Simultaneous ultrasound- and microwave-assisted one-pot ‘click’ synthesis of 3-formyl-indole clubbed 1,2,3-triazole derivatives and their biological evaluation

Article abstract of DOI:10.1007/s11030-021-10212-8

An environment friendly, high yielding, promising one-pot protocol for the click reaction of N-propargyl-3-formylindole 2(a–b), chloroacetic acid/ester 3(a–b) and sodium azide, leading to the formation of 3-formyl-indole clubbed 1,4-disubstituted-1,2,3-triazole derivatives 4(a–b), 5(a–b) and 6(a–f) aided by CuI catalyst accomplished under acceleration of simultaneous ultrasound and microwave irradiation in a very short reaction time has been described. Further, acid derivative 4(a–b) is subjected to acid–amine coupling reaction with secondary amine (p–t) in the presence of HATU to afford 6(p–t) and 7(p–t). The perspective of this protocol is to get rid of the hectic preparation and handling of organic azide which are generated in situ. Consequently, this protocol blossoms the click process by making it environment benign, user-friendly, safe and clean technique. All the synthesized compounds have been preliminarily screen for their in vitro antimicrobial activity against a panel of pathogenic strains. The majority of compounds possess noticeably inhibitory action against E. Coli, S. Typhi, P. Aeruginosa, C. tetani, S. aureus and B. subtillis. Among all compounds, 6p and 7q exhibit excellent inhibitory action against E.Coli and P. Aeruginosa strain, respectively, as compared to standard drug. One compound 5b shows remarkable potency against fungal strain. Molecular docking study was carried out to understand binding of compound with protein. In silico ADME prediction was carried out to check physicochemical properties of synthesized compound. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11030-021-10212-8

Molecular Diversity
https://doi.org/10.1007/s11030-021-10212-8
ORIGINAL ARTICLE
Simultaneous ultrasound‑ and microwave‑assisted one‑pot ‘click’
synthesis of 3‑formyl‑indole clubbed 1,2,3‑triazole derivatives
and their biological evaluation
Jaydeep A. Mokariya1 · Anirudhdha G. Kalola1 · Pratibha Prasad1 · Manish P. Patel1
Received: 27 December 2020 / Accepted: 18 March 2021
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021
Abstract
An environment friendly, high yielding, promising one-pot protocol for the click reaction of N-propargyl-3-formylindole
2(a–b), chloroacetic acid/ester 3(a–b) and sodium azide, leading to the formation of 3-formyl-indole clubbed 1,4-disub-
stituted-1,2,3-triazole derivatives 4(a–b), 5(a–b) and 6(a–f) aided by CuI catalyst accomplished under acceleration of
simultaneous ultrasound and microwave irradiation in a very short reaction time has been described. Further, acid derivative
4(a–b) is subjected to acid–amine coupling reaction with secondary amine (p–t) in the presence of HATU to aford 6(p–t)
and 7(p–t). The perspective of this protocol is to get rid of the hectic preparation and handling of organic azide which are
generated in situ. Consequently, this protocol blossoms the click process by making it environment benign, user-friendly, safe
and clean technique. All the synthesized compounds have been preliminarily screen for their in vitro antimicrobial activity
against a panel of pathogenic strains. The majority of compounds possess noticeably inhibitory action against E. Coli, S.
Typhi, P. Aeruginosa, C. tetani, S. aureus and B. subtillis. Among all compounds, 6p and 7q exhibit excellent inhibitory action
against E.Coli and P. Aeruginosa strain, respectively, as compared to standard drug. One compound 5b shows remarkable
potency against fungal strain. Molecular docking study was carried out to understand binding of compound with protein. In
silico ADME prediction was carried out to check physicochemical properties of synthesized compound.
Graphical abstract
Keywords Click chemistry · 1,2,3-triazole · Microwave · Ultrasonication · Antibacterial activity
* Manish P. Patel
patelmanish1069@yahoo.com
1
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar 388120, Gujarat, India
Vol.:(0123456789)
1 3

Molecular Diversity
In addition to that, metal-catalyzed chemical reactions
are widely supported by ultrasound and microwave irradia-
tion because of their diverse characteristics such as electron
transfer, efcient mass transfer from metal to organic accep-
tor, ambient condition, mechanical depassivation of metal,
safe, environment friendly and energy savings [33, 34].
Since low molecular weight organic azide is unstable and
difcult to handle [35–37], microwave-assisted multicompo-
nent alternative of CuAAC, ofers excellent applicability by
in situ generation of organic azide [26, 27, 38]. Considering
the excellent biological and pharmacological applications
of 1,4-disubstituted 1,2,3-triazole derivatives and in con-
tinuance to our ongoing research work on design and devel-
opment of new methodologies for the synthesis of biologi-
cally active heterocycles [39–42]. Herein, we demonstrate
the very efcient CuI catalyzed, one-pot, ultrasound- and
microwave-assisted synthesis of 1,4-disubstituted 1,2,3-tria-
zole which involves the in situ generation of organic azide
and further in situ acid amine coupling reaction was carried
out under mild reaction condition of synthesized 1,2,3-tria-
zole derivatives.
Introduction
Ubiquitous presence of substituted 1,2,3-triazole in diverse
therapeutics comprising important biological activities
such as antifungal, antimicrobial and anticancer has widely
attracted the interest of scientists in past few decades [1].
Interesting structural features of substituted 1,2,3-triazole
such as hydrogen bond donor, hydrogen bond acceptor,
high dipole moment, potent stability in oxidative and reduc-
tive environment make them promising biomolecular tar-
get. Moreover, 1,2,3-triazole mimics variety of functional
groups, enlightening their utilization as bioisostere for the
synthesis of novel drug analogues [2, 3]. Triazole conju-
gates with diferent scafolds such as indole [4, 5], pyrro-
loindoline [6], benzimidazole [7, 8], thiopurine [9], imida-
zole [10, 11], isatin [12], benzotriazole [8], carbazole [8],
furan [13], thiophene [13], quinolone [14], acridone [15]
and other amide conjugates [16–19] display excellent bio-
logical potential. Thus, fve membered nitrogen-containing
1,2,3-triazole hydrides are the structures of great diversity
and importance, which encourages us in the development of
such indole-triazole-amide hybrid scafolds.
The bioactive form of drug must has profcient biological
activity. The development of drug includes the evaluation of
absorption, distribution, metabolism and excretion (ADME),
but difculty arises when there is limited physical access for
ADME evolution from the plethora of the molecules, in such
scenario, in silico ADME prediction is fast and reliable[43].
Furthermore, synthesis of substituted 1,2,3-triazole
motifs has secured much attraction in the feld of drug dis-
covery, biological chemistry and medicinal chemistry [20].
The Huisgen’s 1,3-dipolar cycloaddition of an organic azide
and an alkyne aforded 1,4-disubstituted and 1,5-disubsti-
tuted regioselective 1,2,3-triazole products under elevated
temperature [21]. The synthesis for regiospecifc 1,4-dis-
ubstituted 1,2,3-triazole product was reported by Sharp-
less [22] and Meldal [23] in 2002 via Cu-catalyzed azide
alkyne cycloaddition (CuAAC). The diverse attributes of
CuAAC reactions such as wide scope, high yield, harmoni-
ous byproduct, complete specifcity and benign solvent make
it powerful tool for the generation of privileged medicinal
scafolds [24]. Nevertheless, the CuAAC reactions proceed-
ing via conventional route are associated with shortcomings
such as long reaction time, elevated temperature, generation
of oxidative coupling byproducts, require prior synthesis
and handling of organic azide [25]. These drawbacks can
be overcome by replacing conventional reaction methodol-
ogy through the implementation of non-conventional reac-
tion techniques [26–32]. Sonochemistry represents favorite
domain for metal-catalyzed reactions as ultrasound favors
mechanical depassivation of metal. Furthermore, use of
simultaneous ultrasound and microwave irradiation enhances
reaction rate. Ultrasound and microwave irradiation acceler-
ate the reaction by allowing conventional number of trans-
formations to occur into a single step, thereby minimizing
laborious process under presence of minimum amount of
solvents and thus proving itself as a high yielding process.
Result and discussion
Chemistry
The required starting material 3-formyl-indole derivatives
1a and 1b were prepared by the Vilsmeier–Haack reaction of
indole derivatives according to a previously reported proce-
dure[44]. Subsequently N-propargyl-indole-3-carbaldehyde
derivatives were synthesized via nucleophilic displacement
of bromo group of propargyl bromide by secondary amine
of starting material indole derivatives 1a and 1b using
potassium bicarbonate as base under dimethyl formamide
solvent at room temperature. Further, in order to synthe-
size the triazole-based amide derivatives of former parent
indole motif, our investigations commenced towards the
available literature fndings reporting synthetic protocol for
Cu-catalyzed 1,2,3-triazole derivatives. We came across
some hitherto documented reports of click reactions which
make use of amide derivative of azidoacetic acid [45–47],
but all such protocols were associated with tedious synthesis
of amide derivative of azidoacetic acid, which was employed
as a starting adduct for further CuAAC (copper catalyzed
azide alkyne cycloaddition reaction) and no advance one-
pot ultrasound or microwave techniques were employed for
1 3

Molecular Diversity
Scheme 1 Synthesis of
3-formyl-indole clubbed
1,2,3-triazole derivatives 6(p–t)
and 7(p–t). (i) DMF, K2CO3,
propargyl bromide; conven-
tional method (iia) DMF, CuI;
microwave and ultrasonica-
tion exposure (iib) DMF, CuI,
US 28 kHz, US power 70 W,
MW 100 W; microwave expo-
sure (iic) DMF, CuI, 100 W;
ultrasonication exposure (iid)
DMF, CuI, US 28 kHz, 70 W
(iii) DMF, DIPEA, amine, US
28 kHz, 70 W
the former synthesis. Furtherance, on the basis of previ-
ously reported ultrasound- and microwave-assisted proce-
dure[27–30, 48–50] and further applying our own independ-
ent investigation in this area here we have demonstrated an
efcient synthetic protocol for 1,2,3-triazole-based amide
derivatives of indole 6(p–t), 7(p–t). This entire synthetic
protocol concludes in two stages, the frst stage includes the
in situ click-reaction step while the second stage involves
acid–amine coupling step. The initial one-pot, CuI cata-
lyzed, click reaction was circumscribed by utilizing both
conventional and non-conventional techniques for the syn-
thesis of compounds 4(a–b) and 5(a–b). Here the conven-
tional methodology employed common heating conditiona,
while non-conventional techniques employed, simultaneous
combine microwave and ultrasonication exposureb, micro-
wave exposurec and ultrasonication exposurec. Compounds
6(a–f) were synthesized via best suitable simultaneous
combine microwave and ultrasonication exposureb method
to check substrate scope of alkyl-azide. Subsequently latter
stage of acid–amine coupling has been described for the
obtained, acid 4(a–b) derivatives under exposure of best
suited ultrasonication technique to yield 6(p–t) and 7(p–t)
derivatives (scheme 1) at room temperature promoted under
the presence of N,N-diisopropylethylamine or Hunig base
(DIPEA) and hexafuorophosphate azabenzotriazole tetra-
methyl uronium (HATU) catalyst.
The synthesis of compounds 4(a–b) and 5(a–b) was
accomplished in two sequential steps. (i) in situ generation
1 3

Molecular Diversity
to the former two methods, execution of independent MWc
or USd radiation resulted in moderate to good amount of
product with decreased quantity of side products observed,
compared to that of conventional method, but it could not
compete with simultaneous US/MWb exposure protocol.
However ultrasonication methodologyd too proved itself
promising up to some extent than the microwave aidedc click
reaction; hence it stands next to the most favorable method.
The scope of reaction among varied methodology found to
be best with ultrasonic and microwave exposure methodb,
and the results are elaborated in Table 1. The completion of
each in situ steps was continuously monitored and evidenced
by TLC. Further in order to obtain desired product 6(p–t)
and 7(p–t), acid amine coupling reaction[52] was carried out
under ultrasonication exposure by adding required catalytic
amount of DIPEA base, HATU as coupling agent in N,N-
dimethylformamide solvent. Henceforth, varied heterocy-
clic-based secondary amines efciently undergo coupling
with the corresponding acid/ester derivatives obtained from
the former in situ azide-alkyne cycloaddition step aford-
ing desired compounds 6(p–t) and 7(p–t). The ultrasound-
assisted acid–amine coupling reaction products results are
elaborated in Table 2.
Table 1 Synthesis and substitution pattern of synthesized compound
4(a–b) and 5(a–b)
Entry
Building Blocks
Synthesis
method
Yielda(%)
Code
4a
R1
H
R2
1
2
3
4
5
6
7
8
OH
Conventional
US/MW
MW
55b
92
60
80
50b
92
55
80
44b
93
68
80
50b
93
65
85
US
4b
5a
5b
Me
H
OH
OEt
OEt
Conventional
US/MW
MW
US
9
Conventional
US/MW
MW
10
11
12
13
14
15
16
US
Me
Conventional
US/MW
MW
US
b
aYield of isolated product. TLC indicated a complicated reaction in
which signifcant amounts of side products were observed
The confrmation of the synthesized compounds 6(p–t),
7(p–t), 4(a–b) and 5(a–b) was determined by 1H NMR, 13
C
of azidoacetic acid/ester obtained via nucleophilic dis-
placement of chloro group of chloroacetic acid/ester (3a,
3b) by sodium azide resulting removal of sodium chloride.
(ii) then in situ generated azidoacetic acid/ester undergoes
cycloaddition reaction with alkyne derivatives (2a, 2b)
in the presence of CuI catalyst via previously reported
CuAAC mechanism[51] to yield 1,2,3-triazole-based acid/
ester derivatives 4(a–b)/5(a–b), respectively.
NMR and LC–MS spectral data. Compounds 6(a–f) were
1
1
characterized by H NMR spectra. In the H NMR spec-
tra of 6(p–t), 7(p–t), 4(a–b) and 5(a–b) the singlet proton
of aldehyde functional group of indole appears at δ 9.9
–10.0 ppm while aromatic protons of indole ring resonate
as multiplet between δ 7.00 and 8.50 ppm, further a singlet
signal resonating around δ 5.10 to 5.35 ppm was observed
for the methylene(–CH2) proton attached to the alpha posi-
tion carbon atom of carbonyl amide/ester, whereas aromatic
proton of triazole ring appeared around δ 7.00 to 7.50 ppm.
The singlet signal of methylene(–CH2) proton which links
indole and 1,2,3-triazole ring confrms the coupling, reso-
nate around δ 5.50 ppm. In 13C NMR spectra aldehyde car-
bon peak was observed around δ 184 ppm and the varied
amide/ester/acid groups resonate around δ 160–170 ppm in
compounds 6(p–t), 7(p–t), 4(a–b) and 5(a–b).
The azide-alkyne cycloaddition product obtained from
conventional heating routea was not leading to good yield.
Moreover, number of side products were observed due to
higher temperature, long reaction time and the product iso-
lation needed hectic column chromatographic technique,
whereas implementation of the combine US/MW (simul-
taneous ultrasound and microwave) exposure techniqueb
efciently led to triazole products with 92–93% high yield,
increased reaction rate and selectivity. Further irrespective
Table 2 Substitution pattern and
yield of synthesized compounds
6(p–t) and 7(p–t)
Building blocks
Yielda (%)
Building Blocks
Yielda (%)
Code
R1
R2
Code
R1
R2
6p
6q
6r
6s
6t
–H
–H
–H
–H
–H
(p)
(q)
(r)
(s)
(t)
95
95
92
78
75
7p
7q
7r
7s
7t
–Me
–Me
–Me
–Me
–Me
(p)
(q)
(r)
(s)
(t)
93
94
90
76
75
aYield of isolated product
1 3

Molecular Diversity
Table 3 Optimization of reaction condition for compound 4a
diferent Cu-catalyst under former solvents favoring click
chemistry, transforming via four conventionala and non-
conventionalb−d protocols for the formation of model com-
pound 4a. To optimize the reaction conditions, the required
alkyne 2a, chloroacetic acid 3a and sodium azide were sub-
jected to reaction mixture in 1.0: 1.1: 1.2 mol ratio, respec-
tively. Initializing the screening with selection of aqueous
tert-butanol concomitant to copper sulphate and sodium
ascorbate mixture as a catalyst (Table 3, entry 1,2,3), the
results showed that the simultaneous US/MW method was
found to be more efective as compared to other three meth-
ods (Table 3, entry 2). As already discussed that, employing
the conventional technique was quiet inappropriate due to
signifcant amount of side product observed (Table 3, entry
1, 4, 8, 12, 15). Among the diferent reaction media, the
use of polar aprotic solvent DMF in contrast to polar protic
solvent aqueous tert-butanol leads to signifcant increase in
the yield. In addition to it, the DMF solvent was also well
supporting the simultaneous US/MW technique, in terms of
quantitative yield (Table 3, entry 5,9,16,18,19) as compared
to other method. In view of this above observation results
support, we sought to examine the diferent copper salt to
optimize the reaction. The Cu-turning catalyst addition too
provides equivalent results as copper sulphate (Table 3,
entry 1–7). We found that copper halide salt (Table 3, entry
25–37) proved to be much more efective as compared to
other Cu catalyst (Table 3, entry 1–24, 38). The consumption
of copper halide salts concentration required only fve mole
percent for the reaction, which was also less. Thus, copper
iodide in the presence of DMF solvent demonstrated supe-
rior activity afording high yield (93%) of 4a at 70 ℃ under
the US/MW radiation exposure (Table 3, entry 30), whereas
other three methods found to be less efective (Table 3, entry
29,31,32). Since the excellent results were obtained for CuI-
DMF system hence, we further checked the assistance of
copper chloride and copper oxide under DMF solvents sys-
tem for the model motif synthesis under preferable method
b. Hereby we observed that copper chloride was also found
to be efectual under same confned reaction condition and
method with 85% product yield (Table 3, entry 37). Nonethe-
less, the efciency of copper(I)oxide catalyst was found to be
decreased under applied favorable conditions (Table 3, entry
38). Among the diferent reaction media, the use of diox-
ane/water solvent system resulted into poor yield of product
(Table 3, entry 9–12, 21–24, 32–36). It is encouraging to
note that among diferent reaction techniques employed, the
results obtained with the choice of US/MW techniques led
to signifcant increase in the yield of 4a rather than inde-
pendent microwave or ultrasonication techniques (Table 3,
entry 30 vs. 31, 32). Moreover, product obtained via US/
MW method required much less time and low temperature
as compared to conventional method. This was probably due
to both faster in situ azide formation and enhance electron
Entry Catalyst
Solvent
Temp Reaction
Yielde
(%)
(℃)
time
(min.)
1
2
3
4
5
6
7
8
CuSO4/
NaAsc
tBuOH/Water 80a
120a
30b
30c
25a,f
48b
80b
80c
20c
80d
30d
39d
DMF
100a 120a
35a,f
62b
80b
80c
80d
30b
30c
30d
30c
55d
9
Dioxane/
water
100a 120a
<10a,f
30b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
80b
80c
80d
30b
30c
30d
120a
30b
30c
30d
<10c
22d
Cu-turning
tBuOH/Water 80a
<10a,f
45b
80b
80c
80d
26c
38d
DMF
100a 120a
25a,f
65b
80b
80c
80d
30b
30c
30d
38c
52d
Dioxane/
Water
100a 120a
<10a,f
65b
80b
80c
80d
30b
30c
30d
120a
30b
30c
30d
30c
50d
CuI
tBuOH/Water 80a
45a,f
78b
80b
80c
80d
55c
70d
DMF
100a 120a
55a,f
93b
70b
70c
80d
15b
15c
30d
60c
80d
Dioxane/
Water
100a 120a
20a,f
48b
80b
80c
80d
70b
70b
30b
30c
30d
15b
30b
25c
35d
CuCl
Cu2O
DMF
DMF
85b
62b
aConventional method. bUS/MW method. cMW method. dUS method.
f
eyield of isolated product. TLC indicated a complicated reaction in
which signifcant amounts of side products were observed
Optimization of reaction condition for compound 4a
According to hitherto reported literature, the Cu-catalyzed
azide-alkyne cycloaddition reactions have been reported to
proceed under dioxane/water, DMF, t-butanol solvents under
varied Cu-based catalyst. Hence, we sought to screen the
1 3

Molecular Diversity
Table 4 Synthesis of
CHO
compounds 4(a-b), 5(a-b)
and 6(a-f) via simultaneous
ultrasound- and microwave-
assisted one-pot reaction.a
CHO
MW and Ultrasonication
exposure
R1
X
+
R1
+
NaN3
N
R
N
N
N
N
3
R
2a,2b
R1= H, Me
X= Cl, Br
4(a-b), 5(a-b),
6(a-f)
Entry
1
R1
H
R
O
X
Cl
Product
4a
Yieldb
92
OH
OH
2
3
4
5
Me
H
O
O
O
Cl
Cl
Cl
Cl
4b
5a
5b
6a
92
93
93
90
OEt
OEt
Me
H
O
O
OEt
O
6
H
Br
6a
92
OEt
NH2
O
O
7
8
H
H
Cl
Br
6b
6c
92
88
O
9
H
H
Cl
Br
6d
6d
90
93
10
11
12
H
H
Cl
Cl
6e
6f
86
82
CN
aReaction condition: 1 mmol 2(a-b), 1 mmol 3, 1.2 mmol Sodium azide; DMF, CuI, US 28 kHz, US
power 70 W, MW 100 W, 15 min. bYield of isolated product
transfer between metal to organic acceptor in US/MW irra-
diation methodb. The results obtained under only microwave
irradiation were afording lower yield of 4a. Although the
ultrasonication irradiation technique provided better yield as
compared to the microwave irradiation technique, it could
not compete with US/MW method. The results signifed that
the formation of compound 4a was best conformed to the
CuI-DMF couple system under US/MW irradiation.
1 3

Molecular Diversity
The scope of the reaction regarding the alkyl halide
component was examined and found to be excellent.
Table 4 shows subtract scope of reaction. We synthesized
desired products 4(a–b), 5(a–b) and 6(a–f) using best opti-
mization condition, and we obtain good to excellent using
variety of alkyl halide.
Antifungal activity
In vitro anti-fungal screening of compounds are depict that
(Table 6), against C. albicans, compounds 5b, 6p, 6q, 6s,
7p, 7p, 7s show better potency as compared to the standard
drug griseofulvin (MIC 500 μg mL−1) and compound 5b
shows better potency as compared to standard drug fucon-
azole (MIC 250 μg mL−1), whereas compounds 4a, 4b, 5a,
6r, 6t and 7r show equipotency to standard drug griseoful-
vin and 6p, 6q, 6s, 7p and 7s show equipotency to standard
drug fuconazole. None of the compound shows signifcant
potency against T. rubrum as compared to standard drug
griseofulvin and fuconazole. Among the entire antifungal
data, compound 5b is found to be most active.
Optimization of reaction condition for the formation
of compound 6p
To optimize the reaction condition for the formation of
compound 6p, the required coupling agent HATU, base
DIPEA and heterocycle-based varied secondary amines
were directly added in the reaction mixture containing 4a.
The reaction was optimized under conventional and ultra-
sound irradiation at room temperature, where the DIPEA
base and amine were required in 3:1 ratio, respectively.
The comparable results were observed between conven-
tional and ultrasound irradiation method in terms of reac-
tion time and yield, for this acid amine coupling reac-
tion step (Table 5). Preliminary results showed that an
intense short sonication (30 min.) of the mixture sufced
to accelerate the reaction in comparison with conventional
method. The product yield further increased when slightly
higher amount of HATU was used (Table 5, entry 1 vs. 3
and 2 vs. 4).
Molecular docking study
Outcome of antibacterial screening encourages us for virtual
screening of compounds against protein target in order to
know the possible binding of these compound in active site
of protein. We use AutoDock Vina[53] for docking approach
in order to predict interaction between indole-triazole con-
jugate and the bacterial enzyme DNA gyrase (topoisomer-
ase II, PDB ID: 1KZN). Several studies of similar type of
compounds have already been reported in the literature to
investigate interaction of 1, 2, 3-triazole containing ligands
with DNA gyrase enzyme (PDB ID:1KZN).
Biological results
The antibacterial screening indicates that compounds
6p and 7q showed potent activity among all derivatives.
Considering their noticeable activity and based on litera-
ture report of DNA gyrase enzyme inhibitory activity of
structurally similar compounds [8, 10, 12, 13, 16–19], we
sought to know the binding of compound with DNA gyrase
enzyme. Docking scores (binding afnity) of compounds
7q and 6p are −8.8 kcal/mole and −8.5 kcal/mole, respec-
tively. A higher antibacterial activity of compounds 7q over
compound 6p is also refected through their docking scores.
The constitutive binding interaction of compounds 7q and
6p with protein is demonstrated in Fig. 1(a–d). The closer
visual inspection of binding pose of ligand with protein as
depicted in Fig. 1(a–d) reveals that both the compounds
show some common molecular interactions with important
residues Thr165, Asp73, Ile78, Asn46, and Ile90. The oxy-
gen of carbonyl group of 3-formyl indole tail of constituent
7q shows H-bond (hydrogen bond) interaction with residues
(amino acid) Thr165 and Gly77 with a distance of 2.45 and
2.53 Å, respectively (Fig. 1a), whereas for 6p such H-bond
interaction is observed with residue Thr165 with a distance
of 2.82 Å (Fig. 1c). Another H-bond interaction in both com-
pounds is observed between oxygen of carbonyl group of
amide and residue Asn46 with a distance of 2.78 Å in 7q
(Fig. 1a) and 3.31 Å in 6p (Fig. 1c).
Antibacterial activity
According to the in vitro antimicrobial screening results
(Table 5), MIC values for all the synthesized compounds
range between 12.5 and 500 μg mL−1 against tested micro-
organisms. It is noticeable that, against gram-negative bac-
teria E. Coli compound 6p against S. Typhi compounds 6q
and 7q against P. Aeruginosa compounds 6p and 7q show
excellent potency as compared to standard drug ampicillin,
whereas compounds 5b, 6r, 6t and 7r against E. Coli, com-
pounds 5b and 7r against S. Typhi, compound 5a against P.
Aeruginosa show considerable equipotency as compared to
standard drug ampicillin (MIC 100 μg mL−1). In inhibiting
Gram-positive bacteria, against B. subtillis compounds 4a,
4b, 5a, 5b, 6q and 7t against C. tetani compounds 4a, 4b,
5b, 6r, 7r, 7 s and 7t against S. aureus compounds 5b, 6p,
6q, 6 s, 6t, 7p, 7r and 7t show outstanding activity to the
standard drug ampicillin (MIC 100 μg mL−1), while com-
pounds 6t and 7q against B. subtillis, compounds 5a, 6p,
6q, 6s and 7q against C. tetani, compounds 4a, 4b, 6r, 7q
and 7s against S. aureus show equipotency to ampicillin.
Among the entire antibacterial data, compounds 7q and
6p are found to be most active.
1 3

Molecular Diversity
Table 5 Optimization
of reaction condition for
compound 6p
Entry
HATU (eq.)
DIPEA
(eq.)
N-methylpip- Method
Reaction time Yielda (%)
(min.)
erazine
(eq.)
1
2
3
4
1
1
1.2
1.2
3
3
3
3
1
1
1
1
Conventional
30
30
30
30
66
70
72
78
Ultrasound
Conventional
Ultrasound
aYield of isolated product
synthesized compound is illustrated in Fig. 2. All derivatives
show high gastrointestinal absorption (i.e. in white region)
while 7q and 6q show blood–brain permeation (I.e. in yellow
region). The points which are colored with blue comprising
six derivatives 6p, 6q, 6r, 7p, 7q and 7r are P-gp substrate and
other eight derivatives 4a, 4b, 5a, 5b, 6s, 6t, 7s and 7t colored
red are non P-gp substrate.
In Silico ADME properties
The main signifcance of ADME parameter is to increase
the drug-likeness of the compound at various stage of
developing the promising drug molecule. Establishment
of signifcant agreeability between physiochemical prop-
erties and ADME properties might be important for novel
drug discovery. For evaluating ADME properties of our
synthesized compounds, we exert online web server Swis-
sADME. (http://www.swissadme.ch) The physicochemical
properties, water solubility, lipophilicity, pharmacokinet-
ics and drug-likeness of synthesized compounds were con-
sidered for ADME prediction [43].
Conclusion
Simultaneous ultrasound and microwave (US/MW)
enhanced, profcient, robust and sustainable three-com-
ponent region-selective synthetic protocol for 3-formyl-
indole clubbed 1,2,3-triazole derivatives was developed.
This protocol reduces the reaction time from hours to min-
utes; thus, avoiding the laborious isolation and handling
of unstable organic azide derivatives and provide high
yielding clean product, which require no further purifca-
tion. The key step of this synthesis is in situ generation
of organic azide and further its copper iodide catalyzed
fusion with alkyne derivative to yield regioselective
1,4-disubstituted-1,2,3-triazole. No any other pretreat-
ment, addition of ligand, amine or base were required for
this synthetic protocol. All the synthesized derivatives
were screened for their various biological potency in the
search of developing the new class of anti-microbial agents
with antimicrobial activities that can be utilized for further
assiduous pre-clinical investigation. Majority of the com-
pounds were found equipotent as compared to standard
drug ampicillin against E. Coli, S. Typhi, P. Aeruginosa,
C. tetani, S. aureus and B. subtillis. Compound 7q shows
excellent inhibitory activity against P. Aeruginosa as com-
pared to standard drug ampicillin and chloramphenicol.
Compound 5b shows better potency against fungi strain C.
albicans as compared to standard drugs griseofulvin and
fuconazole. Based on the noticeable results of molecular
docking study and in silico ADME study, this work can be
explored in advance evolution.
All the derivatives are under threshold value of the
physicochemical properties, which were incorporated
in certain rules such as, Lipinski rule of fve, Ghose’s,
veber’s, Egan’s and Muegee’s rule; hence no violation
of such rules was observed. Lipophilicity and pharma-
cokinetic properties are related with each other and well
explained through in silico study [54]. All the derivatives
show MLogP value in the range of 0.07–1.55, which is
quite under acceptable range. In addition to that all the
derivatives lie under cut-of value of certain parameters,
that are, molecular weight (MW), TPSA (topological polar
surface area), Ali LogS (water solubility), molar refrac-
tivity (MR), number of rotatable bond (nRot), number of
H-bond acceptor (HBA) and number of H-bond donor
(HBD) which are depicted in Table 7 Moreover, the impor-
tant computed pharmacokinetics data of all derivatives are
depict in table 8.
BOILED‑Egg for prediction of GI absorption and brain
penetration
BOILED-Egg delineation was predicted which illustrates
the capability of gastrointestinal absorption and blood–brain
permeation of derivatives. The BOILED-Egg model relies
on lipophilicity (WLogP) and topological polar surface area
(TPSA) of the derivative. The white elliptical region of egg
depicts high probability of gastrointestinal absorption, while
yellow (Yolk) round region of egg depicts blood–brain perme-
ation of molecule [43, 55]. BOILED-egg model of the entire
1 3

Molecular Diversity
Table 6 In vitro antimicrobial activity (MIC, μg mL−1) of the synthesized compounds
Entry
Gram-negative bacteria
E.C S.T
Gram-positive bacteria
B.S C.T
Fungi
P.A
S.A
C.A
T.R
MTCC 443 MTCC 98 MTCC 1688 MTCC 441 MTCC 449 MTCC 96 MTCC 227 MTCC 8477
4a
125
200
250
100
50
125
100
250
100
500
250
100
250
500
100
200
125
250
100
250
62.5
100
250
250
500
62.5
250
500
250
100
50
250
500
100
250
50
250
250
500
200
250
12.5
500
250
125
100
50
125
200
125
100
500
100
500
500
250
500
250
500
500
100
250
50
200
200
250
100
250
250
200
250
500
500
250
100
125
200
250
50
250
250
500
200
100
125
250
200
100
200
250
200
250
125
250
50
500
500
500
100
250
250
500
250
500
250
1000
500
250
>1000
–
1000
>1000
1000
1000
500
1000
500
500
500
1000
1000
500
1000
250
4b
5a
5b
6p
6q
6r
6s
6t
7p
7q
7r
7s
7t
AMPICILLIN
–
–
CHLORAMPHENICOL 50
–
GRISEOFULVIN
FLUCONAZOLE
–
–
–
–
–
–
–
–
–
–
–
–
500
250
100
100
Bold values show the potent compound; E.C., Escherichia coli; S.T., Salmonella typhi. P.A., Pseudomonas aeruginosa; B.S., Bacillus subtilis,
C.T., Clostridium tetani S.A., Staphylococcus aeruginosa; C.A., Candida albicans; T.R., Trichophyton rubrum; MTCC., microbial-type culture
collection; ‘—’indicates not tested
(Merck, Darmstadt, Germany) was used for monitoring the
progress of all reactions, purity, and homogeneity of the
synthesized compounds (eluent ethyl acetate:hexane 7:3).
The melting point of solid compounds was determined
in an open capillary and is uncorrected. Bruker Avance
400F (MHz) spectrometer (Bruker Scientifc Corporation
Ltd, Switzerland) was operated at 400 MHz and 100 MHz
Experimental
The required common chemicals and reagents which are
commercially available were used without further purif-
cation. Indole, 2-methyl indole, 1,2,3 triazole, 1,2,4 tria-
zole, CuI, CuCl, Cu2O and CuSO4.5H2O were purchased
from spectrochem India. Propargyl bromide, 4-methyl
piperidine, N-methyl piperazine and sodium ascorbate
were purchased from Sigma-Aldrich. Solvents were pur-
chased from Spectrochem, and standard methods were
applied for purifcation and drying before being used. The
microwave- and ultrasonication-assisted reactions are
conducted in a “SINEO UWave-1000 Microwave, Ultra-
violat, Ultrasonic Synthesis/Extraction Reactor” wherein
microwaves are generated in varying range of 0 to 1000 W
power having adjustable output power levels; ultrasoni-
cation working frequency ranges from 26 to 28 kHz and
power regulation range of 0 to 800 W. Infrared temperature
measurement and platinum resistance temperature meas-
urement are adopted for temperature measurement and
control. Thin-layer chromatography (TLC, on aluminum
plates pre-coated with silica gel, 60F, 0.25 mm thickness)
1
for H and 13C nuclei, respectively. Chemical shifts are
reported in parts per million (ppm).
General procedure for the synthesis
of 2‑methyl‑1‑(prop‑2‑yn‑1‑yl)‑1H‑indole‑3‑car‑
baldehyde (i) 2(a–b)
2-substituted-1H-indole-3-carbaldehyde (1 mmol), pro-
pargyl bromide (1 mmol) and anhydrous potassium car-
bonate (2.5 mmol) in dimethylformamide (5 mL) were
charged into a 50-mL round-bottom flask equipped with
a mechanical stirrer. The reaction mixture was stirred for
2 h at room temperature and the progress of the reaction
was monitored by TLC. After the completion of the reac-
tion, the reaction mixture was poured into ice cold water
(50 mL) with continuous stirring followed by neutraliza-
tion with dilute HCl solution. The separated precipitates of
1 3

Molecular Diversity
Table 7 Important computed
physicochemical properties of
all synthesis derivatives a
Derivatives
MW
nRot
HBA
HBD
MR
74.5
TPSA
MLogP
Ali LogS
4a
4b
5a
5b
6p
6q
6r
6s
6t
7p
7q
7r
284.27
298.3
5
5
7
7
6
6
6
6
6
6
6
6
6
6
5
5
5
5
5
4
5
6
6
5
4
5
6
6
1
1
0
0
0
0
0
0
0
0
0
0
0
0
90.01
90.01
79.01
79.01
76.26
73.02
82.25
100.49
100.49
76.26
73.02
82.25
100.49
100.49
0.28
0.54
0.79
1.03
0.31
1.32
0.07
0.66
0.66
0.53
1.55
0.31
0.91
0.91
−2.02
−2.44
−2.51
−2.92
−1.46
−2.92
−1.4
−2.01
−2.34
−1.88
−3.34
−1.82
−2.43
−2.75
79.46
83.62
88.59
108.47
106.46
97.93
87.51
87.51
113.43
111.43
102.9
92.47
92.47
312.32
326.35
366.42
365.43
353.38
335.32
335.32
380.44
379.45
367.4
7s
7t
349.35
349.35
aOptimal range: molecular weight (MW)≤600, lipophilicity log or Moriguchi octane−water parti-
tion coefcient (M log P)≤5, aqueous solubility descriptor (Ali log S)≤0, hydrogen-bonded acceptor
(HBA)≤10, hydrogen-bonded donor (HBD)≤5, topological polar surface area (TPSA)≤150 Å2, number
of rotatable bonds (nRot)≤10, and molar refractivity (MR)≤155
Table 8 Important computed pharmacokinetics data of all derivatives
Derivatives
GI absorption
BBB permeant
P-gp substrate
CYP1A2
inhibitor
CYP2C19
inhibitor
CYP2C9
inhibitor
CYP2D6
inhibitor
CYP3A4
inhibitor
4a
4b
5a
5b
6p
6q
6r
6s
6t
7p
7q
7r
High
High
High
High
High
High
High
High
High
High
High
High
High
High
No
No
No
No
No
Yes
No
No
No
Yes
No
No
No
No
No
No
No
No
Yes
Yes
Yes
No
No
Yes
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
Yes
Yes
No
Yes
No
Yes
Yes
No
No
No
No
No
No
Yes
No
Yes
No
No
No
No
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
Yes
No
No
No
No
No
No
No
No
Yes
No
No
No
No
Yes
No
No
No
7s
7t
Yes
Yes
GI absorption=Gastrointestinal absorption, Pgp Substrate=P-glycoprotein, BBB=Blood Brain barrier permeant
2-substituted-1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde 2a
and 2b were fltered, washed with water, dried, and recrystal-
lized from ethanol.
General procedure for the synthesis of 2‑(4‑((3‑for‑
myl‑1H‑indol‑1‑yl)methyl)‑1H‑1,2,3‑triazol‑1‑yl)
acetic acid/ethyl acetate (4a, 4b 5a and 5b)
Conventional method (iia)
In a 50-mL round-bottom fask, equimolar amounts of the
corresponding 2-substituted-1-(prop-2-yn-1-yl)-1H-indole-
3-carbaldehyde, 2–CHloroacetic acid 3a / 2–CHloroethyl
acetate 3b and sodium azide in DMF containing powdered
1 3

Molecular Diversity
Fig. 1 a 2D layout of interaction between 7q and DNA gyrase
enzyme with respective amino acid residues. b 3D layout of inter-
action between 7q and DNA gyrase enzyme with respective amino
acid residues. c 2D layout of interaction between 6p and DNA gyrase
enzyme with respective amino acid residues. d 3D layout of interac-
tion between 6p and DNA gyrase enzyme with respective amino acid
residues.
copper iodide (5 mol%) were mixed thoroughly and sub-
Simultaneous Ultrasonication‑ and Microwave‑assisted
method (iib)
0
jected to oil bath heating at 100 C for 120 min. After the
completion of the reaction (evidenced by TLC, ethyl acetate:
hexane (7: 3)), the resulting solution was cooled to room
temperature. Then, water was added to it slowly with vig-
orous stirring. The solid mass that separated upon cooling
was fltered, washed well with saturated sodium bicarbo-
nate solution, dried and purifed by chromatography using
ethyl acetate:hexane (7: 3) as eluent to obtain a pure solid
compounds.
In a 50-mL round-bottom fask, equimolar amounts of the
corresponding 2-substituted-1-(prop-2-yn-1-yl)-1H-indole-
3-carbaldehyde, 2–CHloroacetic acid 3a / 2–CHloroethyl
acetate 3b and sodium azide in DMF containing powdered
copper iodide (5 mol%) were mixed thoroughly and sub-
jected to ultrasonication at 28 kHz, 70 W and microwave
irradiation at 100 W for 15 min. After the completion of the
1 3

Molecular Diversity
Fig. 2 BOILED-Egg model of all derivatives. Blue dot are P-gp substrate, Red dot are non P-gp substrate
reaction (evidenced by TLC, ethyl acetate: hexane (7: 3)),
the resulting solution was cooled to room temperature. Then,
water was added to it slowly with vigorous stirring. The
solid mass that separated upon cooling was fltered, washed
well with saturated sodium bicarbonate solution, dried and
purifed by leaching in ethyl acetate: hexane (1: 9), afording
pure solid compounds.
chromatography using ethyl acetate:hexane (7: 3) as eluent
to obtain a pure solid sample.
Ultrasonication method (iid)
In a 50-mL round-bottom fask, equimolar amounts of the
corresponding 2-substituted-1-(prop-2-yn-1-yl)-1H-indole-
3-carbaldehyde, 2–CHloroacetic acid 3a / 2–CHloroethyl
acetate 3b and sodium azide in DMF containing powdered
copper iodide (5 mol%) were mixed thoroughly and sub-
jected to ultrasonication at 28 kHz and 70 W for 15–30 min.
After the completion of the reaction (evidenced by TLC,
ethyl acetate: hexane (7: 3)), the resulting solution was
cooled to room temperature. Then, water was added to it
slowly with vigorous stirring. The solid mass that sepa-
rated upon cooling was fltered, washed well with saturated
sodium bicarbonate solution, dried and purifed by chroma-
tography using ethyl acetate:hexane (7: 3) as eluent to obtain
a pure solid sample.
Microwave‑assisted method (iic)
In a 50-mL round-bottom fask, equimolar amounts of the
corresponding 2-substituted-1-(prop-2-yn-1-yl)-1H-indole-
3-carbaldehyde, 2–CHloroacetic acid 3a / 2–CHloroethyl
acetate 3b and sodium azide in DMF containing powdered
copper iodide (5 mol%) were mixed thoroughly and sub-
jected to microwave irradiation at 100 W for 15–30 min.
After the completion of the reaction (evidenced by TLC,
ethyl acetate: hexane (7: 3)), the resulting solution was
cooled to room temperature. Then, water was added to it
slowly with vigorous stirring. The solid mass that sepa-
rated upon cooling was fltered, washed well with satu-
rated sodium bicarbonate solution, dried and purifed by
1 3

Molecular Diversity
125.46, 124.41, 123.31, 122.33, 118.72, 110.16, 62.65,
51.10, 42.52, 14.01, 13.02 ppm, MS (m/z) calc.: 326.36,
found LC–MS: 327.40 [M+1].
General procedure for acid amine coupling reaction
(iii)
1-((1-(2-(4-methylpiperidin-1-yl)-2-oxoethyl)-1H-1,2,3-
triazol-4-yl)methyl)-1H-indole-3-carbaldehyde (6p). of
white solid; m.p. 226–228 °C; 1H NMR (400 MHz, CDCl3):
δ 9.979 (s, H, –CHO), 7.322–8.322 (m, 6H, Ar–H),5.523
(s, 2H, –CH2), 5.192 (s, 2H, –CH2), 3.381–3.411 (dd, 2H,
–CH2, J=2.4 Hz), 2.755–2.822 (td, 2H, –CH2, J=2.4 Hz),
1.581–1.613 (dd, 2H, –CH2, J = 2.4 Hz), 1.361–1.429
(td, 2H, –CH2, J = 2.4 Hz), 1.015–1.087 (m, H, –CH),
0.866–0.906 (d, 3H, –CH3) ppm; 13C NMR (100 MHz,
CDCl3): δ 184.72, 162.51, 142.47, 138.50, 137.00, 125.44,
124.49, 124.33, 123.21, 122.32, 118.68, 110.16, 51.16,
45.59, 42.42, 34.31, 30.81, 21.53 ppm; MS (m/z) calc.:
366.43, found LC–MS: 367.50 [M+1].
In a 50-mL round-bottom fask, corresponding 2-(4-((3-for-
myl-2-substituted-1H-indol-1-yl)methyl)-1H-1,2,3-triazol-
1-yl)acetic acid, amine (p–t), HATU (3 eq) in DMF contain-
ing diisopropyl ethyl amine (3 eq) were mixed thoroughly
and subjected ultrasonication at 28 kHz and 70 W for
30 min. After the completion of the reaction (evidenced by
TLC, ethyl acetate: hexane (8: 2)). Then, 0.1 N HCl solution
was added to it slowly with vigorous stirring. The solid mass
that separated upon cooling was fltered, washed well with
saturated sodium bicarbonate solution followed by water,
dried, afording pure solid compounds.
Characterizations details of all newly synthesized
derivatives
1-((1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H-1,2,3-
triazol-4-yl)methyl)-1H-indole-3-carbaldehyde (6q). pale
yellow solid; m.p. 211–212 °C; 1H NMR (400 MHz, CDCl3):
δ 9.934 (s, H, –CHO), 7.263–8.302 (m, 6H, Ar–H), 5.633
(s, 2H, –CH2), 5.232 (s, 2H, –CH2), 3.566 (s, 2H, –CH2),
3.391 (s, 2H, –CH2), 2.326–2.377 (m, 4H, –CH2), 2.251 (s,
3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 184.68,
164.17, 142.07, 140.65, 136.78, 125.37, 124.66, 123.54,
122.55, 120.97, 117.33, 111.33, 53.65, 50.59, 44.57, 41.79,
41.48 ppm; MS (m/z) calc.: 365.44, found: 366.50 [M+1].
1-((1-(2-morpholino-2-oxoethyl)-1H-1,2,3-triazol-4-yl)
methyl)-1H-indole-3-carbaldehyde (6r). pale yellow solid;
2-(4-((3-formyl-1H-indol-1-yl)methyl)-1H-1,2,3-triazol-
1
1-yl)acetic acid (4a). white solid; m.p. 208–209 °C; H
NMR (400 MHz, DMSO-d6): δ 13.294 (s, H, –COOH),
9.945 (s, H, –CHO), 7.258–8.292 (m, 6H, Ar–H), 5.536 (s,
2H, –CH2), 5.114 (s, 2H, –CH2) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 184.41, 177.70, 142.55, 140.36, 138.50,
137.04, 125.43, 124.41, 123.32, 122.28, 118.71, 110.18,
51.47, 42.54, 13.05 ppm. MS (m/z) calc.: 284.28, found
LC–MS: 285.30 [M+1].
2 - ( 4 - ( ( 3 - fo r my l - 2 - m e t hy l - 1 H - i n d o l - 1 - y l )
methyl)-1H-1,2,3-triazol-1-yl)acetic acid (4b). white solid;
m.p. 220–221 °C; 1H NMR (400 MHz, DMSO-d6): δ 13.282
(s, H, –COOH), 9.947 (s, H, –CHO), 7.260–8.296 (m, 6H,
Ar–H), 5.523 (s, 2H, –CH2), 5.108 (s, 2H, –CH2), 2.563 (t,
3H, –CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ 184.43,
177.78, 142.52, 140.37, 138.54, 137.06, 125.41, 124.45,
123.30, 122.26, 118.73, 110.12, 62.12, 51.10, 42.51 ppm;
MS (m/z) calc.: 298.30, found LC–MS: 299.30 [M+1].
4-ethyl 2-(4-((3-formyl-1H-indol-1-yl)methyl)-1H-1,2,3-
triazol-1-yl)acetate (5a). white solid; m.p. 231–232 °C;
1H NMR (400 MHz, DMSO-d6): δ 9.942 (s, H, –CHO),
7.260–8.294 (m, 6H, Ar–H), 5.523 (s, 2H, –CH2), 5.108
(s, 2H, –CH2), 4.206–4.259 (qt, 2H, –CH2, J = 6.8 Hz),
1.245–1.281 (t, 3H, –CH2, J = 7.2 Hz) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 184.70, 168.40, 142.23, 140.573
136.80, 125.10, 124.70, 123.55, 122.56, 121.00, 117.39,
111.34, 62.13, 50.53, 41.46, 14.63 ppm, MS (m/z) calc.:
312.33, found LC–MS: 313.30[M+1].
1
m.p. 215–216 °C; H NMR (400 MHz, CDCl3): δ 9.987
(s, H, –CHO), 7.298–8.321 (m, 6H, Ar–H), 5.616 (s, 2H,
–CH2), 5.137 (s, 2H, –CH2), 3.527–3.665 (m, 8H, –CH2)
ppm; 13C NMR (100 MHz, CDCl3): δ 184.72, 164.19,
142.02, 140.62, 136.78, 125.40, 124.67, 123.56, 122.56,
120.99, 117.37, 111.33, 66.35, 53.68, 50.60, 42.48 ppm; MS
(m/z) calc.: 353.38, found LC–MS: 354.50 [M+1].
2 - ( 4 - ( ( 3 - fo r my l - 2 - m e t hy l - 1 H - i n d o l - 1 - y l )
methyl)-1H-1,2,3-triazol-1-yl)acetic acid (4b). white solid;
m.p. 220–221 °C; 1H NMR (400 MHz, DMSO-d6): δ 13.282
(s, H, –COOH), 9.947 (s, H, –CHO), 7.260–8.296 (m, 6H,
Ar–H), 5.523 (s, 2H, –CH2), 5.108 (s, 2H, –CH2), 2.563 (t,
3H, –CH3) ppm; 13C NMR (100 MHz, DMSO-d6): δ 184.43,
177.78, 142.52, 140.37, 138.54, 137.06, 125.41, 124.45,
123.30, 122.26, 118.73, 110.12, 62.12, 51.10, 42.51 ppm;
MS (m/z) calc.: 298.30, found LC–MS: 299.30 [M+1].
1-((1-(2-oxo-2-(1H-1,2,4-triazol-1-yl)ethyl)-1H-1,2,3-
triazol-4-yl)methyl)-1H-indole-3-carbaldehyde (6t). off
white solid; m.p. 233–234 °C; 1H NMR (400 MHz, CDCl3):
δ 9.987 (s, H, –CHO), 7.323–8.409 (m, 8H, Ar–H), 5.520 (s,
2H, –CH2), 5.190 (s, 2H, –CH2) ppm; 13C NMR (100 MHz,
CDCl3): δ 185.52, 162.53, 143.55, 142.43, 138.51, 137.00,
125.42, 124.50,124.32, 123.23, 122.34, 118.70, 110.14,
51.44, 42.34 ppm; MS (m/z) calc.: 335.33, found LC–MS:
336.50 [M+1].
Ethyl 2-(4-((3-formyl-2-methyl-1H-indol-1-yl)
methyl)-1H-1,2,3-triazol-1-yl)acetate (5b). white solid; m.p.
238–239 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.947 (s, H,
–CHO), 7.258–7.856 (m, 5H, Ar–H), 5.523 (s, 2H, –CH2),
5.110 (s, 2H, –CH2), 5.522 (s, 3H, –CH3) 1.244–1.282 (t,
3H, –CH2, J=7.2 Hz) ppm; 13C NMR (100 MHz, DMSO-
d6): δ 184.64, 168.90, 142.52, 140.31, 138.50, 137.02,
1 3

Molecular Diversity
2-methyl-1-((1-(2-(4-methylpiperidin-1-yl)-2-oxoethyl)-
1H-1,2,3-triazol-4-yl)methyl)-1H-indole-3-carbalde-
42.38, 13.24 ppm; MS (m/z) calc.: 349.35, found: 350.40
[M+1].
1
hyde (7p). of yellow solid; m.p. 221–223 °C; H NMR
ethyl 4-(4-((3-formyl-1H-indol-1-yl)methyl)-1H-1,2,3-
triazol-1-yl)-3-oxobutanoate (6a). off white solid; m.p.
289–291 °C; 1H NMR (400 MHz, DMSO––d6): δ 9.927 (s,
H, –CHO), 7.241–8.390 (m, 6H, Ar–H), 5.581–5.607 (d,
2H, –CH2), 4.770 (s, 2H, –CH2), 3.827–3.879 (s, 2H, –CH2),
3.365(s, 2H, –CH2), 1.043–1.078(t, 3H, –CH3) ppm.
n2-(4-((3-formyl-1H-indol-1-yl)methyl)-1H-1,2,3-tria-
zol-1-yl)acetamide (6b). of white solid; m.p. 280–283 °C;
1H NMR (400 MHz, DMSO-d6): δ 9.952 (s, H, –CHO),
7.325–8.390 (m, 6H, Ar–H), 6.529 (br, 2NH, S), 5.533 (s,
2H, –CH2), 5.118 (s, 2H, –CH2) ppm.
(400 MHz, CDCl3): δ 9.987 (s, H, –CHO), 7.295–7.913
(m, 5H, Ar–H), 5.613 (s, 2H, –CH2), 5.196 (s, 2H, –CH2),
3.378–3.407 (dd, 2H, –CH2, J = 2.4 Hz), 2.786–2.853 (td,
2H, –CH2, J = 2.4 Hz), 2.583 (s, 3H, –CH3), 1.550–1.579
(dd, 2H, –CH2, J = 2.4 Hz), 1.388–1.425 (m, H, –CH),
1.012–1.083 (td, 2H, –CH2, J = 2.4 Hz), ppm; 13C NMR
(100 MHz, CDCl3): δ 184.77, 162.47, 142.46, 140.14,
136.98, 125.44, 124.46, 124.30, 123.19, 122.29, 118.67,
110.15, 51.18, 45.61, 42.44, 34.29, 30.80, 21.51, 13.13 ppm;
MS (m/z) calc.: 379.46, found LC–MS: 380.55 [M+1].
2-methyl-1-((1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-
1H-1,2,3-triazol-4-yl)methyl)-1H-indole-3-carbalde-
1-((1-(2-oxo-2-phenylethyl)-1H-1,2,3-triazol-4-yl)
methyl)-1H-indole-3-carbaldehyde (6c). pale yellow solid;
m.p. 273–275 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.940
(s, H, –CHO), 7.294–8.292 (m, 11H, Ar–H), 5.221 (s, 2H,
–CH2), 5.106 (s, 2H, –CH2) ppm.
1
hyde (7q). pale yellow solid; m.p. 227–228 °C; H NMR
(400 MHz, CDCl3): δ 9.930 (s, H, –CHO), 7.266–7.920 (m,
5H, Ar–H), 5.626 (s, 2H, –CH2), 5.224 (s, 2H, –CH2), 3.567
(s, 2H, –CH2), 3.383 (s, 2H, –CH2), 2.583 (s, 3H, –CH3),
1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1H-in-
dole-3-carbaldehyde (6d). white solid; m.p. 285–287 °C;
1H NMR (400 MHz, DMSO-d6): δ 9.932 (s, H, –CHO),
7.170–8.284 (m, 11H, Ar–H), 5.513 (s, 2H, –CH2), 5.018
(s, 2H, –CH2) ppm.
2.323–2.375 (m, 4H, –CH2), 2.213 (s, 3H, –CH3) ppm; 13
C
NMR (100 MHz, CDCl3): δ 184.66, 164.37, 142.12, 140.63,
136.54, 125.32, 124.64, 123.49, 122.53, 120.67, 117.58,
111.32, 53.55, 50.52, 44.57, 41.77, 41.46, 13.48 ppm; MS
(m/z) calc.: 380.45, found LC–MS: 381.60 [M+1].
2-methyl-1-((1-(2-morpholino-2-oxoethyl)-1H-1,2,3-
triazol-4-yl)methyl)-1H-indole-3-carbaldehyde (7r).
pale orange solid; m.p. 224–225 °C; 1H NMR (400 MHz,
CDCl3): δ 9.987 (s, H, –CHO), 7.295–7.913 (m, 5H, Ar–H),
5.613 (s, 2H, –CH2), 5.132 (s, 2H, –CH2), 3.529–3.667 (m,
8H, –CH2), 2.213 (s, 3H, –CH3) ppm; 13C NMR (100 MHz,
CDCl3): δ 184.74, 164.22, 142.08, 140.65, 136.82, 125.41,
124.70, 12+ 3.58, 122.59, 120.99, 117.36, 111.36, 66.32,
53.71, 50.62, 42.43 ppm; MS (m/z) calc.: 367.41, found
LC–MS: 368.40 [M+1].
nnn1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1H-in-
dole-3-carbaldehyde (6e). white solid; m.p. 293–295 °C;
1H NMR (400 MHz, DMSO-d6): δ 9.973 (s, H, –CHO),
7.322–8.456 (m, 6H, Ar–H), 5.806 (s, 2H, –CH2), 5.689 (s,
2H, –CH2) ppm.
2-(4-((3-formyl-1H-indol-1-yl)methyl)-1H-1,2,3-tria-
zol-1-yl)acetonitrile (6f). of white solid; m.p. 311–313 °C;
1H NMR (400 MHz, DMSO): δ 9.925 (s, H, –CHO),
7.242–8.394 (m, 6H, Ar–H), 5.606–5.580 (d, 2H, –CH2),
3.209–3.246 (t, 2H, –CH2), 1.173–1.457 (m, 10H, –CH2),
0.796(t, 3H, –CH3) ppm.
2-methyl-1-((1-(2-oxo-2-(1H-1,2,3-triazol-1-yl)
ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-indole-3-car-
baldehyde (7 s). of white solid; m.p. 239–240 °C; 1H NMR
(400 MHz, CDCl3): δ 9.979 (s, H, –CHO), 7.230–7.886 (m,
7H, Ar–H), 5.526 (s, 2H, –CH2), 5.198 (s, 2H, –CH2), 2.588
(s, 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 185.02,
163.08, 142.34, 138.56, 137.12, 130.45, 130.34, 125.48,
124.53, 124.36, 123.20, 122.31, 118.60, 110.12, 51.52,
42.56, 13.23 ppm; MS (m/z) calc.: 349.35, found LC–MS:
350.50 [M+1].
Pharmacological evaluation
In vitro antimicrobial activity
All the synthesized compounds were screened against three
gram-positive bacteria S. aureus (MTCC 96), B. Subtillis
(MTCC 441), C. tetani(MTCC 449), three gram-negative
bacteria E. coli (MTCC 443), S. Typhi (MTCC 98), P. Aer-
uginosa (MTCC 1688) and two fungi C. Albicans (MTCC
227), T. Rubrum (MTCC 8477) by the use of disk difusion
method as described by the National Committee for Clinical
Laboratory Standards (NCCLS)[56]. Mueller–Hinton broth
was used as the nutrient medium to grow and dilute the
compound suspension for the test bacteria, and Sabouraud
Dextrose broth was used for fungal nutrition. Serial dilu-
tions were prepared in primary and secondary screening.
The compound was run in the primary screening at three dif-
ferent concentrations 1000, 500 and 250 μg/mL. Further, the
2-methyl-1-((1-(2-oxo-2-(1H-1,2,4-triazol-1-yl)
ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-indole-3-car-
baldehyde (7t). of white solid; m.p. 231–232 °C; 1H NMR
(400 MHz, CDCl3): δ 9.979 (s, H, –CHO), 7.326–8.412
(m, 7H, Ar–H), 5.524 (s, 2H, –CH2), 5.196 (s, 2H, –CH2),
2.586 (s, 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3):
δ 185.55, 162.43, 143.51, 142.40, 138.53, 136.96, 125.44,
124.52,124.31, 123.25, 122.37, 118.68, 110.12, 51.47,
1 3

Molecular Diversity
compounds that were found to be active in primary screen-
ing were similarly diluted to obtain 100, 62.5, 50, 25 and
12.5 μg/mL concentrations for secondary screening. DMSO
was used as diluent to get desired concentration of drugs to
test upon standard bacterial strains. The tube, free from anti-
biotics, was subcultured by applying a loopful evenly over
a quarter of plate of medium, which was used, for growth
of test organism. The tubes were then incubated at 37 °C
for 24 h in case of bacteria and 48 h in case of fungi. The
minimum concentration of the compound which can inhibit
the growth of the microorganism completely was considered
and recorded as minimum inhibitory concentration (MIC,
μg/mL). The amount of growth from the control (solvent)
tube before incubation was compared. All bio-assays were
repeated at least three times. All required strains were pur-
chased from MTCC (Microbial Type Culture Collection),
Institute of Microbial Technology, Chandigarh. Ampicillin
and chloramphenicol were used as standard drugs for com-
parison of anti-bacterial and griseofulvin and fuconazole
were used for anti-fungal activities.
Declarations
Conflicts of interest There are no conficts to declare.
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