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org/journal/acsodf Review

Synthesis and Pharmacological Activities of Chalcone and Its

Derivatives Bearing N‑Heterocyclic Scaffolds: A Review
Kibrom Mezgebe, Yadessa Melaku, and Endale Mulugeta*

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ABSTRACT: The incorporation of heterocyclic moieties into the standard

chemical structure with a biologically active scaffold has become of crucial practice
for the construction of pharmacologically potent candidates in the drug arena.
Currently, numerous kinds of chalcones and their derivatives have been synthesized
using the incorporation of heterocyclic scaffolds, especially chalcones bearing
heterocyclic moieties that display improved efficiency and potential for drug
production in pharmaceutical sectors. The current Review focuses on recent
advances in the synthetic approaches and pharmacological activities such as
antibacterial, antifungal, antitubercular, antioxidant, antimalarial, anticancer, anti-
inflammatory, antigiardial, and antifilarial activities of chalcone derivatives
incorporating N-heterocyclic moieties at either the A-ring or B-ring.

■ INTRODUCTION
Chalcone scaffolds are privileged chemical structures in the
medicine to prepare potential drug discovery and improve
pharmaceuticals (Figure 2).10
medicinal chemistry sector.1 They are secondary metabolites of Chalcone derivatives incorporating heterocyclic scaffolds are
plants and found in α,β-unsaturated forms, which have a more become promising candidates as future drug sources owing to
thermodynamically stable trans-conformation between two aryl their similar or superior activities compared to those of the
groups.2 Chalcone and its derivatives are the cores of various standard derivatives.11 To date, the basic chemical structure of
biologically interesting compounds, and frequently they have chalcone serves as potential source of much research for
been isolated from different medicinal plants such as Dracaena planning to design and develop various drugs. On top of this,
cinnabari, Medicago sativa, and Angelica keiskei (Figure 1).3−6 many researchers are exhaustively devoted to synthesizing a
chalcone derivative incorporating a heterocyclic scaffold.
Chalcones incorporating heterocyclic scaffolds have been
reported with various biological and pharmacological activities,
such as antioxidant activity,12 antibacterial activity,12 antifungal
activity,13 antileishmanial activity,14 anti-inflamatory activity,15
anticancer activity,16 antitubercular activity,17 antiproliferative
Figure 1. General chemical structures of chalcone 1 and its derivative 2. agents,17 antimalarial activity,18 antiplatelet activity,19 carbonic
anhydrase inhibitors,20 an inhibitor of microsomalenzyme
glutathione-S-transferases,21 and CYP1 enzyme inhibitors.22
Chemically chalcones are easily prepared using various Chalcones with an N-heterocyclic moiety such as pyrrole,
reaction procedures and strategies. For instance, the named imidazole, thiazole, pyrazole, oxazole, isooxazole, pyridine,
reaction Claisen-Schmidt condensation is one common pyrazoline, indole, benzothiazole, benzimidazole, and quinoline
methodology to prepare the title compound through carbonyl scaffolds play a significant role in the area of medicine.11
derivative condensation in the presence of base. Additionally, Compounds 10, imidazole-based chalcone derivatives, displayed
the carbonylative Heck coupling reaction, the Sonogashira
isomerization coupling reaction, the continuous flow deutera-
tion reaction, the Suzuki−Miyaura coupling reaction, and solid Received: February 15, 2023
acid catalyst-mediated reactions are known.7 The precursors of Accepted: May 5, 2023
the flavonoids and isoflavones, chalcones serve as promising Published: May 22, 2023
template scaffolds for synthesizing and developing pharmaco-
logically active compounds in conjugation with other hetero-
cyclic moieties8,9 which have a large role in the sector of
© 2023 The Authors. Published by
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Figure 2. Chemical structures of chalcone scaffold-based drugs.

Figure 3. Chemical structures of heterocycle-based chalcone derivatives.

Scheme 1. General Synthetic Route toward Chalcone Derivatives Incorporating Pyrrole

inhibition activity on MAO-A better than the standard drug.23 2- Thus, the current Review presents the various synthetic
Benzimidazole chalcone (11) with a p-bromo group substituted protocols used to prepare chalcones incorporated with N-
to the phenyl ring acted as an insect antifeedant agent.24 heterocyclic moieties and their wide spectrum of biological
Williams and co-workers reported a series of pyrrole-based activities.
chalcone derivatives and evaluated the biological activity of the
CPY1 enzyme inhibition potential. The derivative 12a displayed 2. SYNTHESIS OF CHALCONE BEARING AN
the most selective inhibition of CYP1B1, and 12b was shown to N-HETEROCYCLIC SCAFFOLD
inhibit both CYP1A1 and CYP1B1 isoforms with minimum IC50 2.1. Chalcone Bearing Pyrrole. Series of pyrrole-based
values.25 Among the heterocyclic derivatives, thiophene-based chalcone derivatives were reported through the classical
chalcone derivative 13 displayed a calculated inhibitory constant Claisen−Schimdt condensation reaction protocol.28 The
value of approximately 0.64 μM toward the active site of MAO- synthesized compounds displayed potential activity on the
inhibition of CYP1 isoforms. As depicted in Scheme 1, the
B.26 Most of the time, furan-containing chalcone derivatives
reaction afford products of various derivatives 18 starting from
were found to be more active than the others. Derivative 14 aromatic aldehyde derivatives 16 and pyrrole-based acetophe-
displayed high activity against Streptococcus mutans and was the none 17 in basic media. The 2-pyrrole chalcone derivatives 18
most potent derivative.27 The chalcone derivative 15 containing were possible to synthesize using either a liquid phase or solid
a difluorophenyl scaffold displayed 2.6× more activity than the through a grinding method with moderate to good yields.
standard drug. This suggests that the degree of electronegativity Ö zdemir and co-workers synthesized and reported new
played a key role in modulating the physicochemical properties potent antimicrobial and anticancer active pyrrole-based
of the derivative (Figure 3).17 chalcone derivatives using the Claisen−Schmidt condensation
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Scheme 2. General Synthetic Route toward Pyrrole-Based Chalcone Derivatives

Scheme 3. General Synthetic Route toward Chalcone Derivatives Incorporating a Pyrrole Scaffold

Scheme 4. General Synthetic Route toward Imidazole-Based Chalcone Derivatives

Scheme 5. Synthetic Route toward Chalcone Derivatives Incorporating an Imidazole Moiety

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Scheme 6. General Synthesis of Thiazole-Based Chalcone Derivatives

Scheme 7. General Synthesis of Thiazole-Based Chalcone Derivatives 43

reaction.28 Using the reaction procedure of the reference, 2- recrystallized from ethanol and methanol to afford pure
acetyl-1-methylpyrrole 19 and aryl-furfural 20 were subjected to imidazole chalcone derivatives 27, as depicted in Scheme 4.
sodium hydroxide in methanol and further stirred at room An antimicrobial active novel series of chalcone-imidazole
temperature for about two days. At the completion of the derivatives 36(a−m) were synthesized and reported through the
reaction, the final chalcone derivatives 21 were recrystallized common Claisen−Schmidt condensation reaction procedure.30
from ethano, and the precipitated reaction mixture was filtered, Here, the synthesized derivatives of chalcone further function-
washed, and dried to afford a good yield (Scheme 2). alized using the known reaction procedure to afford imidazole-
Similarly, Sharma and co-workers’ pyrrole-based chalcone based chalcone derivatives. The synthesized substituted
derivatives 24 were synthesized and reported from 2- chalcones 28 were mixed with NBS and CCl4 in a round flask
acetylpyrrole with substituted benzaldehyde derivatives using a in the presence of AIBN. The mixture was refluxed and then
condensation reaction under basic conditions.29 During the filtered and distilled with CCl4 in vacuum to get compounds
reaction, substituted benzaldehyde derivative 23 was added to 2- 29(a−i). Compounds 29 were subsequently further subjected to
acetylpyrrole 22 that was dissolved in methanol and a 10% imidazole to afford compounds 30(j−m) through SN2
nuclephilic substitution reaction. Compounds 32(a−m) were
aqueous NaOH solution was added, and the reaction mixture
subjected to K2CO3 and KOH with stirring, followed by the
was kept in stirred conditions until the completion of the
addition of imidazole in anhydrous CH3CN at ambient
reaction. After the completion of the reaction, the mixture was temperature under a nitrogen atmosphere. Finally, the
diluted with distilled water, and precipitated solid was filtered chalcone−imidazole derivatives 33(a−m) were obtained after
and recrystallized from the EtOH/EtOAc solvent mixture to removal of the solvent following purification using column
afford chalcone derivatives 24 (Scheme 3). chromatography (Scheme 5).
2.2. Chalcones Bearing Imidazole. Sasidharan and co- 2.3. Chalcones Bearing Thiazole. Kasetti and co-workers
workers reported a series of 11 imidazole-based chalcone- reported antioxidant active thiazole-based chalcone derivatives
substituted derivatives using the Claisen−Schmidt condensa- through the common Claisen−Schmidt condensation reac-
tion reaction between ethanone 25 and various para-substituted tion.31 Here, thiazole-carbaldehyde 34 was dissolved in glacial
aromatic aldehyde derivative 26.30 A mixture of ethanone 25 acetic acid and hydrochloric acid. To this mixture was added aryl
and para-substituted benzaldehyde 26 in ethanol and aqueous or heteroaryl ketone moiety 35, which was previously dissolved
potassium hydroxide was added and stirred at room temper- in ethanol, and the mixture was refluxed. Once the reaction
ature. The resulting product was kept overnight in a refrigerator, completed, the precipitate was filtered, washed, and dried,
and the solid was filtered off, washed with water, and followed by procedural purification by column chromatography
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Scheme 8. General Synthesis of Thiazole-Based Chalcone Derivatives 46

Scheme 9. General Synthesis of Pyridine-Based Chalcone Derivatives

Scheme 10. General Synthesis Routes toward Pyridine-Incorporated Chalcone Derivatives 61

to isolate pure thiazole-based chalcone derivatives 36(a−u), as 40, followed by a Dess−Martin oxidation reaction to afford the
depicted in Scheme 6. key target intermediate 41. The synthesized aldehyde was
A series of anticancer active thiazole-based chalcone reacted with aryl methyl ketone in ethanol, and KOH was added
derivatives 43 were reported by Kasetti and co-workers.31 dropwise to the mixture with continuous stirring. Finally, the
Here, thiazole-carbaldehyde 41 was synthesized in three steps. mixture was filtered, washed, and dried to get a yellow solid
First, thiazole-carboxylate 39 was formed through subjecting compound, which was further purified using recrystallization
benzamide 37 to 2-chloroacetate 38. The ester moiety of with ethanol to get pure yellow solid thiazole-based chalcone
compound 39 was reduced using LiAlH4 to alcohol compound derivatives 43 with a good yield, as described in Scheme 7.
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Scheme 11. General Synthesis Routes toward Chalcone Incorporating a Pyridine Moiety

Scheme 12. General Synthesis Routes toward Chalcone Derivatives Incorporating Piperazine

Scheme 13. General Synthesis Routes Towards a Chalcone−Piperazine Hybrid

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Scheme 14. General Synthesis Routes toward Chalcone Containing an Indole Scaffold

Antitumor active thiazole-incorporated chalcone derivatives TEA with stirring to afford 66. Compounds 66 were further
were reported by Farghaly and co-workers.32 A mixture of 4- allowed to react with 3-aminomethylpyridine 67 in DCM with
acetylthiazole 44 derivative was subjected to the aromatic TEA base at room temperature to afford various pyridine-based
aldehyde derivatives 45 in anhydrous ethanol. An aqueous chalcone derivatives 68, as described in Scheme 11.
solution of NaOH was added dropwise, and the reaction mixture 2.5. Chalcones Bearing Piperazine. Ahmed and co-
was stirred. The solid formed was collected using filtration and workers reported the synthesis of piperazine-chalcone hybrid
recrystallized from a mixture of ethanol/dioxane solvents to derivatives as potential vascular endothelial growth factor
afford the thiazole-based chalcone derivatives 46 (Scheme 8). receptor-2 (VEGFR-2) inhibitors.36 A mixture of a derivative
2.4. Chalcones Bearing Pyridine. Rupala and co-workers of acetophenone 71 and corresponding aldehyde derivatives 72
reported a series of imidazo-pyridine derivatives through the was dissolved in 10% alcoholic sodium hydroxide and stirred at
condensation of aryl methyl ketone and aryl aldehyde in the room temperature. After the reaction completed, the precipitate
presence of alcoholic alkali media.32 The synthesis mixture of was filtered, washed, dried, and recrystallized from ethanol to
pyridine-3-carbaldehyde 52 and ethanone 53 was refluxed in afford the target compounds 73 (Scheme 12).
methanol, followed by the addition of NaOH as a catalyst. The A series of novel chalcone hybrids with piperazine derivatives
crude was poured on to crushed ice, and the resulting product were synthesized and reported as potent antitumor agents.37
was further recrystallized from dichloromethane to give During the preparation of the target compounds, acetophenone
compound 54, as provide in Scheme 9. 74 reacted with benzaldehyde 75 in the presence of KOH via
The synthesis of novel anticancer active chalcone incorporat- aldol condensation to give chalcone 76. Subsequently, the key
ing a pyridine scaffold was reported by Madhavi and co- intermediate 78 was prepared through the substitution of the
workers.33,34 The iodopyridine 56 was subjected to a Buchwald fluorine atom of 76 with piperazine 77. Finally, acylation and
coupling reaction with trimethoxyaniline 55 in the presence of sulfonylation of the −NH group with acyl chloride or carboxylic
dioxane as the solvent and mild base to afford pyridin-3-amine acid and sulfonyl chloride afforded hybrid compounds 84 and 82
compound 57 in a good yield. The intermediate 57 undergoes in good yields, respectively. Further tertiary amines 83 were
Suzuki coupling with a boronic acid 58 using a palladium salt to synthesized by treatment with 2-bromoacetophenone (Scheme
afford the key skeleton pyridin-3-yl benzaldehyde 59. Finally, 13).
the intermediate aldehyde 59 was refluxed with substituted 2.6. Chalcones Bearing Indole. Antiproliferative active
acetophenone derivatives 60(a−j) in ethanol as the solvent and compounds based on pyrano-chalcone derivatives containing an
a catalytic amount of piperidine base to afford compounds indole moiety as a major scaffold were reported by Wang and
61(a−j), as shown in Scheme 10. coworkrs.38 Here, ethanone derivative 85 in acetonitrile was
Similarly, the synthesis of a series of anticancer active subjected to 3-chloro-3-methyl-1-butyne 86 in the presence of
pyridine-based chalcone derivatives was reported by Durgapal DBU and catalytic copper salt to afford 1,1-dimethylpropargyl
and co-workers from 3-aminomethylpyridine and 4-amino ether 87 in a good yield. Further, compound 87 underwent a
chalcone.35 Procedurally, 4-aminoacetophenone 62 was sub- Claisen rearrangement reaction in the presence of pyridine,
jected to aldehyde 63 under basic reaction conditions to afford leading to key intermediate compound 88. Finally, condensation
4-amino chalcone derivatives 64. Further, 4-amino chalcones 64 of compound 88 with N−H indole-aldehyde derivatives 89 or
react with bromoacetyl bromide in the presence of DCM and N-alkyl indole aldehyde derivatives 90 under Claisen−Schmidt
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Scheme 15. Ultrasound-Assisted (I) and Solvent-Free (II) Synthesis Protocols for the Preparation of Indole-Based Chalcone
Derivatives

Scheme 16. General Synthesis Routes toward Indole-Based Chalcone Derivatives

Scheme 17. General Synthesis Routes toward Benzimidazole-Based Chalcone Derivatives

reaction conditions using the standard reaction procedure aromatic aldehyde 93 in dioxane under basic reaction condition
provided the desired compounds 91(a and b) (Scheme 14). to furnish indole-based chalcone derivatives 94. On the other
Previously, the syntheses of novel indole-based chalcone hand, using the solvent-free grinding method, similarly indole 92
derivatives were reported by Gao and co-workers using two and aromatic aldehydes 93 under basic reaction condition were
powerful methods, the ultrasound-assisted and solvent-free intimately ground using pestle and mortar at room temperature,
Claisen Schmidt condensation reactions.39 On one hand, using and the resulting product was treated with HCl, filtered, and
the ultrasound-assisted method, indole 92 was subjected to recrystallized from ethanol to provide indole-based derivatives
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Scheme 18. General Synthesis Routes toward Chalcones 113 Incorporating Thiadiazol−Benzimidazol−Quinolinone
Heterocyclic Scaffolds

Scheme 19. General Synthesis Routes toward Benzimidazole−Aryl-Based Chalcone Derivatives

94. Finally, the ultrasonication procedure proved that efficient with glycolic acid in the presence of HCl. The substituted
promotion and push using the Claisen−Schmidt reaction benzimidazole-2-methanol (103) was synthesized through the
condensation move the reaction forward in a short reaction alkylation of compound 101 using a benzyl bromide in the
time with better yields, as depicted in Scheme 15. presence of K2CO3. Subsequently, substituted benzimidazole-2-
In recent report, various class of chalcone derivatives carbaldehyde derivatives 104 were obtained from 103 through
containing indole and naphthalene moieties were reported as oxidation using a Dess−Martin protocol. Compounds 103 were
potent anticancer agents.40 Through the Claisen−Schmidt finally prepared from 104 through a Claisen−Schmidt reaction
condensation reaction, an aromatic ketone derivative 95 and in the presence of appropriate acetophenone derivatives, as
commercial available indole aldehyde derivatives 96 afford depicted in Scheme 17.
indole-based chalcone derivatives 97(a−d) in moderate to good Similarly, Pragathi and co-workers reported a series of
yields. Indole-based chalcone derivatives 97(a−d) further anticancer active benzimidazole-based chalcones incorporating
reacted with alkyl halides 98 under basic conditions to furnish quinoline−benzimidazole−thiadiazole heterocyclic scaffolds
N-alkylated indole-based chalcone derivatives 99(e−r), as through the aldol condensation reaction.42 Compound 109
depicted in Scheme 16. was prepared from 1,2-dihydro-2-oxoquinoline-3-carbaldehyde
2.7. Chalcones Bearing Benzimidazole. A series of 107 and benzene-1,2-diamine 108 through a double con-
benzimidazole-based chalcone derivatives were synthesized densation reaction. Subsequently, the intermediate 109 was
and reported using the Claisen−Schmidt reaction as potential reacted with 4-formylbenzamidine hydrochloride 110 to afford
Topo II-targeting anticancer agents.41 Benzimidazole derivative derivative 111. Compound 111 further subjected to the aldol
101 was obtained through refluxing o-phenylenediamine (100) condensation reaction with acetophenone derivatives 112(a−j)
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Scheme 20. General Synthesis Routes toward Benzothiazole-Based Chalcone Derivatives

Scheme 21. General Synthesis Routes toward Benzothiazole-Based Chalcone Derivatives

Scheme 22. General Synthesis Routes toward Chalcones Incorporating a Quinoline Moiety

to furnish benzimidazole-based chalcone derivatives 113(a−j), phenylenediamine (114) with lactic acid in HCl under reflux
as depicted in Scheme 18. reaction conditions prepared benzimidazole derivatives 115,
A new series of N-substituted benzimidazole-based chalcone followed by an oxidation reaction in the presence of potassium
derivatives were reported by Hsieh and co-workers through the permanganate as a strong oxidizing agent and solid aluminum
conjugation of benzimidazole and aromatic aldehyde derivatives oxide to afford compound 116. Benzimidazolyl-aryl chalcone
under basic conditions as anticancer agents.43 The reaction of o- derivatives 118(a−d) were obtained through the aldol
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Scheme 23. General Synthesis Routes toward Quinoline-Based Chalcone Derivatives

Figure 4. Chemical structures of antibacterial active chalcone derivatives.

Figure 5. Chemical structures of antifungal active chalcone derivatives.

condensation reaction of compound 116 with substituted 2.8. Chalcones Bearing Benzothiazole. Wang and co-
aromatic aldehyde derivatives under basic conditions. Further, workers reported a series of novel benzothiazole-based chalcone
benzimidazole−aryl chalcone derivatives 118 subjected to a derivatives as potential antibacterial agents.44 Following the
methylation reaction with the corresponding agent to furnished standard reaction reported procedure to prepare 4-hydroxy-
compound 120, as described in Scheme 19. acetophenone 121, aldosterone condensations were performed
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Figure 6. Chemical structures of antitubercular active chalcone derivatives.

Figure 7. Chemical structures of antioxidant active chalcone derivatives.

Figure 8. Chemical structures of anticancer active chalcone derivatives.

under alkali conditions to prepare chalcone derivatives 123 with Thirumurugan and co-workers through the common aldol
various aldehyde substitutions.45 Compound 125 was prepared condensation reaction.47 Quinoline-based chalcones N-quino-
when compound 123 underwent an etherification reaction with line-2-carboxamides 138 were synthesized using quinoline-2-
2-chlorobenzothiazole 124 in the presence of acetonitrile as a carboxylic acid 136 subjected to ethanone 137 in TEA using
solvent, potassium carbonate as a catalyst, and reflux, as depicted TBTU as the base with reflux for 3 h at room temperature
in Scheme 20. (Scheme 22). Compounds 138 undergo the aldol condensation
Similarly, in recent studies a series of benzothiazole-based reaction with benzaldehyde derivatives 139 using NaOH/EtOH
chalcones were reported to have potential thymidylate kinase at room temperature for 30 min to give quinoline-2-
(BmTMK) enzyme inhibition activity.46 Different derivatives of carboxamide derivatives 140(a−g), as shown in Scheme 23.
phenol and hexamethylenetetramine were dissolved in TFA at
Commonly, quinoline-based chalcone scaffolds are frequently
120 °C with continuous stirring to afford compound 127 in
utilized to design novel anticancer agents. A series of quinoline-
good yields. A dicarbaldehyde compound 127 and different
substituted ketone derivatives 128 were dissolved in 10% aq based chalcone derivatives were synthesized and reported by
KOH and ethanol, and the resulting solution was refluxed to Guan and co-workers as described.48 Here, 4-aminoacetophe-
afford compound 129. A mixture of ortho-substituted chalcone none 138 reacted with aromatic aldehyde derivatives 139(a−j)
derivatives 129 and 2-hydrazinyl benzothiazole 131 was to afford derivatives 140(a−j). Compounds 140(a−j) were
dissolved in ethanol and stirred at room temperature for 3−4 subjected to 4-chloro-2-methylquinoline (141) to afford
h to furnish the final benzothiazole-based chalcone derivative derivatives 142(a−j). Further, compounds 142 (a, b, e, and f)
132, as depicted in Scheme 21. reacted with iodomethane or iodoethane in the presence of
2.9. Chalcones Bearing Quinoline. A series of quinoline- KOH in acetonitrile to afford 144(a, b, e, and f), as depicted in
based chalcone derivatives were synthesized and reported by Scheme 23.
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Figure 9. Chemical structures of anti-inflammatory active chalcone derivatives.

Figure 10. Chemical structures of antimalarial active chalcone derivatives.

3. BIOLOGICAL ACTIVITIES OF CHALCONES BEARING biological activities of chalcone derivatives incorporating N-

AN N-HETEROCYCLIC SCAFFOLD heterocyclic scaffolds in the medicinal chemistry arena and
In the synthesis section, chalcone derivatives incorporating therapeutic issues will discussed in detail. The title compound
heterocyclic scaffolds such as pyrrole, imidazole, thiazole, derivatives become impressive, and literature reports stress the
significance of the α,β-unsaturated carbonyl moiety to drug
target interactions and biological activities.49 Both natural
products and synthetic compounds incorporating N-hetero-
cyclic scaffolds displayed a broad band spectrum of
pharmaceutical activities such as antibacterial, antifungal,
antioxidant, anti-inflammatory, antitubercular, anticancer, anti-
malarial, and antileishmanial activities.50
3.1. Antibacterial Activity. Chalcone derivatives incorpo-
rating heterocyclic scaffolds are basis for the development of
antibacterial agents.51 Shaik and co-workers reported the
synthesis of novel bioactive isoxazole-based chalcones and
Figure 11. Chemical structures of antifilarial active chalcone their dihydropyrazole derivatives.52 All synthesized derivatives
derivatives. were tested for their antibacterial activities through the serial
dilution method against two types of bacterial strain, Staph-
pyridine, piperazine, indole, benzimidazole, benzothiazole, and ylococcus aureus and Pseudomonas aeruginosa. All the synthesized
quinoline were briefly discussed and their broad spectrum compounds exhibited antibacterial activity; in particular,
bioactivities were highlighted. In this section, the scope and compound 145 containing a 2,4,6-trimethoxyphenyl ring was

Figure 12. Chemical structures of antigiardial active chalcone derivaties.

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the most potent agent among the chalcone series, and its 3.4. Antioxidant Activity. Recently, Bhat and co-workers
antibacterial activity was found to be greater than that of the reported a novel series of bioactive 1,2,3-triazolyl chalcone
reference drug ciprofloxacin (Figure 4). Further, the synthesized derivatives that were synthesized via the Claisen−Schimidt
compounds exhibited antifungal, antioxidant, and anticancer reaction.59 The antioxidant activities of the compounds were
activities.53 further evaluated using the ABTS (2,2′-azino-bis(3-ethyl
Similarly, series of benzimidazole-based chalcone derivatives benzothiazoline-6-sulfonic acid)) antioxidant assay technique.
containing an oxadiazole moiety were reported by Meshram and Evaluation of the antioxidant activity revealed that most of the
co-workers through a Claisen−Schimdt condensation reac- tested compounds exhibited moderate to excellent DPPH and
tion.54 The synthesized compounds were evaluated for their ABTS radical scavenging potential compared to the positive
efficiency as antibacterial agents against two Gram-positive control ascorbic acid. Among the synthesized compounds, 155
(Staphylococcus aureus and Streptococcus pyogenes) and two and 156 bearing 3,4-dimethyl phenyl and 1,3-(biphenyl)-1H-
Gram-negative (Escherichia coli and Pseudomonas aeruginosa) pyrazole at the third position of chalcone moiety, respectively,
strains of bacteria using the broth microdilution method. were found to be more effective and potent. They further
Although all tested compounds exhibited potent antibacterial displayed DPPH radical scavenging ability with IC50 values
activity, compounds 146 and 147 displayed the most potent 15.33 and 14.48 μM compared with ascorbic acid with an IC50
activities (Figure 4). Chalcone derivatives possessing an value of 12.27 μM at a 31.5 μg/mL concentration by the DPPH
oxadiazole ring with a benzimidazole scaffold have displayed radical scavenging activity method. The antioxidant activity of
enhanced antimicrobial activity due to incorporation of the the derivatives 155 and 156 was further illustrated by ABTS
heterocyclic moieties compared to the parent compounds. assay method with 80.4% and 81.8% inhibition compared to the
3.2. Antifungal Activity. Osmaniye and co-workers positive control ascorbic acid with 88.5% inhibition. Similarly,
reported the synthesis of imidazole-based chalcones that arylic substitutions with pyrazolic chalcones were reported as
incorporate pharmacophores through a Claisen−Schmidt potent antimicrobial and antioxidant agents by Kumari and co-
condensation reaction from imidazole-acetophenone with the workers through Claisen−Schmidt condensation.60 The in vitro
corresponding 4-substituted benzaldehyde derivatives.55 The antioxidant potential of the synthesized compounds was
antifungal activity of the synthesized compounds was evaluated evaluated using the DPPH method, with ascorbic acid as a
for anticandidal activity against Candida albicans (ATCC standard reference. Among the synthesized compounds assayed
24433), Candida krusei (ATCC 6258), Candida parapsilosis for antioxidant activity in the DPPH method, compound 157
(ATCC 22019), and Candida glabrata (ATCC 90030) in the exhibited good radical scavenging activity an IC50 value of 88.04
presence of reference agents ketoconazole and fluconazole. μg/mL, and the value of standard drug ascorbic acid was found
to be 48 μg/mL (Figure 7).
Compound 148 exhibited similar antifungal activity with the
3.5. Anticancer Activity. Cancer is one of the most serious
reference drug ketoconazole against all Candida species and was
of a devastating diseases and a multifactorial disease. In 2020,
evaluated as the most active derivative in the series. In a similar
19.3 million patients were diagnosed and approximately 10
fashion, Sunitha and co-workers reported the synthesis of series
million deaths were related to cancer.61 These data indicate that
of bisisoxazole derivatives blended with chalcone derivatives.56
the improvement of effective anticancer drugs with minimized
Antifungal activities of all synthesized derivatives were tested side effects is needed. Novel bioactive indole-based chalcone
against Microsporum canis, Microsporum gypseum, and Epidermo- derivatives were reported by Yan and co-workers.62 Anti-
phyton floccosum in 75 and 100 μg/mL concentrations with the proliferative activities of all synthesized compounds were
reference drug nystatin. Compound 149, 150, and 151 display evaluated against various human cancer cell lines by MTT
the highest antifungal activity and also show potent antibacterial assay. Among the tested compounds, compound 158 exhibited
activity (Figure 5). the most potent activity, with IC50 values of 3−9 nM against six
3.3. Antitubercular Activity. Tuberculosis (TB) is a cancer cells. Similarly, a new series of imidazole-based chalcone
chronic infectious disease caused predominantly by Mycobacte- derivatives were reported as tubulin inhibitors and anticancer
rium tuberculosis. The World Health Organization (WHO) agents.63 The cytotoxic activity of the synthesized compounds
reported that about a third of the world’s population is infected was evaluated against four cancer cell lines including MCF7,
with M. tuberculosis.57 Kasetti and co-workers reported bioactive A549, HepG2, and MCF7/MX by MTT assay. Compounds 159
compounds containing thiazole and chalcone pharmaco- and 160 exhibited strong cytotoxic activity with IC50 values
phores.31 All synthesized compounds were evaluated for their ranging from 7.05 to 63.43 μM against all four human cancer
antitubercular activities by MTT assays. Among the tested cells. In previous work, a series of novel chalcones containing
compounds, the monofluorinated compounds 152 and 153 quinoline were reported as antiproliferative agents.63 The in vitro
bearing fluorine atoms at ortho- and para-positions showed antiproliferative efficacy of the prepared compounds was
activity at MIC 20.68 μM that was 0.81× greater than the assessed by MTT assays using human chronic myelogenous
pyrazinamide derivative (Figure 6). Solankee and Tailor leukemia cell K562 and compared to that of the reference
reported a new series of chalcones bearing a 1,3,5-triazine compound CA-4. Among them, compound 161 exhibited the
group that were synthesized by the classical Claisen−Schmidt most potent activity with IC50 values ranging from 0.009 to
condensation of a substituted ketone with the corresponding 0.016 μM in a panel of cancer cell lines. Furthermore, a series of
substituted aldehydes.58 The in vitro antitubercular activities of triazole−benzimidazole−chalcone derivatives were reported
all the newly synthesized compounds were determined using a from the combination of different azide derivatives and
Lowenstein−Jensen medium against Mycobacterial tuberculosis substituted benzimidazole terminal alkynes bearing a chalcone
H37Rv strain relative to the reference drugs isoniazid and moiety.64 The antiproliferative activities of synthesized com-
rifampicin. Among the compounds, a compound 154 was found pounds were examined against two human breast cancer cell
to possess the greatest potency against Mycobacterium tuber- lines (T47-D and MDA-MB-231) and one prostate cancer cell
culosis with 92% inhibition. line (PC3) using a resazurin-based method. Among the
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evaluated compounds, 162 exerted highest cytotoxic effects on caused by thread like nematodes Wucheria bancrofti, Brugia
all the selected PC-3, MDA-MB-231, and T47-D cell lines, with malayi, and Brugia timori and spread via mosquitos infected with
IC50 values of 10.7, 5.89, and 6.23 μM compared to the reference worm larvae.72 Different research has been carried to get an
drug doxorubicin (0.13, 1.51, and 0.73 μM), respectively effective drug for this disease. Sashidhara and co-workers
(Figure 8). reported a series of chalcone−thiazole derivatives.72 All the
3.6. Anti-Inflammatory Activity. In previous work, a series synthesized compounds were evaluated for their in vitro activity
of chalcone derivatives bearing a bispiperazine linker were using motility and MTT 17 reduction assays against microfilaria
reported by Tang and co-workers via a condensation reaction.65 and female adult worms of B. malayi. Compounds 171 and 172
The synthesized compounds were evaluated for their in vitro
were found to be effective in 19 killing microfilaria (LC100 = 5
anti-inflammatory activity in LPS-induced RAW 264.7, and
and 10 μM; IC50= 1.8 and 3.5 μM) and adult worms (LC100 = 2.5
piperazinochalcone significantly inhibited the production of
TNF-α. Most bispiperazine chalcone derivatives exhibited and 10 20 μM; IC50 = 0.9 and 3.2 μM); both the compounds also
excellent anti-inflammatory activities. Specially, the IC50 values inhibited the MTT reduction potential of 21 adult parasites to
of 163 and 164 were 0.42 and 0.82 μM, respectively, compared 49 and 63%, respectively. The in vivo activity of the tested active
to that of the positive control dexamethasone (IC50 < 20 μM). compound 172 further exhibits a 100% embryostatic effect
Recently, Ö zdemir and co-workers were synthesized and (Figure 11).
reported new indole-based chalcone derivatives through the 3.9. Antigiardial Activity. Giardia is a leading cause of
Claisen−Schmidt condensation reaction.66 Colorimetric COX infectious gastroenteritis worldwide and is treatable. It is a water-
(ovine) inhibitor screening assay was carried out to evaluate the born parasitic disease caused by the Giardia lamblia.73,74
ability of the compounds to inhibit COX-1 and COX-2 in vitro. Different researchers were conducting their research to develop
Compound 165 (IC50 = 8.6 ± 0.1 μg/mL) and compound 166 a novel drug for overcoming Giardia-born disease. In previous
(IC50 = 8.1 ± 0.2 μg/mL) were found as the most potent COX-1 work, novel chalcone derivatives were reported by Bahadur and
inhibitors when compared with indometacin (IC50 = 0.7 ± 0.2 co-workers that were synthesized via microwave-assisted
μg/mL). Furthermore, compound 166 exerted a COX-2 Claisen−Schmidt condensation.75 The newly synthesized
inhibitory effect with an IC50 value of 9.5 ± 0.8 μg/mL when compounds were first tested for their antigiardial activity
compared with indometacin (IC50= 10.0 ± 4.2 μg/mL). under anaerobic conditions. Among the tested compounds,
Moreover, according to the CCK-8 assay, the cytotoxic doses
only three of them display significant antigiardial activity. These
of compounds 165 (IC50= 32.3 ± 6.7 μg/mL) and 166 (IC50=
active compounds were tested for their toxicity against Giardia
51.6 ± 15.3 μg/mL) for NIH/3T3 cells were higher than their
effective doses (Figure 9). trophozoites under microaerobic conditions and exhibited good
3.7. Antimalarial Activity. Earlier malarial reports indicate activity. Finally, to assess the selectivity of compounds against
that it is one of the most prevalent and lethal parasitic diseases in Giardia, their toxicity toward a mammalian cell line, Caco-2
the world, affecting more than 300 million people every year.67 cells, was tested after 48 h of incubation. According to the IC50
As there is high level of resistance to all the classes of antimalarial measured on Giardia cells under microaerobic conditions,
compounds, including artemisinin derivatives, it has increased compounds 173 and 174 show preferential toxicity against
the global malaria burden and is a major threat to malaria parasitic cells (Figure 12).
control.68 There is an urgent need for the design and
development of novel and potent antimalarial drugs, particularly 4. CONCLUSION
against the Plasmodium falciparum, which causes severe malaria.
Accordingly, Jyoti and co-workers reported indolyl−chalcone Chalcone derivatives incorporating heterocyclic scaffolds such
derivatives.69 All the indolyl−chalcones were evaluated for their as pyrrole, imidazole, thiazole, pyridine, piperazine, indole,
in vitro antimalarial activity against P. falciparum, NF54 strain. benzimidazole, benzothiazole, and quinoline are briefly high-
Antiplasmodial IC50 activity against malaria parasites in vitro lighted to give a basic information to the researchers who work
provides good screening for identifying the antimalarial with these scaffolds. The above heterocycle-based chalcone
potential of the synthesized compounds. Among them, derivatives almost all displayed a broad spectrum with a variety
compound 167 was the most active compound against of pharmacological activities. Especially, chalcones containing
plasmodia with an IC50 value of 2.1 mM/L. In previous work N-heterocyclic scaffolds have become potential candidates for
it was reported that novel molecular hybrids were synthesized the development of effective medicines and pharmaceutical
when the quinoline moiety was coupled with various chalcone drugs. Chalcone derivatives incorporating nitrogen heterocyclic
derivatives using the appropriate linker.70 The antiplasmodial biological activities greatly attract the attention of researchers,
activities of all synthesized molecular hybrids were evaluated and currently a lot of papers have been reported to find effective
against the drug-sensitive strain (NF54) of P. falciparum using and potent drugs to overcome the influence of different diseases.
chloroquine as reference drug. Compounds 168, 169, and 170 Conventionally, these chalcones are synthesized through
(Figure 10) with IC50 values of 0.10, 0.10, and 0.11 μM,
Claisen−Schmidt condensation reactions under basic or acidic
respectively, were the most active against the plasmodia. These
compounds were further tested against the multidrug-resistant media. Currently, findings proved that chalcones containing N-
K1 strain of P. falciparum. Compound 170 exert about a twofold heterocyclic moieties display various pharmacological activities.
enhancement in rthe esistivity index (RI = 5.36, PfK1 IC50 = 0.59 The most known are antibacterial, antifungal, antitubercular,
μM) relative to Chloroquine, whereas compounds 168 and 169 antioxidant, anti-inflammatory, anticancer, antimarial, antigiar-
were less active against the K1 strain with IC50 values of 2.97 and dial, and antifilarial activities. This implies that further
6 μM, respectively (Figure 10). investigations are needed to design and develop potent, novel,
3.8. Antifilarial Activity. Lymphatic filariasis is a parasitic and effective chalcone derivatives with N-heterocyclic scaffold-
infection that causes acute and chronic inflammation.71 It is based drugs.
19208 https://doi.org/10.1021/acsomega.3c01035
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■ AUTHOR INFORMATION
Corresponding Author
(13) Kiran, K.; Sarasija, M.; Ananda Rao, B.; Namratha, V.; Ashok, D.;
Srinivasa Rao, A. Design, Synthesis, and Biological Activity of New Bis-
1, 2, 3-triazole Derivatives Bearing Thiophene-Chalcone Moiety.
Endale Mulugeta − Department of Applied Chemistry, School of Russian Journal of General Chemistry 2019, 89 (9), 1859−1866.
Applied Natural Science, Adama Science and Technology (14) Ardiansah, B. Chalcones bearing N, O, and S-heterocycles:
University, 1888 Adama, Ethiopia; orcid.org/0000-0002- Recent notes on their biological significances. J. App. Pharm. Sci. 2019, 9
2869-0934; Email: endexindex05@gmail.com, (8), 117−129.
endale.mulugeta@astu.edu.et (15) Mahapatra, D. K.; Bharti, S. K.; Asati, V. Chalcone derivatives:
anti-inflammatory potential and molecular targets perspectives. Current
Authors topics in medicinal chemistry 2017, 17 (28), 3146−3169.
Kibrom Mezgebe − Department of Applied Chemistry, School (16) Jayashree, B. S.; Patel, H. H.; Mathew, N. S.; Nayak, Y. Synthesis
of Applied Natural Science, Adama Science and Technology of newer piperidinyl chalcones and their anticancer activity in human
University, 1888 Adama, Ethiopia cancer cell lines. Res. Chem. Intermed. 2016, 42 (4), 3673−3688.
Yadessa Melaku − Department of Applied Chemistry, School of (17) Kasetti, A. B.; Singhvi, I.; Nagasuri, R.; Bhandare, R. R.; Shaik, A.
Applied Natural Science, Adama Science and Technology B. Thiazole−chalcone hybrids as prospective antitubercular and
antiproliferative agents: Design, synthesis, biological, molecular
University, 1888 Adama, Ethiopia
docking studies and in silico ADME evaluation. Molecules. 2021, 26
Complete contact information is available at: (10), 2847.
https://pubs.acs.org/10.1021/acsomega.3c01035 (18) Atukuri, D.; S, V.; R, S.; L, V.; R, P.; M. M, R. Identification of
quinoline-chalcones and heterocyclic chalcone-appended quinolines as
Notes broad-spectrum pharmacological agents. Bioorganic Chemistry 2020,
The authors declare no competing financial interest. 105, 104419.
(19) Maatougui, A. E.; Yáñez, M.; Crespo, A.; Fraiz, N.; Coelho, A.;

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