Quinoline Based Monocarbonyl Curcumin Analogs as Potential Antifungal and Antioxidant Agents: Synthesis, Bioevaluation and Molecular Docking Study

Article abstract of DOI:10.1002/cbdv.201900624

In search for new fungicidal and free radical scavenging agents, we synthesized a focused library of 2-chloroquinoline based monocarbonyl analogs of curcumin (MACs). The synthesized MACs were evaluated for in vitro antifungal and antioxidant activity. The antifungal activity was evaluated against five different fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, and Cryptococcus neoformans, respectively. Most of the synthesized MACs displayed promising antifungal activity compared to the standard drug Miconazole. Furthermore, molecular docking study on a crucial fungal enzyme sterol 14α-demethylase (CYP51) could provide insight into the plausible mechanism of antifungal activity. MACs were also screened for in vitro radical scavenging activity using butylated hydroxytoluene (BHT) as a standard. Almost all MACs exhibited better antioxidant activity compared to BHT.

Full text of DOI:10.1002/cbdv.201900624

Title: Quinoline based monocarbonyl curcumin analogues as potential
antifungal and antioxidant agents: Synthesis, Bioevaluation and
molecular docking study.
Authors: Amol A. Nagargoje, Satish V. Akolkar, Madiha M. Siddiqui,
Dnyaneshwar D. Subhedar, Jaiprakash N. Sangshetti, Vijay
M. Khedkar, and Bapurao Babruwan Shingate
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Biodiversity 10.1002/cbdv.201900624
Link to VoR: http://dx.doi.org/10.1002/cbdv.201900624

10.1002/cbdv.201900624
Chemistry & Biodiversity
Chem. Biodiversity
Quinoline based monocarbonyl curcumin analogues as potential
antifungal and antioxidant agents: Synthesis, Bioevaluation and
molecular docking study.
Amol A. Nagargoje,a,b Satish V. Akolkar,a Madiha M. Siddiqui,a Dnyaneshwar D.
Subhedar,aJaiprakash N. Sangshetti,c Vijay M. Khedkar,d Bapurao B. Shingate*a
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, 431 004, India
bDepartment of Chemistry, Khopoli Municipal Council College, Khopoli, Raigad, 410 203, India
cDepartment of Pharmaceutical Chemistry, Y. B. Chavan College of Pharmacy, Rafiq Zakaria Campus, Aurangabad 431 001, India
dDepartment of Pharmaceutical Chemistry, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Mumbai-Agra National Highway, Dhule,
424 001, India
E-mail:* bapushingate@gmail.com(B. B. Shingate)
*Corresponding author. Tel.: (91)-240-2403312; Fax: (91)-240-2403113
Abstract: In search of new fungicidal and free radical scavenging agents, we synthesized a focused library of 2-chloroquinoline based
monocarbonyl analogues of curcumin (MACs). The synthesized MACs were evaluated for in vitro antifungal and antioxidant activity. The
antifungal activity was evaluated against five different fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus,
Aspergillus Niger, Cryptococcus neoformans respectively. Most of the synthesized MACs displayed promising antifungal activity as
compared to standard drug Miconazole. Furthermore, molecular docking study on a crucial fungal enzyme sterol 14α-demethylase
(CYP51) could provide insight into the plausible mechanism of antifungal activity. Also, MACs were screened for in vitro radical scavenging
activity using butylated hydroxyl toluene (BHT) as a standard. Almost all MACs exhibited better antioxidant activity as compared to BHT.
Keywords: Monocarbonyl analogues of curcumin • antifungal activity • antioxidant activity • molecular docking study
Introduction
Multidrug resistance microorganisms have exerted a great threat to human health in last few years. Increase in numbers of stem
cell transplantation, organ transplantation, chemotherapy and human immunodeficiency virus infections increased invasive fungal
infections.[1] Most of the fungal infections are caused by Candida albicans, Cryptococcus neoformans and Aspergillus fumigates. Candidosis,
aspergillosis and cryptococcosis, are three major fungal infections responsible for clinical infections in patients having weak immune
system.[2,3] Existing azole based drugs such as Fluconazole, voriconazole, itraconazole and miconazole are some of the widely used broad
spectrum antifungal agents.[4] They displayed broad spectrum antifungal potential against most of the filamentous fungi, however some
of them are not effective against invasive aspergillosis and also suffered from severe drug resistance.[5,6] Moreover, the broad use of
existing azole containing antifungal drugs have caused severe drug resistance.[7] Keeping in view the limited antifungal strategies and
paucity of effective drugs, there is an urgent need for the development of novel and effective antifungals to combat the fungal infections.
Antioxidants plays important role in body defense system by reducing or neutralizing the free radicals, that protects the cells from
oxidative injury.[8] Recently, it has been observed that reactive oxygen species participates in mechanism of action of triazole containing
antifungals.[9] It is important to elucidate possible association among oxidative stress response and antifungal mechanism of action for
developing new targets for novel antifungal agents by rational development of antifungal drugs. Hence, antifungal agents with radical
scavenging properties can be a good choice in designing new fungicidal agents.
Curcumin is an important phytochemical obtained from rootstalks of the plant curcuma longa of the family Zingiberaceae. Curcumin
is found to exhibit broad spectrum of biological activities,[10–18] but its clinical usefulness is restricted due to low oral bioavailability, poor
oral absorption and poor pharmacokinetics.[19] Instability of curcumin is found to decrease by removing central β-diketone and active
methylene group.[20] In past few years,enormous efforts have made by medicinal chemists across the globe in the development of
structurally modified, therapeutically active curcumin analogues/derivatives.[21] Kathryn M. Nelson and colleagues have recently published
a review article on curcumin's essential medicinal chemistry and its analogues, which provides new directions in curcumin science. [22]
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Monocarbonyl analogue of curcumin (Figure 1) is one of the class of structurally modified and potentially active curcuminoids obtained by
removing β-diketone moiety and active methylene group from curcumin.[23,24] Monocarbonyl curcumin analogues displayed a wide array
of biological activities,[25] such as antileishmanial,[26] antiparasitic,[27] anti-inflammatory,[28] antitumor and antioxidant,[29] Alzheimer’s
disease,[30] antibacterial,[31] anticancer,[32] and antitubercular activity[33] are well reported. Although, antifungal potential of curcumin
analogues were not extensively evaluated.
Figure 1: Monocarbonyl Curcumin Analogues (MACs)
The process of scaffold-based drug design can be really effective when we choose one of the already existing privileged structures
or fragments of currently used drugs. Quinolene scaffold is key building element in many synthetic and naturally occurring biologically
active compounds. Quinolines are the main core of many natural and synthetic heterocyclic compounds enhancing their biological and
medicinal properties. It can be found in a variety of synthetic and natural antifungals such as sitafloxacin, ciprofloxacin, and trovafloxacin
(Figure 2), suggesting the preference of nature for this scaffold and identifying it as one of medicinal chemistry's privileged structures.
Specially, 2-Chloroquinoline based molecules[34] are well known to exhibit various biological properties such as antimicrobial,[35,36]
anticancer,[37] antifungal,[38] antitubercular,[39] DNA binding and photonuclease activity.[40]
Figure 2: Known quinoline based antifungals
Under this context and as a part of our ongoing research in the synthesis and biological evaluation of monocarbonyl curcumin
analogues,[41–43] we would like to report herein, synthesis of 2-chloroquinolene based monocarbonyl curcumin analogues and their in vitro
fungicidal and antioxidant activities. Furthermore, molecular docking has been carried out in order to against the crucial fungal target
sterol 14α-demethylase (CYP51) to gauze the binding affinity of these novel analogues and their associated thermodynamic interactions
which could be fruitfully utilized for lead optimization.
Results and Discussion
Chemistry
In present study, we have described the synthesis of 2-chloroquinoline incorporated monocarbonyl curcuminoids by the Claisen-Scimidt
type condensation of substituted 2-chloroquinoline-3-carbaldehydes with different monocarbonyl linker molecules. Acylation of aromatic
primary amines 1a-c with acetic anhydride in presence of pyridine followed by treatment with Vielsmayer-Hack reagent (POCl3-DMF)
results in formation of corresponding substituted 2-chloroquinoline-3-carbaldehydes 3a-c in excellent yields. Mixture of substituted 2-
chloroquinoline-3-carbaldehyde with various monoketone linkers like cyclohexanone, cyclopentanone, acetone and piperidin-4-ones in
alcoholic sodium hydroxide as the base was stirred at room temperature for 2-3 h and resulted in the corresponding 2-chloroquinoline
2
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10.1002/cbdv.201900624
Chemistry & Biodiversity
Chem. Biodiversity
1
based monocarbonyl analogues in excellent yield (Scheme 1). The synthesized analogues were characterized by FT-IR, H NMR, 13C NMR,
and LC-MS and elemental analysis.
Scheme 1. 2-Chloroquinoline based MACs
Antifungal Activity
All the synthesized 2-chloroquinoline incorporated monocarbonyl curcumin analogues were tested for their in vitro antifungal
activity. The antifungal activity of synthesized analogues was assessed against five different fungal strains such as Candida albicans (NCIM
3471), Fusarium oxysporum (NCIM 1332) Aspergillus flavus (NCIM 539) Aspergillus Niger (NCIM 1196), Cryptococcus neoformans (NCIM 576)
respectively, Minimum inhibitory concentration (MIC) values were determined using standard agar plate method.[44,,45]
An antimicrobial compound's MIC value is its lowest concentration which prevents the microorganism's noticeable growth.It is a measure
of the antimicrobial's effectiveness against the microbe concerned. Miconazole was used as a standard for the comparison of antifungal
activity. Dimethyl sulfoxide was used as solvent control.
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Table 1. In vitro antifungal and antioxidant evaluation 2-chloroquinoline based monocarbonyl curcumin analogues.
Entry
DPPH radical
scavenging activity
(IC50 values in
μg/mL ) [f]
Antifungal activity (MIC Values in μg/mL)
Molecular
Docking score
CA[a]
FO[b]
AF[c]
AN[d]
CN[e]
75
50
37.5
25
25
NA
NA
125
200
4a
4b
4c
4d
4e
4f
09.17± 0.57
10.05± 0.44
-7.813
-7.18
NA
10.17± 0.63
14.07± 0.34
50
NA
50
NA
12.5
37.5
200
NA
200
25
75
50
100
50
-7.308
-8.368
-7.95
25
05.39± 0.14
11.41± 0.35
25
NA
NA
175
12.5
12.5
NA
25
50
25
150
175
NA
12.5
NA
25
NA
NA
137.5
25
162.5
150
200
12.5
175
NA
25
-6.822
-6.303
-8.176
-8.512
-6.999
-8.341
-7.985
-7.623
-8.488
-7.716
-8.878
-
15.26± 0.78
4g
4h
4i
07.44± 0.16
11.63± 0.22
08.92 ± 0.18
06.37± 0.55
09.62 ± 0.76
10.12 ± 0.84
09.66 ± 0.53
10.27 ± 0.44
14.89± 0.43
-
5a
5b
5c
100
12.5
75
100
NA
25
50
25
6a
6b
6c
6d
MA
25
NA
NA
200
25
NA
NA
NA
12.5
12.5
-
50
25
25
12.5
25
12.5
25
175
6.25
25
25
12.5
25
25
25
BHT
16.47± 0.18
-
-
-
-
-
[a]
[b]
[c]
[d]
[e]
Candida albicans.
Fusarium oxysporum.
Aspergillus flavus.
Aspergillus Niger.
[f]
Cryptococcus neoformans.NA- No activity. MA- Miconazole. BHT- Butoxy hydroxy tolune.
Values are the average of three readings (n=3) ± standard deviation
MIC values of the tested compounds are presented in Table 1. Many of the newly synthesized compounds were found to display
excellent antifungal activity as compared to standard drug Miconazole. From the antifungal activity data (Table 1), it is observed that
most of the synthesized compounds showed potential antifungal activity against all fungal strains. Particularly, compound 4i and 6d are
the most active among all tested compounds against all fungal strains under study, which point out the broad spectrum nature of these
analogues over most of the fungal strains. MACs 4b, 4d, 4e, 4h, 5b, 5c, 6a, 6b and 6c exhibited equivalent antifungal potency as
compared to standard Miconazole in most of the fungal strains. Compounds 4a, 4c, 4f, 4g and 5a are found to be inactive against all
fungal strains with large deviation in MIC values as compared to Miconazole. Structure activity relationship revealed that use of
cyclopentanone and acetone spacer shows remarkable rise in activity as compared to positive control Miconazole. Furthermore,
piperidone and N-methyl piperidone spacer also increases activity 2-3 fold. Substitution of electron donating groups on quinolene
scaffold showed potential rise in antifungal activity as revealed in MIC values. The comparative study of fungicidal potential of newly
synthesized curcumin analogues with positive control Miconazole were graphically represented as follows (Figure 3), which clearly
indicates that most of the synthesized MACs displayed 2-3 fold more potential when compared to standard Miconazole.
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Antifungal activity of synthesized MACs compared
to standard Miconazole
250
200
150
100
50
Candida albicans
Fusarium oxysporum
Aspergillus flavus
Aspergillus Niger
Cryptococcus neoformans
0
Figure 3. Antifungal activity of synthesized MACs compared to Miconazole
Antioxidant Activity
All the synthesized analogues were evaluated for in vitro radical scavenging activity using 1, 1-diphenyl-2-picrylhydrazyl (DPPH)
radical scavenging assay. Butylated hydroxyl toluene (BHT) was used as positive control for antioxidant activity. It was observed from IC50
values that almost all synthesized analogues displayed better radical scavenging activity as compared to standard BHT (Table 1).
Particularly compound 4e ( IC50 = 05.39± 0.14) and 5b ( IC50 = 06.37± 0.55) exhibit three fold more antioxidant potential, followed by 4h
( IC50 = 07.44± 0.16), 5a ( IC50 = 08.92 ± 0.18) , 5c ( IC50 = 09.62 ± 0.76) and 6b ( IC50 = 09.66 ± 0.53) are two fold more potent as reflected in
IC50 values when compared with standard BHT( IC50 = 16.47± 0.18). These results suggests that monocarbonyl curcumin core in the
synthesized analogues contributes to the radical scavenging effect by resonance phenomenon. Furthermore, structure activity data
revealed that chloro substitution on quinolene scaffold remarkably enhances antioxidant activity as observed in compound 4e as
compared to 4a with one less chloro substitution. Also, open chain linker like acetone shows promising rise in activity as reflected in IC50
values, followed by cyclopentanone, cyclohexanone and N-methyl piperidone spacer. Also, it was observed that substitution at 7 position
of quinolene scaffold has remarkable effect on antioxidant activity than other positions. Overall results strongly suggest that these
analogues can be developed as a potential antioxidant agents.
Molecular Docking
In an effort to elucidate the plausible mechanism by which these MACs can induce the antifungal activity and to establish an SAR
based on our experimental studies, molecular docking against sterol 14α-demethylase (CYP51) was performed to simulate a binding
model derived from its crystal structure (PDB code: 3KHM). Sterol 14α-demethylase (CYP51) catalyzes the conversion of lanosterol to
ergosterol in the fungal cells and its inhibition leads to accumulation of 14α-methyl sterols in the cell causing impaired cell growth. From
the ensuing docked conformations, it was observed that all the MACs occupy the active site CYP51 with varying degrees of affinities at co-
ordinates close the native structure and their complexes are stabilized by formation of close interactions. The docking scores for the series
varied from -8.878 for the most active to -6.303 for moderately active with average docking score of -7.778 which signifies a promising
binding affinity towards CYP51. Furthermore, a detailed investigation of the per-residue interactions with these compounds was carried
out to identify the most significantly interacting residues and their associated thermodynamic interactions. This analysis is elaborated in
detail for one the most active compound 6d while it summarized in supplementary information (Table 1) for other active compounds (6d-
Fig 4, 4d- Fig 5, 4h- Fig 6, 4i- Fig 7, 5b- Fig 8 and 6b- Fig 9).
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Figure 4: Binding mode of 6d into the active site of sterol 14α-demethylase (CYP51 (on right side: the green lines signify pi-pi stacking interaction)
Figure 5: Binding mode of 4d into the active site of sterol 14α-demethylase (CYP51 (on right side: the pink lines represent the hydrogen bonding interactions)
Figure 6: Binding mode of 4h into the active site of sterol 14α-demethylase (CYP51 (on right side: the pink lines represent the hydrogen bonding interactions)
Figure 7: Binding mode of 4i into the active site of sterol 14α-demethylase (CYP51 (on right side: the pink lines represent the hydrogen bonding interactions)
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Figure 8: Binding mode of 5b into the active site of sterol 14α-demethylase (CYP51 (on right side: the pink lines represent the hydrogen bonding interactions)
Figure 9: Binding mode of 6b into the active site of sterol 14α-demethylase (CYP51 (on right side: the pink lines represent the hydrogen bonding interactions)
The lowest energy docked conformation of 6d into the active site of CP51 is shown in figure 4 which revealed that it could snugly fit
into the receptor engaging in a network of steric and electrostatic interactions. The most significant van der Waals interactions were
observed through the central 1-methylpiperidin-4-one nucleus with Val461 (-3.414 kcal/mol), Met460 (-3.289 kcal/mol), Leu356 (-3.716
kcal/mol), Thr295 (-3.59 kcal/mol), His294 (-3.065 kcal/mol), Ile105 (-3.782 kcal/mol) and Tyr103 (-2.845 kcal/mol) residues while the two 2-
chloro-7-methoxyquinolin-3-yl)methylene) scaffolds flanking aside the central piperidone nucleus were engaged in similar type of
interactions with Hem500 (-5.544 kcal/mol), Thr459 (-3.396 kcal/mol), Ala291 (-2.964 kcal/mol), Phe290 (-3.396 kcal/mol), Ala288 (-2.977
kcal/mol), Ala287 (-2.985 kcal/mol), Pro210 (-4.593 kcal/mol), Ile209 (-3.419 kcal/mol), Leu208 (-2.499 kcal/mol), Glu205 (-3.861 kcal/mol),
Leu127 (-2.952 kcal/mol), Tyr116 (-3.826 kcal/mol), Phe110 (-3.777 kcal/mol), Met106 (-3.891 kcal/mol) stabilizing the ligand-receptor
complex. The enhanced binding in also attributed to a relatively smaller network but significant electrostatic interactions observed with
Hem500 (-3.968 kcal/mol), Arg361 (-3.123 kcal/mol), Phe290 (-3.547 kcal/mol), Glu205 (-2.562 kcal/mol), Tyr103 (-2.841 kcal/mol) and
Glu101 (-2.374 kcal/mol) residues lining the active site of CYP51. Furthermore the compound also portrayed a prominent pi-pi stacking
interaction via one of quinoline scaffold with the His458 (2.38Å) which was not observed in other active analogs i.e. 4d, 4h, 4i, 5b and 6b.
However these compounds exhibited a close hydrogen bonding interactions. While 4d (2.58Å), 4h (2.50Å), 4i (2.44Å) and 5b (2.23Å)
showed a hydrogen bonding interaction via the central ketonic function with Tyr103, 6b (2.09Å) was engaged in this interaction through
Phe290. Such hydrogen bonding and pi-pi stacking interactions serve as ″anchor″ to stabilize the 3D orientation of a molecule into the
enzyme active site and also guide the non-bonded i.e. steric and electrostatic interactions. However it is the promising steric as well as
columbic interaction observed with Hem moiety (iron metal) of CYP51 that is of at most important for antifungal activity knowing the
experimental evidence that Miconazole is also coordinated through this heme moiety with CYP51 which suggest that the MACs
investigated herein could also exhibit anti-fungal action through CYP51 inhibition.
Conclusions
In conclusion, we synthesized small focused library of 2-chloroquinoline based MACs and evaluated for in vitro antifungal and
radical scavenging activity. Most of the compound displayed strong to moderate antifungal activity. Particularly, compounds 4i and 6d
are the most active among all tested compounds against all fungal strains under study. All synthesized MACs displayed either equivalent
or 2-3 fold more antioxidant potency as compared to standard BHT. Furthermore, molecular docking study could provide a valuable
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insight into the binding mode of these compounds into the active site of CY51 enzyme. The per-residue interaction analysis could confirm
that the combination of bonded (hydrogen bonding and p-pi stacking) and non-bonded (steric and electrostatic) interactions contribute to
the potent biological activities. The results derived from this study suggest that 2-chloroquinoline based MACs can be developed as a lead
compounds in search of new antifungal and antioxidant agents.
Experimental Section
Experimental Section
General
All chemicals and reagents used were of analytical grade. Thin-layer chromatography (TLC) monitored the progression of the
reactions on silica gel-coated aluminum plates 60 F254, 0.25 mm thick (Merck). The components were identified by exposure to iodine
1
vapors or UV light. Melting point were decided by using open capillary technique and are uncorrected. H-NMR spectra were recorded in
DMSO-d6 and CDCl3 on a Bruker DRX-400 MHz and 200 MHz spectrometer. 13C NMR spectra were recorded in CDCl3 and DMSO-d6 on a
Bruker DRX-100 MHz instrument. IR spectra were recorded using a Bruker ALPHA ECO-ATR FTIR spectrometer. Mass spectra were
recorded on LC-MS spectrometer. The elemental analysis was performed on Thermofisher FA-2001 CHNS analyzer.
General procedure for the synthesis of monocarbonyl curcumin analogues.
Synthesis of 2-chloroquinoline-3-carbaldehyde 3a-c.
A mixture of aromatic amine 1a-c (1 mmol) and acetic anhydride (1 mmol) in pyridine as a solvent and catalyst were taken in 50 mL
round bottom flask equipped with a mechanical stirrer. The obtained intrmediate 2a-c were treated with Veilsmayer-Hack reagent under
heating condition at 800 C for 2-3hrs to give corresponding 2-chloroquinoline-3-carbaldehyde 3a-c in good yeild. TLC was used to monitor
the progress of the reaction. The reaction mixture was poured in to 100 mL ice-water and obtained solid was filtered, dried and
recrystallized from appropriate solvent to obtain a yellow solid product.
General procedure for the preparation of 2-Chloroquinoline based MACs.
A mixture of 2-chloroquinoline-3-carbaldehyde 3a-c (2 mmol) and various monoketone linkers (1 mmol) in 30 % aq. NaOH solution
( 0.3 ml, 2.27 mmol ) and 6 ml ethanol as solvent were charged in a 50 mL round bottom flask equipped with a mechanical stirrer. The
reaction mixture was stirred at room temperature condition for 2-3 h. Reaction prgress was monitored by TLC. The reaction mixture was
poured in to 100 mL ice-water and obtained solid was filtered, dried and recrystallized from ethanol-DMF to obtain a yellow solid product.
(2E,6E)-2,6-bis((2-chloroquinolin-3-yl)methylene)cyclohexanone (4a):
Yield: 81%; Yellow colored solid, mp. 265-268 °C; IR (cm-1): (C=O) 1647, (C=C) 1563, ( C=C Ar ) 1487, ( C-Cl) 888; 1H NMR (400 MHz, DMSO-
d6, δ ppm): 8.21 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.80 (dd, J = 8.0, 4.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.31 (dd, J = 8.0, 8.0
Hz, 2H), 7.23– 7.17 (m, 2H), 2.34-2.33 (m, 4H), 1.92 – 1.87 (m, 2H); 13C NMR (100 MHz, DMSO-d6 + CDCl3 δ ppm): 188.7, 150.4, 147.1, 146.1,
142.0, 139.5, 138.8, 131.8, 129.9, 128.2, 127.0, 124.8, 28.2 and 22.0; LCMS: Calcd for C26H18Cl2N2ONa [M+Na]+, 468.3, found: 469.1; Anal.
Calc. for C26H18Cl2N2O: C 70.12, H 4.07, N 6.29; found: C 70.14, H 4.08, N 6.28.
(2E,6E)-2,6-bis((2-chloro-7-methoxyquinolin-3-yl)methylene)cyclohexanone (4b):
Yield: 83%; Yellow colored solid, mp. 212-214 °C; IR (cm-1): (C=O) 1666, (C=C) 1573, ( C=C Ar ) 1479, ( C-Cl) 823.; 1H NMR (200 MHz, CDCl3 δ
ppm): 8.13 (s, 2 H), 8.00 (s, 2 H), 7.78 (d, J=8.0 Hz, 2 H), 7.59 (d, J=2.o Hz, 2 H), 7.32 (d, J=8.0 Hz, 2H), 4.01 (s, 6 H), 2.91 (t, J = 4Hz, 4 H), 1.91-
1.86 (m, 2H); 13C NMR (100 MHz, DMSO-d6 + CDCl3 δ ppm): 193.5, 162.5, 152.4, 147.5, 143.6, 142.7, 136.9, 134.0, 132.8, 132.6, 128.9, 111.2,
68.7, 27.7 and 19.6; LCMS: Calcd for C28H23Cl2N2O3 [M+H] +, 505.1, found: 505.0; Anal. Calc. for C28H22Cl2N2O3: C 66.54, H 4.39, N 5.54;
found: C 66.58, H 4.35, N 5.56.
(2E,6E)-2,6-bis((2-chloro-7-methylquinolin-3-yl)methylene)cyclohexanone (4c):
1
Yield: 79%; Yellow colored solid, mp. 270-273 °C; IR (cm-1): (C=O) 1717, (C=C) 1654, ( C=C Ar ) 1574, ( C-Cl) 802; H NMR (400 MHz, DMSO-
d6, δ ppm): 8.61 (s, 2H), 8.20-8.15 (m, 4H), 7.99 (s, 2H), 7.75 (d, J = 8 Hz, 2H), 3.79 (s, 6H), 3.22 (s, 4H), 2.09 (s, 2 H). 13C NMR (100 MHz,
DMSO-d6 + CDCl3 δ ppm): 187.4, 179.0, 149.4, 146.1, 141.0, 138.1, 137.8, 130.9, 129.0, 127.3, 126.0, 123.9, 27.2, 22.0 and 21.0; LCMS: Calcd
for C28H23Cl2N2O [M+H] +, 473.1, found: 473.1; Anal. Calc. for C28H22Cl2N2O: C 71.04, H 4.68, N 5.92; found: C 71.07, H 4.66, N 5.93.
(2E,6E)-2,6-bis((2-chloro-6-ethoxyquinolin-3-yl)methylene)cyclohexanone (4d):
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Yield: 81%; Yellow colored solid, mp. 208-210 °C; IR (cm-1): (C=O) 1616, (C=C) 1588, ( C=C Ar ) 1492, ( C-Cl) 918; 1H NMR (400 MHz, DMSO-
d6, δ ppm): δ 7.37 (d, J = 8.0 Hz, 2H), 7.14 – 7.03 (m, 4H), 6.62 – 6.45 (m, 4H), 3.42 – 3.38 (m, 4H), 2.17 (d, J = 4.0 Hz, 4H), 1.07 (d, J = 4.0 Hz,
2H), 0.71 (dd, J = 8.0.0, 8.0 Hz, 6H), 13C NMR (100 MHz, DMSO-d6 + CDCl3 δ ppm): 187.7, 156.9, 146.9, 142.0, 138.0, 137.1, 131.3, 128.5, 127.3,
127.0, 123.4, 105.7, 63.2, 27.5, 22.1 and 14.0; LCMS: Calcd for C30H27Cl2N2O3 [M+H]+, 533.1, found: 533.1; Anal. Calc. for C30H26Cl2N2O3: C
67.55, H 4.91, N 5.25; found: C 67.57, H 4.93, N 5.28.
(2E,6E)-2,6-bis((2,6-dichloroquinolin-3-yl)methylene)cyclohexanone (4e):
1
Yield: 85%; Yellow colored solid, mp. 212-214 °C; IR (cm-1): (C=O) 1667, (C=C) 1562, (C=C Ar) 1480, ( C-Cl) 905; H NMR (400 MHz, DMSO-
d6, δ ppm): 8.21 (s, 1H), 7.82-7-77 (m, 2H), 7.54-7.48 (m, 3H), 7.34-731 (m, 2H), 7.29-717 (m, 2H), 2.32 (t, J = 8.0 Hz, 4H), 1.93 – 1.87 (m, 2H);
13C NMR (100 MHz, CDCl3 δ ppm): 188.2, 154.8, 139.6, 134.3, 132.3, 129.5, 128.8, 128.7, 127.7, 127.4, 119.4, 117.4, 28.9 and 22.4; LCMS:
Calcd for C26H16Cl4N2ONa [M+Na]+, 537.2, found: 537.2; Anal. Calc. for C26H16Cl4N2O: C 60.73, H 3.14, N 5.45; found: C 60.72, H 3.17, N 5.49.
(2E,6E)-2,6-bis((2-chloro-6-methoxyquinolin-3-yl)methylene)cyclohexanone (4f):
1
Yield: 77%; Yellow colored solid, mp. 210-212 °C; IR (cm-1): (C=O) 1669, (C=C) 1607, (C=C Ar ) 1485, (C-Cl) 822; H NMR (200 MHz, CDCl3 δ
ppm) : δ 8.11 (s, 2H), 7.99 (s, 2H), 7.90 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H ), 7.57 (d, J = 1.0 Hz, 2H ), 7.30 (s, 1H ), 3.99 (s, 6H), 2.91 (t, J = 8.0 Hz,
4H), 1.92-1.82 (m, 2 H). 13C NMR (100 MHz, DMSO-d6 + CDCl3 δ ppm): 187.0, 156.3, 146.2, 141.3, 137.3, 136.4, 130.7, 127.9, 126.4, 122.7,
105.0, 62.5, 21.5 and 13.3; LCMS: Calcd for C28H23Cl2N2O3 [M+H] +, 505.1, found: 505.1; Anal. Calc. for C28H22Cl2N2O3: C 66.54, H 4.39, N
5.54; found: C 66.52, H 4.36, N 5.53.
(2E,6E)-2,6-bis((2-chloro-6-methylquinolin-3-yl)methylene)cyclohexanone (4g):
Yield: 81%; Yellow colored solid, mp. 250-254 °C; IR (cm-1): (C=O) 1649, (C=C) 1497, ( C=C Ar ) 1438, ( C-Cl) 880; 1H NMR (400 MHz, DMSO-
d6, δ ppm): δ 8.27 (s, 2H), 7.83 (t, J = 8.0 Hz, 4H), 7.65 (s, 2H), 7.41 (d, J = 8.0 Hz, 2H ), 3.45 (s, 6H ), 2.88 (s, 4H ), 1.75 (s, 2H); 13C NMR (100
MHz, DMSO-d6 + CDCl3 δ ppm): 188.3, 150.4, 147.1, 142.0, 139.1, 138.8, 131.8, 129.9, 128.3, 127.0, 124.8, 28.2, 22.9 and 22.0; LCMS: Calcd
for C28H23Cl2N2O [M+H] +, 473.1, found: 473.1; Anal. Calc. for C28H22Cl2N2O: C 71.04, H 4.68, N 5.92; found: C 71.06, H 4.65, N 5.95.
(2E,5E)-2,5-bis((2-chloro-7-methoxyquinolin-3-yl)methylene)cyclopentanone (4h):
Yield: 80%; Yellow colored solid, mp. 208-211 °C; IR (cm-1): (C=O) 1603, (C=C) 1478, ( C=C Ar ) 1345, ( C-Cl) 885; 1H NMR (400 MHz, DMSO-
d6, δ ppm): δ 7.99 (s, 2H), 7.69 (s, 2H), 7.48 (t, J = 8.0 Hz, 4H), 7.36-7.25 (m, 2H ), 3.92 (s, 6H ), 3.13 (s, 4H ); 13C NMR (100 MHz, DMSO-d6 +
CDCl3 δ ppm): 193.2, 162.7, 152.4, 147.5, 143.5, 142.6, 136.9, 134.0, 132.8, 132.6, 128.9, 111.2, 68.7 and 33.0; LCMS: Calcd for C27H21Cl2N2O3
[M+H] +, 491.1, found: 491.1; Anal. Calc. for C27H20Cl2N2O3: C 66.00, H 4.10, N 5.70; found: C 66.03, H 4.13, N 5.74.
(2E,5E)-2,5-bis((2-chloro-7-methylquinolin-3-yl)methylene)cyclopentanone (4i):
Yield: 82%; Yellow colored solid, mp. 218-220 °C; IR (cm-1): (C=O) 1648, (C=C) 1389, ( C=C Ar ) 1443, ( C-Cl) 909; 1H NMR (400 MHz, DMSO-
d6, δ ppm): δ 8.27 (s, 2H), 7.86-7.81 (m, 4H), 7.65 (s, 2H), 7.41 (d, J = 8.0 Hz, 2H ), 2.88 (s, 6H ), 1.75 (s, 4H ); 13C NMR (100 MHz, DMSO-d6 +
CDCl3 δ ppm): 188.3, 150.4, 147.1, 142.0, 139.1, 139.0, 138.9, 131.9, 129.9, 128.6, 127.0, 124.8, 28.2 and 22.0; LCMS: Calcd for C27H21Cl2N2O
[M+H] +, 460.4, found: 460.0; Anal. Calc. for C27H20Cl2N2O: C 70.59, H 4.39, N 6.10; found: C 70.56, H 4.35, N 6.12.
(1E,4E)-1,5-bis(2-chloro-7-methoxyquinolin-3-yl)penta-1,4-dien-3-one (5a):
Yield: 82%; Yellow colored solid, mp. 242-245 °C; IR (cm-1): (C=O) 1620, (C=C) 1485, ( C=C Ar ) 1412, ( C-Cl) 848; 1H NMR (400 MHz, DMSO-
d6, δ ppm): δ 7.76 (s, 3H), 7.29 (s, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.02-6.98 (m, 6H ), 3.80 (s, 6H ); 13C NMR (100 MHz, DMSO-d6 δ ppm): 187.3,
156.6, 146.5, 141.6, 137.7, 136.7, 131.0, 128.2, 127.0, 126.8, 123.0, 105.3 and 62.7. LCMS: Calcd for C25H28Cl2N2O3K [M+K] +, 504.4, found:
505.1; Anal. Calc. for C25H18Cl2N2O3: C 64.53, H 3.90, N 6.02; found: C 64.55, H 3.94, N 6.05.
(1E,4E)-1,5-bis(2-chloro-7-methylquinolin-3-yl)penta-1,4-dien-3-one (5b):
Yield: 84%; Yellow colored solid, mp. 237-240 °C; IR (cm-1): (C=O) 1642, (C=C) 1561, ( C=C Ar ) 1453, ( C-Cl) 876; 1H NMR (400 MHz, DMSO-
d6, δ ppm): δ 8.27 (s, 2H), 7.86-7.81 (m, 6H), 7.65 (s, 2H), 7.41 (d, J = 8.0 Hz, 2H ), 2.88 (s, 6H ); 13C NMR (100 MHz, DMSO-d6, δ ppm): 188.0,
157.3, 147.2, 142.4, 138.4, 137.5, 131.8, 129.9, 127.7, 127.5, 123.8, 106.0 and 22.5. LCMS: Calcd for C25H28Cl2N2ONa [M+Na] +, 456.1, found:
456.2; Anal. Calc. for C25H18Cl2N2O: C 69.29, H 4.19, N 6.46; found: C 69.25, H 4.22, N 6.45.
(1E,4E)-1,5-bis(2-chloro-6-ethoxyquinolin-3-yl)penta-1,4-dien-3-one (5c):
Yield: 83%; Yellow colored solid, mp. 226-230 °C; IR (cm-1): (C=O) 1655, (C=C) 1494, ( C=C Ar ) 1347, ( C-Cl) 824; 1H NMR (400 MHz, DMSO-
d6, δ ppm): δ 7.71 (d, J = 8.0 Hz, 2H), 7.47-7.37 (m, 5H), 6.96-6.78 (m, 5H), 3.75 (q, J = 8.0 Hz, 4H ), 1.05 (t, J = 8.0 Hz, 6H ); 13C NMR (100 MHz,
DMSO-d6 + CDCl3 δ ppm): 193.2, 162.4, 152.4, 147.5, 143.5, 142.6, 136.9, 134.0, 132.9, 132.6, 128.9, 111.2, 68.7 and 19.6; LCMS: Calcd for
C27H23Cl2N2O3 [M+H] +, 493.1, found: 493.0; Anal. Calc. for C27H22Cl2N2O3: C 65.73, H 4.49, N 5.68; found: C 65.76, H 4.52, N 5.71.
9
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900624
Chemistry & Biodiversity
Chem. Biodiversity
Bioactivity Assay
Antifungal Activity Assay
As per CLSI (formerly, NCCLS) guidelines, standard agar dilution method was used to determine antifungal potential.[46] The
synthesized compounds and standard Miconazole were dissolved in DMSO solvent. In phosphate buffer Ph 7, the medium yeast nitrogen
base was dissolved and autoclaved at 110°C for 10min. With each set a growth control without the antifungal agent and solvent control
DMSO were included. The fungal strains were freshly subculture onto Sabouraud dextrose agar (SDA) and incubated at 25°C for 72 h. The
fungal cells were suspended in sterile distilled water and diluted to get 105cells/mL. Ten microliters of standardized suspension was
inoculated onto the control plates and the media incorporated with the antifungal agents. The inoculated plates were incubated at 25°C
for 48 h. The readings were taken at the end of 48 and 72 h. The MIC was the lowest drug concentration which prevented the growth of
macroscopically visible colonies on drug containing plates when there was significant growth on the drug free control plates.
Antioxidant Activity Assay
1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay was used to evaluate in vitro antioxidant potential of newly
synthesized monocarbonyl curcumin analogues.[47] The obtained results were compared with standard antioxidant BHT (Butylated
hydroxy Toluene). The electron donation ability and the number of hydrogen atoms of the synthesized compounds was measured from
the bleaching of the purple colored methanol solution of 1, 1-diphenyl-1-picrylhydrazyl (DPPH).The spectrophotometric assay uses the
stable radical DPPH as a reagent. 1mL of various concentrations of the test compounds (5, 10, 25, 50 and 100 mg/mL) in methanol was
added to 4 mL of 0.004% (w/v) methanol solution of DPPH. The absorbance was measured against blank at 517 nm after 30 min
incubation period at room temperature. Following equation was used to calculate the percent inhibition (I %) of free radical production
from DPPH.
% of scavenging = [(A control-A sample)/A blank] X 100
Where ‘A control’ is the absorbance of the control reaction (containing all reagents except the test compound) and ‘A sample’ is the
absorbance of the test compound. Experiments were carried in triplicate.
Molecular Docking
The study of molecular docking was carried out to gauze the binding affinity of the new 2-chloroquinoline based monocarbonyl
curcuminoids to the crucial antifungal target sterol 14α-demethylase (CYP51) using the standard protocol implemented in the GLIDE
(Grid-based ligand Docking with Energetics) program of the Schrodinger Molecular modeling package (Schrodinger, LLC, New York, NY,
2015).[48, 49] with this purpose, the X-ray crystal structure of sterol 14α-demethylase (CYP51) enzyme in complex with its inhibitor-
fluconazole (pdb code: 3KHM) was retrieved from the Protein Data Bank (PDB) (http: //www.rcsb. org/pdb) and refined using with the
protein preparation wizard by applying the OPLS-2005 force field. This involved deleting the crystallographic water molecules as there are
no conserved interactions with enzyme; adding the missing hydrogen’s/side chain atoms corresponding to pH 7.0, assigning the
appropriate charge and protonation state followed by energy minimization of the obtained structure in order to relieve the steric clashes
among the amino acid residues till RMSD of 0.30Å is reached for the heavy atoms. The 3D structures of the MAC analogs were sketched
using the build panel in Maestro and optimized using Ligand Preparation tool which involves the addition of hydrogen’s, adjusting realistic
bond lengths and angles, etc. The partial charges were ascribed to the structures using the OPLS-2005 force-field followed by energy
minimization until its average RMSD reached 0.001Å. The shape and properties of the active site of the CYP51 enzyme was defined using
he Receptor Grid Generation for which a grid box of 10X10X10Å dimensions centered on the centroid of the co-crystallized ligand, which
serve as the reference coordinate to define the active site, was generated. With this automatic setup, molecular docking was executed to
gauze the binding affinities of the AC derivatives towards CYP51 using the extra precision (XP) Glide scoring function. The docking poses
generated were visualized and analyzed for the key elements of thermodynamic interactions between the ligand-enzyme complexes
using the Maestro’s Pose Viewer utility.
Supplementary Material
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/MS-number.
Acknowledgements
10
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900624
Chemistry & Biodiversity
Chem. Biodiversity
Author AAN is thankful to Principal, K. M. C. College Khopoli, for providing DST-FIST funded laboratory for this research work. Author
SVA is very thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi for providing a research fellowship. The authors
are also grateful for providing laboratory facilities to the Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad. We are also grateful to Schrodinger Inc. for GLIDE software to perform the molecular docking studies.
Author Contribution Statement
Author Amol A Nagargoje designed and performed the experiments and wrote the article, Satish V Akolkar, Madiha M Siddiqui and
Dnyaneshwar D Subhedar analyzed the data. Jaiprakash N. Sangshetti carried out the Antifungal and Antioxidant assays. Vijay M Khedkar
carried out in silico Molecular docking study. Bapurao B Shingate conceived and designed the experiments.
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This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900624
Chemistry & Biodiversity
Chem. Biodiversity
Graphical Abstract
Summary
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Small focused library of 2-chloroquinoline based monocarbonyl curcuminoids.
Synthesized analogues exhibits potential fungicidal and radical scavenging activity.
Molecular docking study makes more insights on binding affinity towards enzyme CYP51.
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This article is protected by copyright. All rights reserved.