Synthesis and bioevaluation of α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones

Article abstract of DOI:10.1007/s11696-019-00908-5

Abstract: Curcumin is an active component of turmeric that has poor solubility, stability and bioavailability. The monocarbonyl curcumin analogues were modified from curcumin to achieve more stable and active compounds as compared to curcumin. Therefore,

Full text of DOI:10.1007/s11696-019-00908-5

Chemical Papers
https://doi.org/10.1007/s11696-019-00908-5
ORIGINAL PAPER
Synthesis and bioevaluation of α,α’‑bis(1H‑1,2,3‑triazol‑5‑ylmethyle
ne) ketones
1
2
2
3
1
Tejshri R. Deshmukh · Vagolu S. Krishna · Dharmarajan Sriram · Jaiprakash N. Sangshetti · Bapurao B. Shingate
Received: 25 March 2019 / Accepted: 14 August 2019
©
Institute of Chemistry, Slovak Academy of Sciences 2019
Abstract
Curcumin is an active component of turmeric that has poor solubility, stability and bioavailability. The monocarbonyl cur-
cumin analogues were modiꢀed from curcumin to achieve more stable and active compounds as compared to curcumin.
Therefore, we have designed and synthesized a library of 18 compounds of α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones
(
8a–o) and evaluated them for their in vitro antitubercular and antioxidant activities against their respective strains. Results
of biological activities reveal that some of the compounds from the series showed good antitubercular as well as antioxidant
activities. The compound 8l was found as the most active antitubercular agent with MIC value 3.125 µg/mL, against Mtb
H37Rv. Moreover, the compounds, 8c, 8d, 8e and 8g, also showed potent antitubercular activity. The compounds 8e and 8m
displayed potent antioxidant activities with IC values 15.60 and 15.49 µg/mL, respectively. In support of the bioactivities,
5
0
in silico ADME properties’ prediction has also been carried out in this study.
This work was presented at Exploring New Horizons in Chemical
Sciences 2019, an international symposium held in Aurangabad,
India on 10-12 January, 2019.
Extended author information available on the last page of the article
Vol.:(0
1
123456789)
3

Chemical Papers
Graphic Abstract
Keywords α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones · Curcumin · Antitubercular activity · Antioxidant activity
Introduction
under physiological conditions as well as shows poor sol-
ubility and bioavailability. These limitations of curcumin
generate the urgent need to modify the diketo functionality
by diꢂerent curcumin analogues (Mandalapu et al. 2016).
Literature survey reveals that the monocarbonyl curcumin
analogues show better activity, solubility and bioavailability
as compared to bis-α, β-unsaturated β-diketones curcumin
analogues (Fig. 1) (Anand et al. 2007; Mosley et al. 2007;
Wang et al. 2015; Samaan et al. 2014).
Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-hep-
tadien-3,5-dione (Fig. 1) is simply a turmeric powder used
regularly in every kitchen of India and some Asian countries
as a spice, dietary ingredient and traditional multipurpose
medicine (Hatcher et al. 2008; Ammon and Wahl 1991). It
was extracted from the rhizome of the plant Curcuma longa
(
Anand et al. 2008). It shows a wide spectrum of various
therapeutic activities such as anticancer, wound healing
capacity, anti-inꢁammatory, antioxidant, antiseptic, antibac-
terial, antifungal, antiviral, and antidiabetic and also used to
treat a number of skin diseases (Maheshwari et al. 2006).
The curcumin is a bis-α, β-unsaturated β-diketones, in
which diketo functionality of curcumin is generally unstable
Literature survey also reveals that the 1,2,3-triazoles-
incorporated structural motif increases the solubility, sta-
bility and bioavailability of compounds as it easily binds
to various biological targets through hydrogen bonding and
dipole interactions (Kolb and Sharpless 2003). 1,2,3-tria-
zole acts as bioisostere of amide bond which is also one of
1
3

Chemical Papers
Experimental
Materials and methods
All the chemicals were of laboratory grade and purchased
from commercial suppliers such as Alfa Aesar, Sigma-
Aldrich, Spectrochem and Rankem and were used without
further puriꢀcation. Purity and completion of reaction time
of all synthesized compounds were monitored by thin-layer
chromatography (TLC) using silica gel 60-F precoated
2
54
on aluminium sheets as an adsorbent, and visualization
was accomplished by iodine/ultraviolet light. The IR spec-
tra (In KBr pellets) were recorded on Bruker FT-IR spec-
1
trometer. H NMR spectra were recorded on a Bruker DRX
with 400 MHz NMR spectrometer using tetramethylsilane
(
(
TMS) as an internal standard, and chemical shifts are in δ
ppm). The splitting pattern abbreviations are designed as
singlet (s), doublet (d), triplet (t), quintet (quin) and multi-
1
3
Fig. 1 Modiꢀcation of curcumin diketo group into monocarbonyl cur-
plet (m). C NMR spectra were recorded on a Bruker DRX
cumin analogue
with 100 MHz NMR in CDCl /DMSO-d . High-resolution
3
6
mass spectra (HRMS) were obtained using Agilent 6520
the reasons behind its high binding aꢃnity towards many
biological targets (Dheer et al. 2017). It is easy to synthe-
sized via Cu (I)-catalysed 1,3-dipolar cycloaddition reac-
tion between azide and alkyne using Sharpless and Meldal’s
greener approach of click chemistry (Kolb et al. 2001; Tor-
noe et al. 2002). Literature survey shows a broad spectrum
of various biological activities with number of compounds
bearing 1,2,3-triazolyl scaꢂolds such as antitubercular (Ali
et al. 2017), antifungal (Lima-Neto et al. 2012), antioxidant
(
Q-TOF) ESI-HRMS instrument. Melting points of all the
synthesized compounds were determined in open capillary
tubes and are uncorrected.
General procedure for synthesis of α,α’‑bis(1H‑1,2,3‑
triazol‑5‑ylmethylene) ketones (8a–o)
In separate round bottom ꢁasks, 0.01 mol of acetone (5)/
cyclopentanone (6)/cyclohexanone (7) was allowed to react
with 0.02 mol of freshly prepared substituted 1,2,3-triazolyl
aldehydes (4a–f) for 2–3 h at room temperature in 2–3 mL
ethanol and catalytic amount of acetic acid. The progress of
reaction was monitored by TLC. After completion of reac-
tion, the reaction mass was poured on crushed ice and the
obtained solid was ꢀltered and dried well. The ꢀnal prod-
ucts (8a–o) were puriꢀed by crystallization in EtOH:DMF
(
Mady et al. 2014), antibacterial (Agalave et al. 2011), anti-
microbial (Banday et al. 2012), antiviral (Jordao et al. 2009),
anticancer (Pokhodylo et al. 2013), antimalarial (Raj et al.
2
013) and anti-HIV (Boechat et al. 2011).
In immune-deꢀcient patients, the co-infections of various
diseases such as TB, HIV, fungal, bacterial and oxidative
stress were frequently observed (Nucci and Marr 2005). In
such cases, the co-administration of a number of drugs to
treat various diseases at a same time increases pill burden
on patient as well as there will be a possibility of drug–drug
interaction. To overcome these diꢃculties, in this study we
are trying to synthesize such compounds, which show antitu-
bercular, antifungal as well as antioxidant activities.
(
3:1) solvent system. All the α,α’-bis(1H-1,2,3-triazol-5-
ylmethylene) ketones were obtained as yellowish crystals.
Spectral data analysis of all compounds
(
1E,4E)-1,5-bis(1-phenyl-1H-1,2,3-triazol-4-yl)penta-
,4-dien-3-one (8a): The compound (8a) was obtained by
acid-catalysed reaction between 1,2,3-triazolyl aldehyde
By considering the therapeutic signiꢀcance of the above
and urgent need of synthesizing antitubercular, antifungal
and antioxidant agents, herein, we have designed and syn-
thesized α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones
using various ketones such as acetone, cyclopentanone and
cyclohexanone as a source of monocarbonyl moiety. All the
newly synthesized compounds were evaluated for their in vitro
antitubercular, antifungal and antioxidant activities. In addi-
tion to this, we have also performed in silico ADME proper-
ties’ prediction of all the newly synthesized compounds.
1
(
4a) and acetone (5) as dark yellow solid; Yield: 88%;
−1
Mp: > 270 °C; IR ѵ max/cm 1658 (C=O), 2897, 3137;
1
H NMR (400 MHz, DMSO-d6, δ ppm) 7.31 (s, 2H, CH),
H
7
.50 (d, 4H, Ar–H), 7.57 (t, 4H, Ar-H), 7.63 (t, 2H, Ar-
1
3
H), 7.80 (s, 2H, CH), 8.09 (s, 2H, triazolyl-H); C NMR
100 MHz, DMSO-d6, δ ppm) 119.3, 120.5, 120.6, 120.8,
(
C
1
29.7, 129.8, 130.0, 151.2, 181.7.
1
3

Chemical Papers
(
1E,4E)-1,5-Bis(1-(2-methoxyphenyl)-1H-1,2,3-triazol-
(t, 4H, cyclopentanone-CH ), 7.33 (d, 4H, Ar-H), 7.57 (t,
2
4
-yl)penta-1,4-dien-3-one (8b): The compound (8b) was
2H, Ar-H), 7.95 (d, 4H, Ar-H), 8.74 (s, 2H, CH), 9.17 (s,
obtained by acid-catalysed reaction between 1,2,3-triazolyl
2H, triazolyl-H).
aldehyde (4b) and acetone (5) as pale yellow solid; IR ѵ
(2E,5E)-2,5-bis((1-(4-methoxyphenyl)-1H-1,2,3-tria-
zol-4-yl)methylene)cyclopentanone (8 h): The compound
(8 h) was obtained by acid-catalysed reaction between
1,2,3-triazolyl aldehyde (4c) and cyclopentanone (6) as
brown yellow solid; Yield: 92%; Mp: 260–262 °C; IR ѵ
−
1
1
max/cm 1677 (C=O), 2888, 3110; H NMR (400 MHz,
DMSO-d6, δ ppm) 3.88 (s, 6H, O-CH ), 7.18 (s, 2H, CH),
H
3
7
.34–7.71 (m, 8H, Ar-H), 8.33 (s, 2H, CH), 8.97 (s, 2H,
13
triazolyl-H); C NMR (100 MHz, DMSO-d6, δ ppm)
C
−
1
1
5
1
6.2, 112.5, 113.7, 119.1, 119.5, 123.6, 128.3, 128.7, 131.9,
max/cm 1696 (C=O), 2901, 3132; H NMR (400 MHz,
49.4, 160.3, 192.2. HRMS (ESI) calcd. For C H N O
DMSO-d6, δ ppm) 3.17 (t, 4H, cyclopentanone-CH ), 3.85
2
3
20
6
3
H
2
+
[
M+H] : 429.1676; found: 429.1649.
(s, 6H, OCH ), 7.19 (d, 4H, Ar-H), 7.45 (s, 2H, CH), 7.90 (d,
3
13
(
1E,4E)-1,5-bis(1-(4-methoxyphenyl)-1H-1,2,3-triazol-
4H, Ar-H), 9.07 (s, 2H, triazolyl-H); C NMR (100 MHz,
4
-yl)penta-1,4-dien-3-one (8c): The compound (8c) was
DMSO-d6, δ ppm) 28.0, 56.2, 116.8, 122.3, 126.9, 130.3,
C
obtained by acid-catalysed reaction between 1,2,3-triazolyl
133.4, 136.3, 157.6, 166.6, 193.8.
aldehyde (4c) and acetone (5) as light yellow solid; Yield:
(2E,5E)-2,5-Bis((1-(4-tolyl)-1H-1,2,3-triazol-4-yl)
methylene)cyclopentanone (8i): The compound (8i) was
obtained by acid-catalysed reaction between 1,2,3-tria-
zolyl aldehyde (4d) and cyclopentanone (6) as light yellow
−
1
8
3
2%; Mp: > 270 °C; IR ѵ max/cm 1673 (C=O), 2888,
1
164; H NMR (400 MHz, DMSO-d6, δ ppm) 3.85 (s, 6H,
H
O-CH ), 7.19 (d, 4H, Ar-H), 7.44 (s, 2H, CH), 7.78 (s, 2H,
3
13
−1
1
CH), 7.83 (d, 4H, Ar-H), 9.21 (s, 2H, triazolyl-H); C NMR
solid; IR ѵ max/cm 1696 (C=O), 2867, 3133; H NMR
(
100 MHz, DMSO-d6, δ ppm) 57.5, 110.9, 119.3, 120.8,
(400 MHz, DMSO-d6, δ ppm) 2.31 (s, 6H, 2CH ), 3.09 (t,
C
H
3
1
23.3, 126.9, 133.1, 155.5, 167.3, 191.7.
1E,4E)-1,5-bis(1-(p-tolyl)-1H-1,2,3-triazol-4-yl)penta-
,4-dien-3-one (8d): The compound (8d) was obtained by
4H, cyclopentanone-CH ), 7.41 (d, 4H, Ar-H), 7.72 (s, 2H,
2
13
(
CH), 7.84 (d, 4H, Ar-H), 9.08 (s, 2H, triazolyl-H); C NMR
1
(100 MHz, DMSO-d6, δ ppm) 23.6, 31.1, 122.6, 126.2,
C
acid-catalysed reaction between 1,2,3-triazolyl aldehyde
132.0, 133.4, 134.6, 138.3, 142.2, 153.0, 196.4.
(
4d) and acetone (5) as cream yellow solid; Yield: 80%;
(2E,5E)-2,5-bis((1-(4-nitrophenyl)-1H-1,2,3-triazol-
4-yl)methylene)cyclopentanone (8j): The compound (8j)
was obtained by acid-catalysed reaction between 1,2,3-tri-
azolyl aldehyde (4e) and cyclopentanone (6) as dark yel-
−
1
1
Mp:>270 °C; IR ѵ max/cm 1671 (C=O), 2893, 3140; H
NMR (400 MHz, DMSO-d6, δ ppm) 2.43 (s, 6H, CH ),
H
3
7
8
.45 (d, 4H, Ar-H), 7.81 (d, 4H, Ar-H), 7.99 (s, 2H, CH),
−
1
.71 (s, 2H, CH), 9.23 (s, 2H, Triazolyl-H).
low solid; Yield: 89%; Mp:>270 °C; IR ѵ max/cm 1686
1
(
1E,4E)-1,5-bis(1-(4-nitrophenyl)-1H-1,2,3-triazol-
(C=O), 2885, 3138; H NMR (400 MHz, DMSO-d6, δ
H
4
-yl)penta-1,4-dien-3-one (8e): The compound (8e) was
ppm) 2.84 (t, 4H, cyclopentanone-CH ), 7.24 (s, 2H, CH),
2
obtained by acid-catalysed reaction between 1,2,3-triazolyl
7.63 (d, 4H, Ar-H), 7.91 (d, 4H, Ar-H), 9.32 (s, 2H, tria-
1
3
aldehyde (4e) and acetone (5) as light yellow solid; Yield:
zolyl-H); C NMR (100 MHz, DMSO-d6, δ ppm) 27.9,
C
−
1
8
3
4
3%; Mp: > 270 °C; IR ѵ max/cm 1672 (C=O), 2882,
122.0, 125.5, 127.0, 132.3, 137.0, 141.7, 148.0, 150.8,
1
116; H NMR (400 MHz, DMSO-d6, δ ppm) 7.47 (d,
190.6.
H
H, Ar-H), 7.78 (d, 4H, Ar-H), 7.92 (s, 2H, CH), 8.48 (s, 2H,
(2E,5E)-2,5-bis((1-(4-chlorophenyl)-1H-1,2,3-triazol-
4-yl)methylene)cyclopentanone (8k): The compound (8k)
was obtained by acid-catalysed reaction between 1,2,3-tria-
zolyl aldehyde (4f) and cyclopentanone (6) as green yel-
13
CH), 9.47 (s, 2H, triazolyl-H); C NMR (100 MHz, DMSO-
d6, δ ppm) 121.4, 123.1, 126.3, 130.4, 133.1, 143.1, 146.2,
C
1
49.3, 189.0.
−
1
(
1E,4E)-1,5-bis(1-(4-chlorophenyl)-1H-1,2,3-triazol-
low solid; Yield: 85%; Mp: > 270 °C; IR ѵ max/cm
1
4
-yl)penta-1,4-dien-3-one (8f): The compound (8f) was
1657 (C=O), 2880, 3117; H NMR (400 MHz, DMSO-d6,
δ ppm) 2.93 (t, 4H, cyclopentanone-CH ), 7.25 (s, 2H,
obtained by acid-catalysed reaction between 1,2,3-triazolyl
H
2
aldehyde (4f) and acetone (5) as green yellow solid; Yield:
CH), 7.74 (d, 4H, Ar-H), 7.98 (d, 4H, Ar-H), 9.22 (s, 2H,
−
1
7
3
9%; Mp: 268–270 °C; IR ѵ max/cm 1676 (C=O), 2884,
triazolyl-H).
1
123; H NMR (400 MHz, DMSO-d6, δ ppm) 7.53 (s, 2H,
(2E,6E)-2,6-bis((1-phenyl-1H-1,2,3-triazol-4-yl)
methylene)cyclohexanone (8 l): The compound (8l) was
obtained by acid-catalysed reaction between 1,2,3-triazolyl
aldehyde (4a) and cyclohexanone (7) as light yellow solid;
H
CH), 7.77 (d, 4H, Ar-H), 8.01 (d, 4H, Ar-H), 8.65 (s, 2H,
CH), 9.37 (s, 2H, triazolyl-H).
(
2E,5E)-2,5-bis((1-phenyl-1H-1,2,3-triazol-4-yl)meth-
−
1
ylene)cyclopentanone (8 g): The compound (8 g) was
obtained by acid-catalysed reaction between 1,2,3-triazolyl
aldehyde (4a) and cyclopentanone (6) as brown yellow solid;
Yield: 88%; Mp: 218–221 °C; IR ѵ max/cm 1670 (C=O),
1
2928, 3128; H NMR (400 MHz, DMSO-d6, δ ppm) 1.95
H
(quin, 2H, cyclohexanone-CH ), 3.18 (t, 4H, cyclohexanone-
2
−
1
Yield: 87%; Mp: > 270 °C; IR ѵ max/cm 1667 (C=O),
CH ), 7.58 (s, 2H, CH), 7.65 (t, 2H, Ar-H), 7.70 (d, 4H, Ar-
2
1
2
899, 3157; H NMR (400 MHz, DMSO-d6, δ ppm) 2.92
H), 8.03 (d, 4H, Ar-H), 9.20 (s, 2H, triazolyl-H).
H
1
3

Chemical Papers
(
2E,6E)-2,6-bis((1-(4-methoxyphenyl)-1H-1,2,3-triazol-
96-well microtiter plate using 100 µL 7H9-S. A growth con-
trol containing no antibiotic and a sterile control were also
prepared on each plate. Sterile water was added to all perim-
eter wells to avoid evaporation during the incubation. The
plate was covered, sealed in a plastic bag and incubated at
37 °C in normal atmosphere. After 7 days incubation, 30 µL
of alamar blue solution was added to each well and the plate
was re-incubated overnight. A change in colour from blue
(oxidized state) to pink (reduced) indicated the growth of
bacteria, and the MIC was deꢀned as the lowest concentra-
tion of drug that prevented this change in colour. The MIC
(in µg/mL) was recorded as the lowest concentration/high-
est dilution of the compounds/control drugs that completely
inhibited the growth of MTB cultures. The MIC values of
compounds (8a–o) have been compared with standard drugs
(rifampicin, isoniazid, ethambutol and ciproꢁoxacin).
4
-yl)methylene)cyclohexanone (8 m): The compound (8 m)
was obtained by acid-catalysed reaction between 1,2,3-tri-
azolyl aldehyde (4c) and cyclohexanone (7) as bright yel-
−
1
low solid; Yield: 86%; Mp:>270 °C; IR ѵ max/cm 1658
1
(
C=O), 2873, 3170; H NMR (400 MHz, DMSO-d6, δ ppm)
H
2
.02 (quin, 2H, cyclohexanone-CH ), 3.07 (t, 4H, cyclohex-
2
anone-CH ), 3.78 (s, 6H, OCH ), 7.25 (d, 4H, Ar-H), 7.60
2
3
(
d, 2H, CH), 7.89 (d, 4H, Ar-H), 9.27 (s, 2H, triazolyl-H);
1
3
C NMR (100 MHz, DMSO-d6, δ ppm) 17.6, 57.9, 120.0,
C
1
22.1, 126.6, 129.7, 131.9, 133.8, 143.7, 163.9, 193.4.
(
2E,6E)-2,6-Bis((1-(4-tolyl)-1H-1,2,3-triazol-4-yl)
methylene)cyclohexanone (8n): The compound (8n) was
obtained by acid-catalysed reaction between 1,2,3-tria-
zolyl aldehyde (4d) and cyclohexanone (7) as bright yellow
−
1
1
solid; IR ѵ max/cm 1660 (C=O), 2850, 3157; H NMR
(
400 MHz, DMSO-d6, δ ppm) 1.59 (quin, 2H, cyclohex-
H
anone-CH ), 2.29 (s, 6H, 2CH ), 3.07 (t, 4H, cyclohex-
General procedure for (evaluation of DPPH radical
scavenging) antioxidant activity
2
3
anone-CH ), 7.40 (d, 4H, Ar-H), 7.65 (s, 2H, CH), 7.81 (d,
2
1
3
4
H, Ar-H), 9.07 (s, 2H, triazolyl-H); C NMR (100 MHz,
DMSO-d6, δ ppm) 23.7, 28.9, 30.3, 123.8, 128.2, 129.2,
The antioxidant activity of all the synthesized compounds
has been assessed in vitro by the 1,1-diphenyl-2-picrylhydra-
zyl (DPPH) radical scavenging assay (Kinsella et al. 1993).
The hydrogen atom or electron donation ability of the com-
pounds was measured from the bleaching of the purple col-
oured methanol solution of 1,1-diphenyl-1-picrylhydrazyl
(DPPH). The spectrophotometric assay uses the stable radi-
cal DPPH as a reagent. 1 mL 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 reaction mixture was incubated at 37 °C. The
scavenging activity on DPPH was determined by measuring
the absorbance at 517 nm after 30 min. All tests were per-
formed in triplicate and the mean values were entered. The
percent of inhibition (I%) of free radical production from
DPPH was calculated by the following equation:
C
1
31.0, 132.1, 134.6, 143.5, 145.9, 193.1; HRMS (ESI) calcd.
+
For C H N O [M+H] : 437.2091; found: 437.2100.
2
6
25
6
(
2E,6E)-2,6-bis((1-(4-nitrophenyl)-1H-1,2,3-triazol-
4
-yl)methylene)cyclohexanone (8o): The compound (8o)
was obtained by acid-catalysed reaction between 1,2,3-tri-
azolyl aldehyde (4e) and cyclohexanone (7) as turmeric
−
1
yellow solid; Yield: 90%; Mp: > 270 °C; IR ѵ max/cm
1
1
H
675 (C=O), 2840, 3152; H NMR (400 MHz, DMSO-d6,
δ ppm) 1.91 (quin, 2H, cyclohexanone-CH ), 3.12 (t, 4H,
2
cyclohexanone-CH ), 7.66 (s, 2H, CH), 8.33 (d, 4H, Ar-
2
1
3
H), 8.50 (d, 4H, Ar-H), 9.35 (s, 2H, triazolyl-H); C NMR
100 MHz, DMSO-d6, δ ppm) 23.7, 25.4, 119.9, 121.4,
(
C
1
24.1, 130.3, 132.8, 137.5, 141.4, 145.1, 196.1.
Experimental protocol for biological activity
In vitro MTB MABA assay
ꢀꢁ ꢂ ꢁ
× 100ꢂꢃ
sample
%
of scavenging =
Acontrol−Asample ∕ A
where A
is the absorbance of the control (DPPH radi-
control
The antitubercular activity of newly synthesized compounds
cal without test sample), A
is the absorbance of the
sample
(
8a–o) has been screened for their in vitro eꢂects against
test sample (DPPH radical with test sample). The control
contains all reagents except the test samples. The results
were compared with the standard synthetic antioxidant BHT
(butylated hydroxy toluene).
Mtb H37Rv (ATCC 27294) using Microplate Alamar Blue
Assay (MABA) (Franzblau et al. 1998) for determination of
MIC in triplicates. The experimental method for antituber-
cular activity is brieꢁy described as follows.
Initially, the inoculum was prepared from fresh LJ
medium re-suspended in 7H9-S medium (7H9 broth, 0.1%
casitone, 0.5% glycerol, supplemented oleic acid, albumin,
dextrose, and catalase [OADC]), adjusted to a McFarland
tube No. 1, and diluted 1:20; 100 µL was used as inoculum.
Each drug stock solution was thawed and diluted in 7H9-S at
fourfold the ꢀnal highest concentration tested. Serial twofold
dilutions of each drug were prepared directly in a sterile
Results and discussion
Chemistry
Molecular hybridization technique is used as a design
strategy for the synthesis of new α,α’-bis(1H-1,2,3-triazol-
5-ylmethylene) ketones. It is a common strategy used for
1
3

Chemical Papers
(
(
A)
C)
(B)
(
D)
Fig. 2 Design for synthesis of α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones (8a-o)
developing new therapeutic agents by uniting two or more
active pharmacophores in a single molecular framework.
The molecular hybridization of various pharmacophores of
therapeutic agents (Wang et al. 2011; Manohar et al. 2013;
Costa et al. 2006; Liu et al. 2013) was hybridized together
to form newly hybridized α,α’-bis(1H-1,2,3-triazol-5-
ylmethylene) ketones as shown in Fig. 2.
According to the designed strategy, we have planned
and synthesized the titled compounds (8a-o) via multistep
synthetic route. To synthesize ꢀnal targeted compounds, we
have synthesized the starting material, 1-phenyl-1H-1,2,3-
triazole-4-carbaldehydes (4a–f) using the reported proce-
dure (Danne et al. 2018; Khare et al. 2018) as shown in
Scheme 1.
The newly designed scaꢂold was broadly divided into
three segments, namely, two units of 1,2,3-triazoles, mono-
carbonyl linker and substitutional variant unit. The 1,2,3-tri-
azoles acts as a main backbone of the newly hybridized
compounds. It generally shows drug-like properties and
also interacts with various biological targets through hydro-
gen bonding as well as dipole interactions. The monocar-
bonyl linker of modiꢀed curcumin anlogues were help to
improve the activity as well as stability of the compounds
as compared to curcumin. Acetone, cyclopentanone and
cyclohexanone are used as the source of monocarbonyl
linker in the designing strategy of α,α’-bis(1H-1,2,3-triazol-
These freshly synthesized 1-phenyl-1H-1,2,3-triazole-
4-carbaldehydes (4a–f) were crystallized to get pure form
of compounds as a starting material and allowed further to
react separately with acetone (5), cyclopentanone (6) and
cyclohexanone (7), respectively, in ethanol and acetic acid
at room temperature to form yellow solids with good yields.
The schematic representation of the reaction is shown in
Scheme 2. The obtained compounds had various shades of
turmeric yellow colours, which was one of the conꢀrmative
characteristics of the formation of α,α’-bis(1H-1,2,3-triazol-
5-ylmethylene) ketones (8a–o).
All the newly synthesized compounds have been char-
acterized using physical data and spectral analysis for their
5
-ylmethylene) ketones. The substitutional variant units
1
show pharmacophoric properties that help to control the
lipophilicity.
structural conꢀrmation. One of the representative H NMR
spectra of compound (8n) displays peaks at δ 2.29 and
Scheme 1 Synthetic route for
1
4
-phenyl-1H-1,2,3-triazole-
-carbaldehydes. Reagents and
conditions: (i) NaNO , HCl,
2
0
°C; NaN , 2–4 h, rt; (ii) pro-
3
pargyl alcohol, CuSO , sodium
4
2
ascorbate, PEG-400:H O (1:1),
2
5 h, rt; (iii) CrO :2Py, CH Cl ,
3
2
2
3
h, rt
1
3

Chemical Papers
Scheme 2 Synthesis of α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones (8a-o)
9
.07 ppm as a singlet due to the presence of Ar-CH and
From Table 1, it was observed that compound 8l was
the most potent antitubercular agent among all the newly
synthesized compounds of the series with MIC 3.125 µg/
mL. In case of compound 8l, cyclohexanone was used as a
source of monocarbonyl linker. Other than compound 8l, the
compounds 8d and 8e also showed promising antitubercular
activity with MIC 12.5 and 6.25 µg/mL, respectively. Both
these compounds were synthesized using acetone as a source
of monocarbonyl linker and the variant substitutional units
with 4-methyl and 4-nitro groups, respectively responsible
for diꢂering bioactivity. The compounds 8c and 8 g were
also found as potent antitubercular agents with MIC 25 µg/
mL.
3
triazolyl-H, respectively. In addition to this, the peaks at δ
3
.07 and 1.59 ppm as triplet and quintet, respectively, were
observed due to CH of cyclohexanone. The presence of four
2
characteristic carbon signals was observed at δ 23.7, 193.1,
13
2
8.9 and 30.3 ppm in C NMR spectrum of compound (8n),
respectively, representing the presence of Ar-CH , carbonyl
3
carbon and 3CH of cyclohexanone in the structure of com-
2
pound. The HRMS spectrum further strengthens the struc-
+
ture assigned to (8n) as it displays [M+H] ion peak at m/z
4
37.2091 for the molecular formula C H N O and it was
26 25 6
+
observed equivalent to the calculated [M+H] ion peak at
37.2100.
4
From the obtained results, it was observed that the cur-
cumin analogues-bearing acetone and cyclohexanone as
source of monocarbonyl linker show better antitubercular
activity than cyclopentanone-bearing curcumin analogues.
It was also found that there is an eꢂect of substitutional vari-
ants on the bioactivity results. According to the obtained
results, some of the compounds from the newly synthesized
series were act as potent antitubercular agents and, therefore,
it oꢂers an attractive lead series for the discovery of new
therapeutic antitubercular agents in future by synthesizing
structurally similar compounds of potent derivatives from
the synthesized series.
Biological assay
All the newly synthesized α,α’-bis(1H-1,2,3-triazol-5-
ylmethylene) ketones (8a–o) were evaluated for their in vitro
antitubercular and antioxidant activities against their respec-
tive strains. The obtained activity results were compared
with the standards used for the study as incorporated in
Table 1.
In vitro antitubercular activity
All the newly synthesized compounds were evaluated for
their in vitro antitubercular activity against Mtb H37Rv
using Microplate Alamar Blue Assay (MABA) (Franzblau
et al. 1998). The obtained results were compared with the
standard antitubercular drugs such as isoniazid, rifampicin,
ethambutol and ciproꢁoxacin as shown in Table 1.
In vitro antioxidant activity
All the newly synthesized compounds were further screened
for their in vitro antioxidant activities. All these compounds
have been evaluated for their antioxidant activity using
1
3

Chemical Papers
Table 1 In vitro antitubercular
and antioxidant activity of all
the compounds (8a-o)
Anti-TB
Antioxidant
Entry
Structure
activity MIC activity IC50
(
µg/mL)
(µg/mL)
8
a
>
25
25
26.12±±.ꢀ5
8
b
>
29.19±±.ꢁ1
ꢁ±.ꢀꢀ±±.18
19.52±±.19
15.6±±±.ꢂꢂ
29.1±±±.5±
8
c
2
5
8
d
1
6
2.5
.25
8
e
8
f
>25
8
g
2
5
22.21±±.11
ꢁ9.1ꢂ±±.29
21.ꢁꢁ±±.±5
8
h
>
25
25
8
i
>
8
j
>
25
25
ꢂ1.±9±±.25
ꢀ6.ꢁꢀ±±.26
8
k
>
8
l
ꢁ
.125
ꢂ±.9ꢂ±±.ꢁ1
15.ꢀ9±±.2ꢀ
22.ꢁ9±±.±8
ꢁ2.±ꢂ±±.ꢂꢀ
8
m
>
25
25
25
8
n
>
8
o
>
Isoniazid
Rifampicin
Ethambutol
Ciprofloxacin
BHT
±.±5
±.1
NT
NT
1.56
1.56
NT
NT
NT
16.ꢀꢂ±±.18
NTnot tested
1
3

Chemical Papers
Table 2 In silico ADME properties’ prediction of the compounds (8a-o)
b
2
n-ROTBc
MVd
MWe
miLogf
n-ONg
n-OHNHh
Entry
% ABSa
TPSA (A )
Lipinski
Drug-like-
ness model
score
i
violations
Rule
–
–
–
6
8
8
6
8
6
4
6
4
6
4
4
6
4
6
–
< 500
≤ 5
< 10
7
9
9
7
13
7
7
9
7
13
7
7
9
7
< 5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
≤ 1
0
0
0
0
1
0
0
0
0
1
0
0
0
0
1
–
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
81.91
75.55
75.55
81.91
50.29
81.91
81.91
75.55
81.91
50.29
81.91
81.91
75.55
81.91
50.29
78.51
96.97
96.97
78.51
170.16
78.51
78.51
96.97
78.51
170.16
78.51
78.51
96.97
78.51
170.16
326.19
377.29
377.29
359.32
372..86
353.57
348.96
400.05
382.08
395.62
376.03
365.76
416.85
398.88
412.43
368.40
428.45
428.45
396.45
458.39
437.29
394.44
454.49
422.49
484.43
463.33
408.46
468.52
436.52
498.46
2.68
3.12
2.80
3.58
2.60
4.04
2.96
3.08
3.86
2.88
4.32
3.47
3.58
4.36
3.38
− 0.64
− 1.23
− 1.11
− 0.94
− 0.99
− 0.78
− 0.21
− 0.58
− 0.50
− 0.57
− 0.28
− 0.15
− 0.47
− 0.43
− 0.54
g
h
i
j
k
l
m
n
o
13
a
Percentage absorption
b
c
d
e
f
Topographical polar surface area
Number of rotatable bonds
Molecular volume
Molecular weight
Lipophilicity
g
No. of hydrogen bond acceptors
No. of hydrogen bond acceptors
h
i
Number of violations
DPPH radical scavenging method (Kinsella et al. 1993).
Here, the results were compared with BHT (Butylated
Hydroxy Toluene). All the obtained antioxidant activity
results are given in Table 1.
to this, we have observed that both the compounds 8e and
8m bearing –NO and –OCH groups, respectively, were the
2
3
most antioxidant agents in the series. Lahsasni et al. have also
been experienced this similar type of contradictory antioxi-
dant activities’ results of chalcones analogues (Lahsasni et al.
2014). In addition to this, many antioxidant agents exist with
From the antioxidant activity results, it was found that
the only two compounds from the newly synthesized series,
8
e and 8m, act as potent antioxidant agents as both having
–NO group in their structural framework (Temel et al. 2014;
2
better antioxidant activities than standard BHT with IC
Archie et al. 2017). This may be observed because the bioac-
tivity of any compound depends not only on any individual
group or atom but also on the contribution of group of atoms
in a molecule known as pharmacophore, their arrangement as
well as their interactions with the target molecules and many
more factors may also be responsible for it.
5
0
values 15.60 µg/mL and 15.49 µg/mL, respectively. The
compound 8e was synthesized using acetone as a source of
monocarbonyl linker with 4-NO substituent unit, whereas
2
cyclohexanone was used as a source of monocarbonyl linker
for the synthesis of compound 8m bearing 4-OCH as a vari-
3
ant unit. Therefore, it was again proved that the curcumin
analogues-bearing acetone and cyclohexanone as source of
monocarbonyl linker show better antioxidant activity than
cyclopentanone-bearing curcumin analogues.
In silico ADME prediction
The in silico ADME properties of newly synthesized cur-
cumin analogues were also predicted in this study and the
obtained results are well summarized in Table 2.
The substituent units also play a major role to vary bio-
activity results. It is known that generally, –OCH group
3
is used to act as a better antioxidant agent, whereas –NO
A molecule is considered as an orally active drug if the
dug violets only one criteria of the Lipinski’s rule of ꢀve.
2
group shows oxidative properties. However, in contradiction
1
3

Chemical Papers
The Lipinski’s rule of ꢀve having following four criterias:
miLog P (octanol–water partition coeꢃcient)≤5, molecular
weight≤500, number of hydrogen bond acceptors≤10 and
number of hydrogen bond donors ≤ 5. Here, we have also
calculated absorption (% ABS) for all the derivatives of the
series using the following formula (Zhao et al. 2002)
in future by generating more similar analogues of potent
derivatives as well as by continuing the research with respect
to in vivo bioactivities of potent analogues.
Acknowledgements The authors are thankful to the Head, Depart-
ment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad-431 004, India for providing laboratory facility.
%
ABS = 109 - (0.345 × TPSA).
In addition to this, topological polar surface area (TPSA),
References
number of rotatable bonds (n-ROTB), molecular volume
(
MV), molecular weight (MW), logarithm of partition
coeꢃcient (mi LogP), number of hydrogen bond acceptors
n-ON), number of hydrogen bonds donors (n-OHNH), and
Agalave SG, Maujan SR, Pore VS (2011) Click chemistry: 1,2,3-tria-
zoles as pharmacophores. Chem Asian J 6:2696–2718. https://doi.
org/10.1002/asia.201100432
(
Lipinski’s rule of ꢀve (Lipinski et al. 2001) for all the newly
synthesized compounds were also calculated using Molin-
spiration online property calculation toolkit (http://www.
molinspiration.com/cgi-bin/properties 2014). Drug-likeness
model score (a collective property of physico-chemical
properties, pharmacokinetics and pharmacodynamics of a
compound is represented by a numerical value) of every
compound was computed by MolSoft software (http://www.
molsoft.com/mprop).
Ali AA, Gogoi D, Chaliha AK, Buragohain AK, Trivedi P, Saikia PJ,
Gehlot PS, Kumar A, Chaturvedi V, Sarma D (2017) Synthesis
and biological evaluation of novel 1,2,3-triazole derivatives as
anti-tubercular agents. Bioorg Med Chem Lett 27:3698–3703.
https://doi.org/10.1016/j.bmcl.2017.07.008
Ammon HP, Wahl MA (1991) Pharmacology of Curcuma longa. Planta
Med 57:1–7. https://doi.org/10.1055/s-2006-960004
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007)
Bioavailability of curcumin: problems and promises. Mol Pharm
4:807–818. https://doi.org/10.1021/mp700113r
Anand P, Thomas SG, Kunnumakkara AB, Sundaram C, Hari-
kumar KB, Sung B, Tharakan ST, Misra K, Priyadarsini IK,
Rajasekharan KN, Aggarwal BB (2008) Biological activities
of curcumin and its analogues (Congeners) made by man and
Mother Nature. Biochem Pharmacol 76:1590–1611. https://doi.
org/10.1016/j.bcp.2008.08.008
From Table 2, it was observed that all the synthesized
compounds show moderate to good % ABS ranging from
5
0.29 to 81.91%. Therefore, most of the compounds from
the series have the ability to be orally active drugs in future.
It was also observed that most of the property predictions
were found to be in an acceptable range and possess average
to good potential to develop orally active drug molecules.
In addition to this, all the compounds of the series follow
Lipinski’s rule of five. Hence, all the compounds from
the series possess all the qualities to be orally active drug
molecules.
Archie SR, Das BK, Hossain MDS, Kumar U, Rouf ASS (2017) Syn-
thesis and antioxidant activity of 2-substituted-5-nitro benzimi-
dazole derivatives. Int J Pharm Pharm Sci 9:308–310. https://doi.
org/10.22159/ijpps.2017v9i1.14972
Banday AH, Shameem SA, Ganai BA (2012) Antimicrobial studies of
unsymmetrical bis-1,2,3-triazoles. Org Med Chem Lett 13:2–7.
https://doi.org/10.1186/2191-2858-2-13
Boechat N, Ferreira VF, Ferreira SB, Ferreira ML, da Silva FC, Bastos
MM, Costa MS, Lourenco MC, Pinto AC, Krettli AU, Aguiar AC,
Teixeira BM, da Silva NV, Martins PR, Bezerra FA, Camilo AL,
da Silva GP, Costa CC (2011) Novel 1,2,3-triazole derivatives for
use against Mycobacterium tuberculosis H37Rv (ATCC 27294)
strain. J Med Chem 54:5988–5999. https://doi.org/10.1021/jm200
Conclusion
3
624
Costa MS, Boechat N, Rangel EA, Silva FC, de Souza AMT, Rodrigues
CR, Castro HC, Junior IN, Lourenco MCS, Wardell SMSV, Fer-
reira VF (2006) Synthesis, tuberculosis inhibitory activity, and
SAR study of N-substituted-phenyl-1,2,3-triazole derivatives.
Bioorg Med Chem 14:8644–8653. https://doi.org/10.1016/j.
bmc.2006.08.019
In conclusion, this research study reports the synthesis and
biological evaluation of new α,α’-bis(1H-1,2,3-triazol-5-
ylmethylene) ketones (8a–o). Some of the compounds from
the present series exhibit potent antitubercular and antioxi-
dant agents. Among the newly synthesized series, compound
Danne AB, Choudhari AS, Chakraborty S, Sarkar D, Khedkar VM,
Shingate BB (2018) Triazole-diindolylmethane conjugates as new
antitubercular agents: synthesis, bioevaluation, and molecular
docking. MedChemComm 9:1114–1130. https://doi.org/10.1039/
C8MD00055G
8
l was found as the most potent antitubercular agent with
MIC 3.125 µg/mL. The compounds 8d and 8e showed prom-
ising antitubercular activities with MIC 12.5 and 6.25 µg/
mL, respectively, whereas the compounds 8c and 8g were
also found as potent antitubercular agents with MIC 25 µg/
mL. Furthermore, the compounds 8e and 8m showed potent
antioxidant activities with IC values 15.60 and 15.49 µg/
Dheer D, Singh V, Shankar R (2017) Medicinal attributes of 1,2,3-tria-
zoles: Current developments. Bioorg Chem 71:30–54. https://doi.
org/10.1016/j.bioorg.2017.01.010 (references cited theirin)
Drug-likeness and molecular property prediction. http://www.molso
ft.com/mprop. Accessed 11 Dec 2018
5
0
mL, respectively. From the biological activity results, we
can conclude that the library of newly synthesized titled
compounds (8a–o) oꢂered an attractive lead series for the
discovery of potent antitubercular and antioxidant agents
Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G, Her-
nandez A, Degnan MT, Cook MB, Quenzer VK, Ferguson RM,
Gilman RH (1998) Rapid, low-technology MIC determination
with clinical Mycobacterium tuberculosis isolates by using the
1
3

Chemical Papers
microplate Alamar Blue assay. J Clin Microbiol 36:362–366. https
and their selective anticancer activity against breast and prostate
cancer cell lines. Bioorg Med Chem Lett 26:4223–4232. https://
doi.org/10.1016/j.bmcl.2016.07.053
:
//jcm.asm.org/content/36/2/362
Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008) Curcumin:
from ancient medicine to current clinical trials. Cell Mol Life Sci
Manohar S, Khan SI, Kandi SK, Raj K, Sun G, Yang X, Molina ADC,
Ni N, Wang B, Rawat DS (2013) Synthesis, antimalarial activ-
ity and cytotoxic potential of new monocarbonyl analogues of
curcumin. Bioorg Med Chem Lett 23:112–116. https://doi.
org/10.1016/j.bmcl.2012.11.004
6
5:1631–1652. https://doi.org/10.1007/s00018-008-7452-4
Jordao AK, Afonso PP, Ferreira VF, de Souza MC, Almeida MC,
Beltrame CO, Paiva DP, Wardell SM, Wardell JL, Tiekink
ERT, Damaso CR, Cunha AC (2009) Antiviral evaluation of
N-amino-1,2,3-triazoles against Cantagalo virus replication in cell
culture. Eur J Med Chem 44:3777–3783. https://doi.org/10.1016/j.
ejmech.2009.04.046
Molinspiration Chemoinformatics Brastislava, Slovak Republic (2014)
http://www.molinspiration.com/cgi-bin/properties. Accessed 10
Dec 2018
Khare SP, Deshmukh TR, Sangshetti JN, Krishna VS, Sriram D, Khed-
kar VM, Shingate BB (2018) Design, synthesis and molecular
docking studies of novel triazole-chromene conjugates as antitu-
bercular, antioxidant and antifungal agents. ChemistrySelect
Mosley CA, Liotta DC, Snyder JP (2007) Highly active anticancer
curcumin analogues. Adv Exp Med Biol 595:77–103. https://doi.
org/10.1007/978-0-387-46401-5_2
Nucci M, Marr KA (2005) Emerging fungal diseases. Clin Infect Dis
41:521–526. https://doi.org/10.1086/432060
3
:13113–13122. https://doi.org/10.1002/slct.201801859
Kinsella JE, Frankel E, German B, Kanner J (1993) Possible mecha-
nisms for the protective role of antioxidants in wine and plant
foods. Food Technol 47:85–89
Pokhodylo N, Shyyka O, Matiychuk V (2013) Synthesis of 1,2,3-Tria-
zole derivatives and evaluation of their anticancer activity. Sci
Pharm 81:663–676. https://doi.org/10.3797/scipharm.1302-04
Raj R, Singh P, Singh P, Gut J, Rosenthal PJ, Kumar V (2013)
Azide-alkyne cycloaddition en route to 1H-1,2,3-triazole-
tethered 7-chloroquinoline-isatin chimeras: synthesis and anti-
malarial evaluation. Eur J Med Chem 62:590–596. https://doi.
org/10.1016/j.ejmech.2013.01.032
Kolb HC, Sharpless KB (2003) The growing impact of click chemistry
on drug discovery. Drug Discovery Today 8:1128–1137. https://
doi.org/10.1016/S1359-6446(03)02933-7
Kolb HC, Finn MG, Sharpless KB (2001) Click chemistry: diverse
chemical function from a few good reactions. Angew Chem Int
Ed 40:2004–2021. https://doi.org/10.1002/1521-3773(20010
Samaan N, Zhong Q, Fernandez J, Chen G, Hussain AM, Zheng S,
Wang G, Chen QH (2014) Design, Synthesis, and evaluation of
novel heteroaromatic analogs of curcumin as anti-cancer agents.
Eur J Med Chem 75:123–131. https://doi.org/10.1016/j.ejmec
h.2014.01.041
6
01)40:11%3c2004:AID-ANIE2004%3e3.0.CO;2-5
Lahsasni SA, Korbi FHA, Aljaber NAA (2014) Synthesis, char-
acterization and evaluation of antioxidant activities of some
novel chalcones analogues. Chem Cent J 8:32–41. https://doi.
org/10.1186/1752-153X-8-32
Temel E, Alasalvar C, Gokce H, Guder A, Albayrak C, Alpaslan YB,
Alpaslan G, Dilek N (2014) DFT calculations, spectroscopy
and antioxidant activity studies on (E)-2-nitro-4-[(phenylimino)
methyl]phenol. Spectrochim Acta A Mol Biomol Spectrosc
136B:534–546. https://doi.org/10.1016/j.saa.2014.09.067
Tornoe CW, Christensen C, Meldal M (2002) Peptidotriazoles on
solid phase: [1,2,3]-triazoles by regiospeciꢀc copper(I)-catalyzed
1,3-dipolar cycloadditions of Terminal alkynes to azides. J Org
Chem 67:3057–3064.
Lima-Neto RG, Cavalcante NNM, Srivastava RM, Mendonca FJB,
Wanderley AG, Neves, dos Anjos JV (2012) Synthesis of 1,2,3-tri-
azole derivatives and in vitro antifungal evaluation on Candida
strains. Molecules 17:5882–5892. https://doi.org/10.3390/molec
ules17055882
Lipinski CA, Lombardo L, Dominy BW, Feeney P (2001) Experimental
and computational approaches to estimate solubility and perme-
ability in drug discovery and development settings. J Adv Drug
Deliv Rev 46:3–26
Wang Y, Xiao J, Zhou H, Yang S, Wu X, Jiang C, Zhao Y, Liang D, Li
X, Liang G (2011) A novel monocarbonyl analogue of curcumin,
(1E,4E)-1,5-bis (2,3-dimethoxyphenyl)penta-1,4-dien-3-one,
induced cancer cell H460 apoptosis via activation of endoplasmic
reticulum stress signaling pathway. J Med Chem 54:3768–3778.
Wang R, Chen C, Zhang X, Zhang C, Zhong Q, Chen G, Zhang Q,
Zheng S, Wang G, Chen QH (2015) Structure-activity relationship
and pharmacokinetic studies of 1,5-Diheteroarylpenta-1,4-dien-
3-ones: a class of promissing curcumin-based anticancer agents.
J Med Chem 58:4713–4726. https://doi.org/10.1021/acs.jmedc
hem.5b00470
Liu Z, Sun Y, Ren L, Huang Y, Cai Y, Weng Q, Shen X, Li X, Liang
G, Wang Y (2013) Evaluation of a curcumin analog as an anti-
canceragent inducing ER stress-mediated apoptosis innon-
small cell lung cancer cells. BMC Cancer 13:494. https://doi.
org/10.1186/1471-2407-13-494
Mady MF, Awad GEA, Jorgensen KB (2014) Ultasound-assisted syn-
thesis of novel 1,2,3-triazoles coupled diaryl sulfone moieties by
the CuAAC reaction, and biological evaluation of them as anti-
oxidant and antimicrobial agents. Eur J Med Chem 84:433–443.
https://doi.org/10.1016/j.ejmech.2014.07.042
Maheshwari RK, Singh AK, Gaddipati J, Srimal RC (2006) Multi-
ple biological activities of curcumin: a short review. Life Sci
Zhao YH, Abraham MH, Le (2002) Rate-limited steps of human oral
absorption and QSAR studies. J Pharm Res 19:1446–1457
7
8:2081–2087. https://doi.org/10.1016/j.lfs.2005.12.007
Mandalapu D, Saini KS, Gupta S, Sharma V, Malik MY, Chaturvedi
S, Bala V, Hamidullah Thakur S, Maikhuri JP, Wahajuddin M,
Konwar R, Gupta G, Sharma VL (2016) Synthesis and biological
evaluation of some novel triazole hybrids of curcumin mimics
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional aꢃliations.
1
3

Chemical Papers
Aꢀliations
1
2
2
3
1
Tejshri R. Deshmukh · Vagolu S. Krishna · Dharmarajan Sriram · Jaiprakash N. Sangshetti · Bapurao B. Shingate
2
*
Bapurao B. Shingate
Department of Pharmacy, Birla Institute of Technology
and Science-Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad, Telangana 500 078, India
bapushingate@gmail.com
1
Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad, Maharashtra 431 004,
India
3
Department of Pharmaceutical Chemistry, Y. B. Chavan
College of Pharmacy, Dr. Raꢀq Zakaria Campus,
Aurangabad, Maharashtra 431 001, India
1
3