Pd-catalyzed post-Ugi intramolecular cyclization to the synthesis of isoquinolone-pyrazole hybrid pharmacophores & discover their antimicrobial and DFT studies

Article abstract of DOI:10.1016/j.tetlet.2021.153353

A novel microwave assisted ligand-free palladium-catalyzed post Ugi reaction for the synthesis of isoquinolone and pyrazole mixed pharmacophore derivatives was achieved from isocyanide and pyrazole substituted amide molecules (synthesized by using Ugi rea

Full text of DOI:10.1016/j.tetlet.2021.153353

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed post-Ugi intramolecular cyclization to the synthesis of
isoquinolone-pyrazole hybrid pharmacophores & discover their
antimicrobial and DFT studies
c,
c
Keyur M. Pandya a,b, , Satyanarayana Battula , Parth J. Naik
⇑
⇑
a Department of Chemistry, Arts, Science and Commerce College, Veer Narmad South Gujarat University, Surat 394185, Gujarat, India
b Department of Product Research & Development, Alexza Pharmaceuticals Inc., Mountain View, CA 94043, USA
c Tarsadia Institute of Chemical Sciences, Uka Tarsadia University, Bardoli, Gujarat 394350, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel microwave assisted ligand-free palladium-catalyzed post Ugi reaction for the synthesis of iso-
quinolone and pyrazole mixed pharmacophore derivatives was achieved from isocyanide and pyrazole
substituted amide molecules (synthesized by using Ugi reaction). Benzaldehyde, aniline, t-butyl iso-
cyanide and a variety of pyrazole carboxylic acids are being used as starting materials for the Ugi-MCR
to generate diverse amide precursors, which in turn provided an access to the synthesis of various iso-
quinolone-pyrazole hybrid derivatives in moderate to good yields through the isocyanide insertion and
successive intramolecular cyclization. The newly synthesized target compounds were characterized by
1H NMR, 13C NMR, HRMS, and elemental analysis. In vitro antimicrobial activity of the prepared mole-
cules was studied against various pathogenic strains; the results obtained were further described with
the help of DFT and molecular orbital calculations. Compound 6e and 6g revealed good antimicrobial
activity compared to standard drugs kanamycin and amphotericin B.
Received 30 April 2021
Revised 14 August 2021
Accepted 17 August 2021
Available online xxxx
Keywords:
Ugi reaction
Isoquinolone
Pyrazole
Post-Ugi cyclization
Hybrid molecules
Antimicrobial
Ó 2021 Elsevier Ltd. All rights reserved.
The Ugi multicomponent reaction (MCR) is one of the most pre-
dominant isocyanide-based MCRs and attracts wide diversity of
fascinated chemists owing to its four-component transformation
and remarkable functional tolerance [1]. Besides, significant num-
ber of efforts has been made to the synthesis of diverse hetero-
cyclic libraries through the post Ugi annulation reactions of
functionalized Ugi adducts [2]. Synthesis of single molecular archi-
tecture through the combination of two or more pharmacophoric
structural units to improvise the activity and affinity than their
parent molecules has been emerged as a promising strategy to
the field of recent drug discovery [3]. Isoquinolone, a significant
N-containing heterocyclic scaffold ubiquitous in a range of biolog-
ically active natural molecules and pharmaceuticals and these are
familiar for their antitumor, antiallergic and antipsychotic activ-
ities [4]. Fig. 1 Pyrazole is another nitrogenous heterocycle cover-
ing a broad range of synthetic as well as natural products
displaying innumerable chemical, biological, agrochemical and
pharmacological properties and their derivatives represent most
active class of compounds possessing a wide spectrum of biological
activities including COX-2 inhibitor, alcohol dehydrogenase inhibi-
tor, PDE5 inhibitor and etc [5]. Some of these compounds exhibit
important applications in material chemistry such as brightening
agents [6], chemosensors [7], photoluminescence agents [8], as
well as organic light emitting diodes [9]. Further, pyrazole ring sys-
tem accounts a wide range of synthetic applications, as synthetic
reagent in MCR’s, chiral auxillaries [10], guanylating agents [11],
chelating and extracting reagents for many metal ions [12]. View-
ing the significance of these N-containing heterocycles in countless
areas, particularly in medicinal chemistry the present work focuses
on the synthesis of the hybrid molecules of these two structural
units. Over the past few decades antibiotic deposits become less
effective worldwide as its overuse and its emerging antimicrobial
drug resistance. Even the drug resistance has been developed by
the common bacterial and fungal pathogens against frequently
prescribed drugs (amphotericin B, fluconazole, penicillin,
chloroamphenicol and etc.). Hence, it would be an emerged field
of study as it relates to a global health challenge, thereby, numer-
ous strategies will be required to develop new therapeutic com-
pounds. In this context to enrich the biological applications, we
designed the synthesis of hybrid molecules of isoquinolone and
pyrazole pharmacophores [13].
⇑
Corresponding authors at: Tarsadia Institute of Chemical Sciences, Uka Tarsadia
University, Bardoli, Gujarat-394350, India.
E-mail addresses: doctorkpandya@gmail.com (K.M. Pandya), satyanarayana.
battula@utu.ac.in (S. Battula).
https://doi.org/10.1016/j.tetlet.2021.153353
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: K.M. Pandya, S. Battula and P.J. Naik, Pd-catalyzed post-Ugi intramolecular cyclization to the synthesis of isoquinolone-pyrazole
hybrid pharmacophores & discover their antimicrobial and DFT studies, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153353

K.M. Pandya, S. Battula and P.J. Naik
Tetrahedron Letters xxx (xxxx) xxx
formation of 6a (<10% yield) in a post Ugi reaction of the Ugi pro-
duct 5a (amide, 1 mmol) with tertiary butyl isocyanide (1.2 mmol)
in presence of PdCl2 (10 mol%) and a base Cs2CO3 (2 mmol) in DMF
solvent at 150 °C under microwave irradiation (entry 1, Table 1).
Later, we studied the reaction at various reaction conditions
including different catalysts, bases, solvents and temperatures.
No product was formed while in absence of catalyst (entry 2).
When we tested the reaction with Pd(PPh3)4 and Pd(OAc)2 at the
same reaction conditions (entry 3 & 4), the reaction with Pd
(OAc)2 could give 91% yield of 6a in DMF solvent at 150 °C under
microwave conditions. The reaction with Pd(OAc)2 was studied
further at lower temperatures (entry 5 & 6), but better yields were
not observed for the reaction. Further, distinct bases were investi-
gated at similar reaction conditions by using Pd(OAc)2 as a catalyst,
and Cs2CO3 was erected to be the most persuasive base catalysts at
various reaction conditions (entry 7, 8, 9 & 10; Table 1). In addition,
no improvement of the reaction was observed when it performed
in DMSO solvent (entry 11). Nevertheless, we studied the reaction
at room temperature in different solvents DMF, DMSO, toluene,
and CH3CN (entry 12, 13, 14 and 15; Table 1) in absence of MW
conditions, although the reaction gave appreciable yield of 6a (81
%) in DMF solvent in 8 h, but no one procure competitive yield of
the reaction while it was conducted under microwave conditions.
The reaction proceeded to accomplish the product 6a in a period
of 15 min under MW reaction conditions at 150 °C, while the same
reaction required 7–8 h to attain its completion stage (vanishing of
amide precursor on TLC) to obtain 6a.
Fig. 1. Biologically active isoquinolone and pyrazole molecules.
Isocyanides have been served as an extremely valuable syn-
thons for the decades in a variety of multi component reactions
to the generation of valuable molecules which are broadly applied
in organic, medicinal, and polymeric chemistry owing to their
important chemical and biological applications [14]. Herein, we
demonstrated the combination of these isoquinolone - pyrazole
pharmacophores through a microwave assisted ligand free Pd-cat-
alyzed post Ugi isocyanide insertion reaction of Ugi amide precur-
sors and followed by an intramolecular cyclization.
As depicted in Scheme 1, aniline 1, tertiary butyl isocyanide 2a,
various pyrazole based carboxylic acids 3a-3g, and o-bromoben-
zaldehyde 4 were employed for the Ugi 4 component reaction in
MeOH at 40 °C for about 18 h to the generation of the parallel
amide precursors 5a to 5g up to 96% yields. Later these molecules
5a-5g as the starting materials were subjected to the ligand-free
microwave assisted palladium-catalyzed post Ugi reaction with
tertiary butyl isocyanide, and it comprises isocyanide insertion
and intramolecular cyclization reactions.
With this optimized reaction procedure in the hand, we
extended the scope of the reaction protocol to the synthesis of var-
ious substituted isoquinolone - pyrazole hybrid molecules (6a-6g)
by subjecting different Ugi- MCR synthesized amide precursors 5a-
5g reactions with tertiary butyl isocyanide 2a. Irrespective of the
substituents on pyrazole scaffold, all the representative reactions
could produce good to excellent yields of 6 (Scheme 2). Unsubsti-
tuted phenylpyrazole compound 5a was produced good yield of
the mixing scaffolds 6a (91%) than the remaining pyraz ole
The inspection of the Pd-catalyzed isocyanide insertion and
cyclization reaction was started with an observation of the
Scheme 1. Pyrazole based Ugi products. aReaction conditions: 1 (1 mmol), 2a (1 mmol), 3 (1 mmol), 4 (1.2 mmol) in MeOH (3 mL), 35–40 °C, 15–18 h, 77–96%.
2

K.M. Pandya, S. Battula and P.J. Naik
Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of Pd-catalysed isocyanide insertion and cyclization reactiona.
Entry
catalyst
Base
solvent
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
PdCl2
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOtBu
K3PO4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
150
150
150
150
120
100
150
150
150
150
150
rt
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
8
<10
Nr
35
91
80
75
61
52
47
<10
71
80
59
15
22
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
DMF
DMF
10
11
12c
13c
14c
15c
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO
DMF
DMSO
Toluene
CH3CN
rt
rt
rt
8
8
8
aReaction conditions: 5a (1 mmol), t-butyl isocyanide 2a (1.2 mmol), catalyst (10 mol%), base (2 mmol), solvent (2.5 mL) under inert (N2) condition; bIsolated yields, cThermal
conditions.
Scheme 2. Pyrazole based Ugi products. Reaction conditions: 5 (1 mmol), t-butyl isocyanide 2a (1.2 mmol), Pd(OAc)2 (10 mol%), Cs2CO3 (2 mmol), DMF (2.5 mL), at 150 °C for
15–20 min in inert (N2) atmosphere under microwave irradiation.
3

K.M. Pandya, S. Battula and P.J. Naik
Tetrahedron Letters xxx (xxxx) xxx
isocyanide electrophilic carbon to form intermediate (III). Through
few rearrangements via intermediates (IV) and (V), it produces 6.
The newly synthesized mixed scaffold molecules 6a-6g were
examined for their in vitro antimicrobial activity according to Clin-
ical and Laboratory Standard Institute (CLSI) protocols [16].
Antibacterial activities of these compounds were estimated against
five clinical bacterial strains (Staphylococcus aureus, Escherichia coli,
Enterococcus faecalis, Streptococcus pyogens, and Vibrio cholera) and
the results were summarized in Table 2. The activities of 6a-6g in
terms of their MIC are ranging from 250
lM to 20.85 lM. The
antibacterial activities of these molecules were compared with
the routinely used standard antibiotic drug kanamycin [17]. To
our surprise, the compounds 6e and 6g were found to be the
promising potent molecules of the synthesized compounds and
are comparable to kanamycin in S. aureus and V. cholerae strains
and less comparable with E. coli. The compound 6f also showed sig-
nificant activity against S. aureus and V. cholerae strains (about 34 %
and 66 % less potent than compare to kanamycin respectively).
Antifungal activities of the synthesized compounds 6a-6g were
assessed by using five different fungal strains (Candida albicans,
Candida glabrata, Candida krusei, Candida tropicalis, and Candida
parapsilosis) and the results of their MIC values are depicted in
Table 3. Among the tested molecules, 6e and 6g as standalone
and were found to be more active when amphotericin B is used
as standard antifungal drug [18]. 6f molecule showed little activity
against C. parapsilosis strain. In general, the halogen atom (Cl) sub-
stitution on phenyl ring attached to pyrazole perhaps responsible
to the antimicrobial potency, as its presence enhances (6g, and less
effectively 6f) the lipophilicity and that leads to raise the cell pen-
etration rate, which is an important factor to exhibit antimicrobial
potency. The presence of nitro group on phenyl ring linked to pyra-
zole in 6e, could cause to show the promising antimicrobial
efficacy.
The inspiring results achieved in the antimicrobial screening
prompted us to move ahead with the elementary screening of
the synthesized compounds 6a-6g for their in vitro antitubercular
efficacy. The antitubercular activity of these compounds was inves-
tigated against M. tuberculosis H37Rv strain by the Lowenstein–Jen-
sen slope method. Initial screening of all the synthesized
compounds was charged at a concentration of 250 mg/mL. Rifampi-
cin and isoniazid were employed as the standard drugs for the cor-
relation of activities with synthesized compounds. The screening
results are summarized in Table 4, as the percentage of inhibition
relative to the standard drugs isoniazid and rifampicin. Amongst
the tested compounds, 6e and 6g (less effectively 6f) were found
to be the promising antitubercular molecules and as comparable
to the standards.
Scheme 3. a) Pd-catalyzed post-Ugi intramolecular cyclization with different
isocyanides; b) Plausible reaction mechanism.
compounds with substituted phenyl groups. Of the aryl substitu-
tions of pyrazoles, substitutions on N-aryl group gave more yield
of the isoquinolone-pyrazole derivatives than compared to the
substitution on 3-aryl pyrazole precursors.
Among the various isocyanides 2 being tested with 5a for this
transformation, only tert-butyl isocyanide 2a was found to be con-
structed efficiently the hybrid structures 6 of mixed scaffolds iso-
quinolone - pyrazole, through its insertion and intramolecular
cyclization, and hence it was the only isocyanide employed for
the reaction (Scheme 3a). It clearly indicates that, tertiary butyl
group in the isocyanide could assist the reaction in the generation
of the target compound that no other isocyanide does the same.
On the basis of these results and literature reports [15], the
plausible reaction mechanism to the generation of 6 is depicted
in Scheme 3b. It initiates by the formation of Pd(II) complex (I)
with the amide precursor 5. Then tertiary butyl isocyanide inserts
in to the (I) to produce another Pd(II) complex (II), and that later
undergoes intramolecular amide oxygen nucleophiolic attack on
To explain rationally these biological activities, DFT studies
were conducted for the synthesized molecules. The energies of
Table 2
In vitro antibacterial activities (MIC) of 6a-6g against five bacterial strains.
Entry
Minimum inhibitory concentration (l
M)a
S. aureus
E. coli
E. faecalis
S. pyogens
V. cholerae
6a
6b
6c
6d
6e
6f
6g
>250
>250
>250
>250
20.85
90.5
>250
>250
>250
>250
31.5
100
>250
>250
>250
>250
>250
200
>250
>250
>250
>250
200
>250
>250
62.5
>250
>250
>250
>250
41.25
125
37.25
31.3
37.25
3.9
>250
62.5
90.5
62.5
Kanamycinb
aMIC values of compounds estimated by CFL plating method.
bPositive control for the study, commonly used antibacterial drug.
4

K.M. Pandya, S. Battula and P.J. Naik
Tetrahedron Letters xxx (xxxx) xxx
Table 3
In vitro antimicrobial activities (MIC) of 6a-6g against five microbactreial strains.
Entry
Minimum inhibitory concentration (l
M)a
C. albicans
C. glabrata
C. krusei
C. tropicalis
C. parapsilosis
6a
6b
6c
6d
6e
6f
>250
>250
>250
>250
62.5
100
>250
>250
>250
>250
62.5
120
>250
>250
>250
>250
120
>250
>250
0.78
>250
>250
>250
>250
250
120
120
0.78
>250
>250
>250
>250
62.5
62.5
62.5
0.78
6g
62.5
0.78
200
0.78
Amp Bb
aMIC values of compounds estimated by CFL plating method.
bPositive control for the study; Amp B: Amphotericin B
Table 4
energies of HOMO of all the molecules were comparable and a little
exception with 6e. As its consequence, LUMO energies could be the
differentiating aspect to the prediction/support to the biological
activities. Generally, LUMO energies are influenced by the nature
of groups (electron donating/electron withdrawing groups) pre-
sent in the molecular structure. The differences in the antimicro-
bial activities of the molecules could explain by using the
variations in their LUMO energies. The presence of electron with-
drawing groups perhaps stabilized the LUMO and thereby, lowers
In vitro antituberculosis activity (% inhibition) of com-
pounds (6a-g) against M. tuberculosis H37Rv.
% Inhibition
Entry
250 mg/mL
6a
6b
6c
6d
6e
6f
6g
30
32
55
73
97
89
94
98
99
the gap of HOMO and LUMO (
cules to exhibit significant biological activity, amongst the synthe-
sized molecules, 6e and 6g are accounted with low E (-2.498 ev
DE). These factors assisting to mole-
Rifampicina
Isoniazidea
D
and À5 865 ev respectively; Fig. 2). Along with energy aspects of
molecular orbitals, the site locations of these orbitals show a strong
agreement for the biological activities. Both location and energy of
LUMO together described the biological activity of molecule. The
location of LUMO was influenced by the substitution of electron
withdrawing group on aryl groups linked to the pyrazole in the
6. It has been revealed from electrostatic results that biological
activity of isoquinolone-pyrazole hybrid molecules was due to
electron withdrawing groups on pyrazole and that consequently
lowered its LUMO energy. The remarkable activity of 6e perhaps
due to the location of LUMO on pyrazole moiety owing to the nitro
substitution than compare to the 6g which although possess signif-
icantly lower LUMO energy due to contain two chlorine atoms on
the N-phenyl pyrazole but exists in unnerving location.
aStandard antitubercular drugs.
In conclusion, we have developed a ligand free Pd-catalysed
microwave assisted post-Ugi cyclization of Ugi diamide product
with tertiary butyl isocyanide through isocyanide insertion fol-
lowed by cyclization to the synthesis of mixed pharmacophores
of isoquinolone and pyrazoles. The synthesized molecules were
studied for their antimicrobial activities. Amongst, 6e and 6g
hybrid molecules are found to be very potent and comparable to
the standard molecule kanamycin and amphotericin B (antibacte-
rial and antifungal respectively). Further we elucidated the DFT
studies and that supported the biological potency of the synthe-
sized molecules. The further study of the molecules is in progress.
Fig. 2. Configurations of HOMO and LUMO of 6e and 6g.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
HOMO and LUMO of a particular molecule can determine its reac-
tivity in terms of their electron donating and receiving ability.
Higher HOMO energy causing to raise the reactivity of a molecule
owing to its high electron donating ability. According to Mabkhot
et al., the energy difference of these molecular orbitals HOMO
and LUMO is an important factor to explain the feasibility of
intramolecular charge transfer as well as to the study of biological
activities [19]. The theoretical results of the molecular orbitals
depicted in supporting information (section 3.4). As observed, the
Acknowledgment
KMP thank to Prof. N. B. Patel, Dr. P. S. Desai (VNSGU, Surat,
India), and Dr. R. J. Patel (S. P. University, Anand) for their support
in the project completion.
5

K.M. Pandya, S. Battula and P.J. Naik
Tetrahedron Letters xxx (xxxx) xxx
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153353.
(i) M.P. Keyur, J.P. Janki, H.P. Arpan, B.P. Navin, S.D. Piyush, Lett. Org. Chem. 17
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