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