Indole-chalcone linked 1,2,3-triazole hybrids: Facile synthesis, antimicrobial evaluation and docking studies as potential antimicrobial agents
Graphical abstract
Introduction
Microbial infections-based diseases are the most common cause of mortality after heart attack across the world [1]. Emerging multi-drug resistance, intractable pathogenic microorganisms and newly rising pathogens have posed a serious public health threat for humanity worldwide in recent times [2]. It is predicted that around 700,000 death occurs annually due to drug resistant microbes and this may go up to 10 million around 2050 [3]. These circumstances highlight an essential need to develop novel class of antimicrobial agents, particularly, structurally diverse molecules with new or multi-target mechanism of action from currently available clinical antimicrobial drugs.
Indole based compounds are endowed with various pharmacodynamics properties. Indole nucleus is found in various natural and synthetic molecules [4]. A large number of drug molecules containing indole ring are reported with medicinal significance as anticancer [5], anti-viral [6], antimalarial [7], anti-inflammatory [8], antioxidant [9], anti-Alzheimer's activity [10], anti-tubercular [11], analgesic effects etc. [12,13]. Indole-based chalcones have huge biological importance like photo-induced DNA cleavage and photo generation of reactive oxygen species [14,15].
Chalcones contains an α,β-unsaturated carbonyl moiety and termed as 1,3-diphenyl-2-propen-1-one derivatives, obtained from base promoted Claisen-Schmidt reaction of benzaldehyde and acetophenone derivatives. Chalcones are also present in plants in the form of precursors of flavonoids and isoflavonoids and are typically found in vegetables, fruits and herbs and exhibit potential pharmaceutical applications. Significant biological activities are reported mainly because of double bond conjugation with carbonyl group [16]. Natural and synthetic chalcones possesses extensive pharmacological activities [17] including antitubercular [18], antifungal [19], anticancer [20], [21], enzyme inhibition [22], anti-Alzheimer’s [23], anti-HIV [24,25], α-glucosidase inhibitory activity [26], estrogenic [27], antimalarial [28], [29], [30], antioxidant [31], anti-inflammatory [32], antimicrobial activities [33]. Some chalcones also possesses the ability to block voltage-dependent potassium channels [34].
1,2,3-Triazoles are important five-membered heterocyclic compounds synthesized by click reaction between terminal alkynes and organic azides under ambient conditions. This heterocyclic scaffold has attracted interest from medicinal chemists across the globe owing to its immense pharmacological potential. 1,2,3-Triazole based heterocycles have been well exploited in many medicinal scaffolds exhibiting anti-HIV [35,36], anticancer [37], [38], [39], antimicrobial [40,41], antitubercular [42,43], anti-inflammatory [44], antioxidant [45]. Molecular hybridization is an emerging approach in medicinal chemistry and allow to design and synthesize molecular hybrids with very good pharmacological properties by the tethering of two or more pharmacophores with improved efficacy and are supposed to be more active than the parent molecule [46,47]. A large number of reports are available on synthesis and biological evaluation of 1,2,3-triazole moiety with chalcones [48], Schiff base [49], amino acids [50], isatin [51], semicarbazones [52], thiosemicarbazones [53], oxazolones [54], pyrazolines [55], etc. In view of the biological significance of triazole based hybrid molecules, we embarked on the incorporation of indole, chalcone and 1,2,3-triazole units into a single molecule. We report herein the synthesis of a new series indole-chalcone-1,2,3-triazole hybrids (4a–4e, 6a–6j) from CuAAC with an expectation to find out the antimicrobial lead molecules (Fig. 1).
Section snippets
Chemistry
A well-studied and convenient Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) [56] was used to synthesize indole-chalcone linked 1,2,3-triazole hybrids (Scheme 1; Fig. 2). Initially, Indole-3-carboxaldehyde was propargylated with propargyl bromide (80% in toluene) in using K2CO3 in DMF at room temperature. The IR spectrum of Indole-3-carboxaldehyde linked alkyne (2) exhibited two characteristics bands at 3267 and 2115 cm–1 because of C-H and CC stretching, respectively. The 1H NMR spectrum
Conclusion
In conclusion, this paper reported the synthesis of a new series of indole-chalcone-1,2,3-triazoles hybrids via click chemistry methodology. Antimicrobial assay results showed that antimicrobial potential of the synthesized triazole hybrids found to be more than the alkyne precursors which led to the conclusion that, incorporation of the triazole moiety increased the antimicrobial activity of the synthesized compounds. Compound 6b exhibited highest efficacy towards E. coli with MIC value of
General
All the chemicals were procured from commercial suppliers like sigma Aldrich, Hi-Media and used as received. The melting points (mp) of all compounds were recorded in open capillaries and are uncorrected. The completion of the reactions and the purity of all the synthesized compounds was monitored by the TLC, on silica plated aluminium sheet (SIL G/UV 254, ALUGRAM) and visualized with Ultraviolet light. IR spectra were recorded with SHIMAZDU IR AFFINITY-I using KBr pellet method. The 1H NMR and
CRediT authorship contribution statement
Monika Yadav: Validation, Formal analysis, Investigation, Writing – original draft. Kashmiri Lal: Conceptualization, Methodology, Resources, Data curation, Supervision. Aman Kumar: Validation, Formal analysis, Investigation. Ashwani Kumar: Software, Data curation. Devinder Kumar: Methodology, Formal analysis, Resources, Data curation.
Declaration of Competing Interest
No conflict of interest.
Acknowledgments
One of the authors (MY) acknowledges DST, New Delhi for the financial assistance (JRF) from PURSE program No. SR/PURSE 2/40(G). Aman Kumar thanks University Grants Commission for providing financial assistance as Senior Research Fellowship. The authors also acknowledge the support of A P J Abdul Kalam Central instrumentation laboratory, Guru Jambheshwar University of Science & Technology, Hisar, India for providing NMR and MS spectra of the compounds.
References (67)
- et al.
synthesis, in vitro anticancer and antibacterial activities and in silico studies of new 4-substituted 1,2,3-triazole–coumarin hybrids
Eur. J. Med. Chem.
(2016) Isatin derivatives and their anti-bacterial activities
Eur. J. Med. Chem.
(2019)- et al.
Computational investigations and molecular dynamics simulations envisioned for potent antioxidant and anticancer drugs using indole-chalcone-triazole hybrids
DNA Repair
(2020) - et al.
a multicomponent reaction to design antimalarial pyridyl-indole derivatives: synthesis, biological activities and molecular docking
Bioorg. Chem.
(2020) - et al.
Indole chalcones: design, synthesis, in vitro and in silico evaluation against mycobacterium tuberculosis
Eur. J. Med. Chem.
(2020) - et al.
Study of prototropic reactions of indole chalcone derivatives in ground and excited states using absorption and fluorescence spectroscopy
J. Mol. Liq.
(2020) - et al.
photogeneration of reactive oxygen species and photoinduced plasmid DNA cleavage by novel synthetic chalcones
J. Photochem. Photobiol. B Biol.
(2011) - et al.
QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity
Eur. J. Med. Chem.
(2017) - et al.
Antifungal activity of chalcones: a mechanistic study using various yeast strains
Eur. J. Med. Chem.
(2008) - et al.
The significance of N-methyl- picolinamides in the development of anticancer therapeutics: synthesis and structure-activity relationship (SAR) studies
Bioorg. Chem.
(2019)