Indole-chalcone linked 1,2,3-triazole hybrids: Facile synthesis, antimicrobial evaluation and docking studies as potential antimicrobial agents

https://doi.org/10.1016/j.molstruc.2022.132867Get rights and content

Highlights

  • New series of indole-chalcone linked 1,2,3-triazole hybrids was synthesized.

  • Indole-chalcone linked 1,2,3-triazole hybrids exhibited better antimicrobial activity compared to Indole aldehyde linked 1,2,3-triazoles.

  • 6a with MIC of 0.0063 µmol/mL was found to be most effective against R. oryzae.

  • Docking studies were performed with E. coli Gyr A and C. albicans 14-α-demethylase.

Abstract

The design and synthesis of a new series of indole-chalcone linked 1,2,3-triazole hybrids via Cu(Ι)-catalyzed azide-alkyne cycloaddition is reported. All the compounds (2, 4a–4e and 6a–6j) were well characterized by different analytical and spectral methods and screened in vitro for antimicrobial evaluation against Gram-positive bacteria, Gram-negative bacteria and fungal strains. Most of the synthesized hybrids showed significant potency with MIC values from 10.9 µM to 39.4 µM against bacterial strains. Antifungal data revealed that compound 6a with MIC of 6.3 µM was found to be most effective against R. oryzae. Docking simulations of the compounds 2, 4b and 6b were performed with of E. coli DNA gyrase, while molecule 6g along with 4b and 2 was docked into active sites of C. albicans alpha lanosterol demethylase.

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-Alzheimers [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 triple bondC-H and Ctriple bondC 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.

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