtktsc). Hydrogen evolution and catalytic properties of palladacyclic [Pd (κ4-C, Nim,(μ-S),(μ-S)-dtktsc-2H)]4

    Inorg. Chim. Acta

    (2020)
  • M. Bakir

    X-ray crystallographic, spectroscopic and electrochemical properties of a bi-stable di-2-thienyl ketone 2,4-dinitrophenyl hydrazone (dtkdnph)

    J. Mol. Struct.

    (2018)
  • M. Bakir et al.

    Spectroscopic and electrochemical properties of di-2-thienyl ketone thiosemicarbazone (dtktsc): electrochemical reactions with electrophiles (H+ and CO2)

    Electrochim. Acta

    (2016)
  • M. Bakir et al.

    X-ray crystallographic, electrochemical and spectroscopic properties of 2-pyridinio 2-pyridyl ketone phenyl hydrazone chloride hydrate

    J. Mol. Struct.

    (2004)
  • G. Distefano et al.

    Ab initio determination of the geometric structure of oligo-2-thienyl ketones

    J. Mol. Struct.: THEOCHEM

    (1998)
  • D. Sajan et al.

    Natural bond orbital analysis, electronic structure, non-linear properties and vibrational spectral analysis of L-histidinium bromide monohydrate: a density functional theory

    Spectrochim. Acta A

    (2011)
  • S. Xavier et al.

    NMR and electronic spectral study on 1-phenyl-1-propanol by quantum computational methods

    Spectrochim. Acta A

    (2015)
  • M.M. Makhlouf et al.

    Experimental and DFT insights into molecular structure and optical properties of new chalcones as promising photosensitizers towards solar cell applications

    Appl. Surf. Sci.

    (2018)
  • A. Bouchoucha et al.

    Synthesis and characterization of new complexes of nickel (II), palladium (II) and platinum(II) with derived sulfonamide ligand: Structure, DFT study, antibacterial and cytotoxicity activities

    J. Mol. Struct.

    (2018)
  • J.B. Bhagyasree et al.

    Vibrational spectroscopic (FT-IR, FT-Raman, (1)H NMR and UV) investigations and computational study of 5-nitro-2-(4-nitrobenzyl)benzoxazole

    Spectrochim. Acta A

    (2013)
  • Z. El Adnani et al.

    DFT theoretical study of 7-R-3methylquinoxalin-2 (1H)-thiones (RH; CH3; Cl) as corrosion inhibitors in hydrochloric acid

    Corros. Sci.

    (2013)
  • H. Mi et al.

    Theoretical evaluation of corrosion inhibition performance of three antipyrine compounds

    Comput. Theor. Chem.

    (2015)
  • M. Messali et al.

    A new schiff base derivative as an effective corrosion inhibitor for mild steel in acidic media: Experimental and computer simulations studies

    J. Mol. Struct.

    (2018)
  • A. Padmaja et al.

    Synthesis and antioxidant activity of oxazolyl/thiazolylsulfonylmethyl pyrazoles and isoxazoles

    Eur. J. Med. Chem.

    (2011)
  • R.H. Bisby et al.

    Effect of antioxidant oxidation potential in the oxygen radical absorption capacity (ORAC) assay

    Food Chem.

    (2008)
  • R. Cherdtrakulkiat et al.

    Derivatives (halogen, nitro and amino) of 8-hydroxyquinoline with highly potent antimicrobial and antioxidant activities

    Biochem. Biophys. Rep.

    (2016)
  • T.M. Kadayat et al.

    Modified 2, 4-diaryl-5H-indeno[1,2-b] pyridines with hydroxyl and chlorine moiety: synthesis, anticancer activity, and structure–activity relationship study

    Bioorg. Chem.

    (2015)
  • S.S. Giles et al.

    Cytochrome c peroxidase contributes to the antioxidant defense of Cryptococcus neoformans

    Fungal. Genet. Biol.

    (2005)
  • T. Guo et al.

    Biological activity evaluation and action mechanism of chalcone derivatives containing thiophene sulfonate

    RSC Adv.

    (2019)
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