A strategic approach to the synthesis of ferrocene appended chalcone linked triazole allied organosilatranes: Antibacterial, antifungal, antiparasitic and antioxidant studies

Article abstract of DOI:10.1016/j.bmc.2018.11.038

A series of ferrocene appended chalcone allied triazole coupled organosilatranes (FCTSa 7–FCTSa 12) were synthesised with the aim of amalgamating the pharmacological action of the constituting moieties into a single molecular scaffold. All the synthesised

Full text of DOI:10.1016/j.bmc.2018.11.038

Accepted Manuscript
A strategic approach to the synthesis of ferrocene appended chalcone linked
triazole allied organosilatranes: Antibacterial, Antifungal, Antiparasitic and
Antioxidant studies
Gurjaspreet Singh, Aanchal Arora, Pooja Kalra, Indresh Kumar Maurya,
Cristobal Espinosa Ruizc, M. Angeles Estebanc, Shweta Sinha, Kapil Goyal,
Rakesh Sehgal
PII:
S0968-0896(18)31177-5
https://doi.org/10.1016/j.bmc.2018.11.038
BMC 14642
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 June 2018
16 November 2018
28 November 2018
Please cite this article as: Singh, G., Arora, A., Kalra, P., Maurya, I.K., Ruizc, C.E., Estebanc, M.A., Sinha, S.,
Goyal, K., Sehgal, R., A strategic approach to the synthesis of ferrocene appended chalcone linked triazole allied
organosilatranes: Antibacterial, Antifungal, Antiparasitic and Antioxidant studies, Bioorganic & Medicinal
Chemistry (2018), doi: https://doi.org/10.1016/j.bmc.2018.11.038
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A strategic approach to the synthesis of ferrocene appended chalcone linked triazole
allied organosilatranes: Antibacterial, Antifungal, Antiparasitic and Antioxidant studies
Gurjaspreet Singha, *, Aanchal Arorab, *, Pooja Kalraa, Indresh Kumar Mauryac, Cristobal
Espinosa Ruizcd, M. Angeles Estebancd, Shweta Sinhae, Kapil Goyale, Rakesh Sehgale
aDepartment of Chemistry and Centre of Advanced Studies, Panjab University, Chandigarh,
160014, India
bDepartment of Chemistry, Khalsa College for Women, Civil Lines, Ludhiana, 141001, India
cDepartment of Microbial Biotechnology, Panjab University, Chandigarh, 160014, India
dFish Innate Immune System Group, Department of Cell Biology and Histology, Faculty of
Biology, University of Murcia, 30100 Murcia, Spain
eDepartment of Medical Parasitology, Post Graduate Institute of Medical Education and
Research, Chandigarh, 160024, India
*Corresponding Authors
1. Dr. Gurjaspreet Singh
Assistant Professor
Department of Chemistry and Centre of Advanced Studies
Panjab University, Chandigarh, India
+91-0172-2534428
Email: gjpsingh@pu.ac.in
2. Dr. Aanchal Arora
Assistant Professor
Department of Chemistry, Khalsa College for Women
Civil Lines, Ludhiana, India
+91-9530520506
Email: arora.aanchal511@gmail.com
1

Abstract
A series of ferrocene appended chalcone allied triazole coupled organosilatranes (FCTSa 7-
FCTSa 12) were synthesised with the aim of amalgamating the pharmacological action of the
constituting moieties into a single molecular scaffold. All the synthesised silatranes were well
characterized by various spectroscopic techniques like IR, 1H NMR, 13C NMR and elemental
analysis. Organosilatranes were then evaluated for their biological alacrity against bacterial
and fungal strains compared with the standard drugs Rifampicin and Amphotericin B
respectively. The ferrocene conjugates were found to be only moderately effective against the
tested microbes. However, the organosilatranes conceded excellent efficacy against parasite
G. lamblia with FCTSa 11 arraying the leading results. On the other hand against another
parasite T. vaginalis, FCTSa 8 has emerged as an outstanding composite. Further, Total
Antioxidant Assay (TAA) with 2,2’-azino-bis-3-(ethylbenzothiazoline-6-sulphonic acid)
revealed FCTSa 10 to be the best claimant for radical scavenging activity. Along these lines,
introducing some different substituents in the synthesised hybrids may act as a useful strategy
for increasing the biological profile of the drugs.
Keywords: Ferrocene, Chalcone, Silatrane, Antimicrobial activity, Antiparasitic
activity, Antioxidant activity
1. Introduction
Hot off the press is the molecular hybridization that has emanated as a constructive
contrivance for drug design and medicinal research. This methodology inculcates the
covalent linking of diverse range of pharmacophoric units into a single entity harvesting
synergistic outcome [1]. The structural variations pioneered may trounce the emerging
quandary of drug resistance and augment the existing drug’s activity profile [2]. In
consideration of this, we have contemplated the hybridisation of potentially active
2

functionalities autonomously playing exceptional roles in pharmaceutical industries with the
aim of fabricating a conjugate with excellent effects.
Since the discovery of ferrocene, the lucrative amalgamation of classical organometallic
functionality to medicinal imperative analogues has emerged as an elementary strategy
towards more effective therapeutic applications [3-5]. Decoding the action mechanism of
ferrocene based drugs reveal an indispensable role of this metallocenic moiety in drug action
thus widening the scope of bioorganometallic chemistry for the next generation drug
discovery [6]. Ferrocene-based assemblies have attracted the keen attention of researchers
from many years for their inimitable physicochemical properties, crouched toxicity,
remarkable stability, swift membrane permeability, reversible redox property and plethora of
biological feats [7-12]. Introducing this moiety into some other potentially active modules
may lead to synergic effect on individual activities.
Silatranes are the genre of cage compounds enclosing a hypervalent silicon atom with a
transannular bond to nitrogen [13]. Multifarious silatrane derivatives have been synthesised
in the past decades which are known for their potential pharmacological alacrity [14]. The
bioactive moieties are covalently bonded to the silatranyl fragment by means of a passable
linker embracing biofissionable properties. In some reports, ferrocene moiety is linked to
silatranyl fragment and the resultant ferrocenylsilatranes have been reported as proficient
agents that can significantly enhance the activity profile of the bioactive pharmacophores
[15].
1,2,3-triazoles form an invigorating class of compounds that can act as effective linker
clubbing the potentially active molecular frameworks [16]. Besides acting as linking thread,
these five membered heterocyclic systems have myriad of flattering assets like high dipole
moment, astonishing stability, synthetic accessibility and capability to form hydrogen bonds
3

with biological targets that has attracted the attention of both synthetic and medicinal
chemists [17-20]. A convenient and easily accessible route of “click chemistry” for the
synthesis of 1,2,3-triazoles is also accountable for their extensive use in shaping diverse
structural chimeras [21].
Literature also reports the blending of ferrocene fragment to another medically budding
functionality, chalcone; known for its anticancer, antioxidant, antitubercular and antiviral
drug profile [22-25]. Ferrocenyl chalcones are considered as excellent targets as the derived
reveries flaunt broad spectrum of lipophilic profile and versatile biological concert [26,27].
Kumar et al. have authenticated the antimalarial and antitubercular role of ferrocenyl-
chalcone conjugates [28,29]. Recent revelation from our group has shown the introduction of
silatranyl nucleus into the chalcone fragment, linked via 1,2,3-triazole ring with the resulting
hybrids presenting a spectacular antiparasitic conduct [30].
In a quest to synthesise new hybrids with enhanced drug profile, we have designed a series of
ferrocenyl hybrids following a persistent decorum of “click silylation”, thus upholding the
incentive of high atom economy and wide structural diversity. To the best of our knowledge,
the concoction of silatranyl fragment with the potentially dynamic ferrocenyl-chalcone-
triazole hybrid has been reported for the first time in this manuscript. The present work aims
to exploit the structural diversity of chalcone, chemical tunability of ferrocene, incalculable
stability of triazole and unique chattels of silatrane to design a family of conjugated silatranyl
frameworks which are then evaluated for their antibacterial, antifungal, antiparasitic and
antioxidant drug profile.
2. Results and Discussion
2.1. Drug Design
4

The agility of the ferrocene moiety to undergo extensive chemical modification has lead to
rapid expansion in the field of ferrocene chemistry. Amendments are done in allure of
synthesising substrates that mimic organic drugs and are spectacularly more effectual than the
original organic pedestal. In view of this, we have designed a series of ferrocenyl chalcone
linked triazole allied silatranes 7-12 following “Molecular hybridization”. The synthesis was
planned in such a way that the dynamic fraction of all the functionalities contributes to the
ultimate hybrid producing certain kind of concerted response. Ferrocenyl chalcone
derivatives can be designed by either substituting Ring A or Ring B of chalcones with a
ferrocenyl fragment thus generating two series of ferrocenyl chalcones with Type 1 in which
carbonyl group is directly linked to ferrocene ring while Type 2 contains carbonyl group
attached to phenyl ring a shown in Fig. 1. Both categories of compounds have been
synthesised and different substitutions are auditioned for the purpose of studying the
Structure Activity Relationship (SAR) of the resultant compounds.
O
O
N
O
O
N
Si
O
Si
N
O
O
O
N
O
N
N
O
N
N
Fe
Fe
TYPE 1
TYPE 2
Figure 1. Type 1 and Type 2 of ferrocenyl chalcone linked triazole allied silatranes.
2.2. Chemistry
The synthetic route followed for the synthesis of four component conjugated system of
ferrocene linked chalcone allied triazole encapped silatranes (FCTSa 7-12) is summarized in
Scheme 1. Isomeric compounds differ in their properties and may exhibit a completely
different biological role. So, to investigate the effect of isomers, isomeric compounds were
5

synthesized and then compared for their biological properties to see whether the reversal of
the rings joined by the conjugation bridge has any effect on their drug action or not.
Acetylinic aldehydes were initially prepared by the reaction of hydroxy aldehydes with
propargyl bromide in the presence of K2CO3 as catalyst and DMF as reaction medium. These
alkyne terminated aldehydes then undergo base catalysed Claisen-Schmidt condensation with
acetyl ferrocene to give ferrocene chalconyl linked acetylenes FCA. For the synthesis of
isomeric FCA, aldol condensation of ferrocene 2-carboxaldehyde was done with alkyne
terminated acetophenones in the presence of methanolic NaOH.
The next step involves the click reaction of FCA with AzPTES following highly efficient
copper catalysed azide-alkyne cycloaddition (CuAAC) in the presence of THF/Et3N solvent
system and bromotris(triphenylphosphine)copper (I) as catalyst to give ferrocenyl chalcone
linked triazole encapped organotriethoxysilanes FCTS 1-6 in good to excellent yields. In the
final step, ethoxy groups of the silanes are transesterified with triethanolamine by refluxing
for about 5 h in the presence of KOH as catalyst to yield corresponding ferrocene appended
chalcone linked triazole encapped silatranes FCTSa 7-12 as dark red colored solid.
6

O
O
O
O
Ar
b
CHO
Ar
CH3
c
a
Fe
Fe
Fe
Fe
+
7-10
1-4
O
O
O
O
Ar
COCH3
Ar
H
+
a
b
c
Fe
Fe
Fe
Fe
5,6
11,12
11,12
O
O
OCH3
Ar:
O
OCH3
O
O
O
O
O
Si
O
O
5
Sil
O
Sil
OCH3
O
:
N
Sil:
OCH3
O
Sil
Sa
O
Sil
O
Sil
Sil
N
N
2
3
1
4
6
O
Sa
O
Sa
OCH3
Sa
O
:
Si
OCH3
Sa
Sa:
O
O
N
O
O
N
O
Sa
O
7
8
9
10
12
N
N
11
Scheme 1. Synthetic procedure for ferrocene tethered chalcone appended triazole encapped
organosilatranes. Reagents and conditions: a) 10% NaOH, Methanol, rt, 16 h; b) AzPTES
CuBr(PPh3)3, THF, Et3N, 60 °C, 5 h; c) Triethanolamine, KOH, Toluene, 5 h reflux.
The IR spectra of the newly synthesized compounds 7-12 were recorded in the range of 4000-
400 cm-1. The absorption frequencies were found to be in agreement with the structure of the
prepared compounds. All the compounds show absorption bands in the range of 473-483 cm-
1, 1235-1258 cm-1 and 1368-1378 cm-1 typical of ferrocenyl stretching vibrations and in the
range of 1640-1648 cm-1 corresponding to C=O stretching. Stretching vibrations of C=CH of
the triazole ring in the range of 2958-2973 cm-1 gives the evidence of cycloaddition of
acetylinic unit. Furthermore, Si-O stretching vibrations appear in all the silatranes in the
range of 792-799 cm-1 and 1074-1075 cm-1. In the IR spectra of all organosilatranes,
7

stretching vibration corresponding to N→Si coordinate bond appears in the range of 538-540
cm-1.
1H NMR spectra are well consistent with the structure of the synthesized compounds. In the
NMR spectra of organosilatranes 7, two equivalent triplets appear at δ = 2.72 ppm and δ =
3.67 ppm corresponding to -NCH2 and -OCH2 protons respectively of Si(OCH2CH2)3N
skeleton. These signals of -NCH2 and -OCH2 protons were observed at δ = 2.74 ppm and 3.68
ppm, 2.51 ppm and 3.75 ppm, 2.69 ppm and 3.63 ppm, 2.74 ppm and 3.68 ppm, 2.73 ppm
and 3.68 ppm for organosilatranes 8-12 respectively. Additionally, presence of a signal
around δ = 7.60 ppm, 7.67 ppm, 7.45 ppm, 7.55 ppm, 7.48 ppm and 7.40 ppm for
organosilatranes 7-12 respectively validates the presence of a triazole proton. Furthermore,
absence of a triplet around δ = 1.2 ppm and quartet around δ = 3.7 ppm affirms the complete
esterification of the silyl group into silatranyl fragment. Parallel shifting is scrutinized in the
carbon spectra of the respective compounds. The highly shielded protons are the ones
attached to the carbon directly linked to silicon appearing at δ = 12.9 ppm, 13.7 ppm, 13.4
ppm, 13.2 ppm, 13.0 ppm and 12.2 ppm for organosilatranes 7-12 respectively.
The carbonyl carbon appears as the least shielded carbon in the spectrum at δ = 189.0-193.1
13
ppm. In C NMR spectra of the organosilatranes, the ferrocenyl carbons appear around δ =
68.8-80.8 ppm in all the compounds 7-12. The vinylic carbons of the chalcone functionality
appear at 124.0-129.9 ppm and 134.1-139.5 ppm. In ferrocene linked organosilatranes 7-12,
the peaks at δ = 49.8-51.5 ppm and δ = 56.0-56.6 ppm are assigned to -NCH2 and -OCH2
carbons of silatranyl moiety. Moreover, absence of signals around δ = 18.0 ppm and 58.0
ppm corresponding to CH3 and OCH2CH3 carbons of the ethoxy groups of the silanes affirms
the complete esterification of the silanes. Carbon attached to silicon appears as the most
shielded carbon at δ = 12.2-13.7 ppm clearly indicating the hypervalency in the final
8

compounds. Additionally, carbons of the triazole ring emerging at δ = 119.9-122.9 ppm and δ
= 135.2-141.6 ppm clearly mark the presence of triazole assembly.
2.3. Computational Analysis
Traditional clinical methods involve multi-step time consuming drug testing against a
series of biological screens that may sometimes lead to adverse findings ultimately
resulting into haltering of the project to find some other clinical candidate. This deplorable
burden on the research and development may be overcome by prior computational
screening of the designed compounds. The high throughput screening of the synthesised
library reduces the risk of late stage debilitation of the tested compounds.
Pharmacokinetics parameters like absorption, distribution, metabolism, excretion and
toxicity are therefore tested using computer based ADMET predictor. All these properties
have been listed in Table 1.
First step is the absorption of drugs for which a drug must be orally bio available and after
reaching the gastro-intestinal tract, drugs must be able to surpass the biological
membranes to enter the systemic circulation. This process depends on parameters like
permeability and compound solubility. So, the permeation of the drugs is being assayed
here using artificial membrane assays such as Caco-2 and MDCK cell lines. Results reveal
that chalcone appended ferrocenyl silatranes offer moderate permeability through both the
cell lines. Solubility in the intestinal fluid is also considered as a significant asset of any
oral drug as the inadequate solubility may hinder its intestinal absorption through the
hepatic portal system. Next is the penetration of the drugs that have to enter into the
central nervous system for which they must primarily cross the blood brain barrier (BBB)
through either active transport or by passive diffusion. However, for non-CNS drugs, BBB
penetration must be minimized to reduce the risk of detrimental pharmacological actions
9

and possible neurotoxicity. Another important parameter is Plasma Protein Binding (PPB).
As only the unbound drug can cross membranes and interact with the protein target, so
interaction with plasma proteins must be vigilantly monitored during the drug discovery
process.
Further parameters like Human Intestinal Absorption (HIA) and Skin Permeability
identifies the potential drug for oral and transdermal delivery. HIA describes the
percentage of orally administered drug reaching the hepatic portal vein and our
computational analysis has shown a high value of HIA for all the synthesised compounds.
Skin Permeability is analysed from the permeability coefficient data (Kp) that provides an
imperative insight into the molecular transport through the stratum corneum.
Kp = Km*D/h
where Km is distribution coefficient between stratum corneum and vehicle, D is average
diffusion coefficient (cm2/h) and h is thickness of skin (cm). All these assays together can
significantly assist the selection of potential drug candidates with enhanced probability of
clinical success.
Table 1. Pharmacokinetic descriptors of FCTSa 7-12.
Descriptors
Organo
silatranes
Caco-2 cell
permeability solubility
Buffer
Skin
permeability
(logKp)
-4.91
Plasma
protein
binding (%)
HIA
(%)
MDCK
(nm/s)
BBB
(nm/s)
33.52
31.68
31.34
31.40
33.39
31.37
(mg/l)
1304.91
2329.01
1265.37
1265.37
652.10
7
8
9
10
11
12
2.59
2.59
2.10
2.10
2.83
2.83
97.79
97.79
97.74
97.74
97.79
97.79
0.025
0.037
0.024
0.024
0.030
0.034
100.00
100.00
100.00
100.00
100.00
100.00
-4.91
-4.93
-4.93
-4.90
1163.86
-4.90
BBB: Blood Brain Barrier; HIA: Human Intestinal Absorption; MDCK: Madin-Darby Canine Kidney
2.4. Biological Assays
10

Ferrocene moiety is extensively known for its pharmacological implication. In the
synthesized motifs, besides ferrocene, there are three auxiliary bioactive functionalities, that
is chalcone, 1,2,3-triazole and silatrane. All these vibrant clusters have been clubbed together
with a motive to augment their pharmaceutical action. To have a look into their synergistic
effect, ferrocenyl silatranes FTCSa 7-12 were evaluated for their antimicrobial activities
against several strains of bacteria and fungi, antiparasitic activities against G. lamblia and T.
vaginalis and antioxidant assays.
2.4.1. In vitro anti-microbial activity
Microbial infections are posing a serious threat to public health worldwide accounting for
around 50,000 deaths each day [31]. The progressively increasing multidrug resistance to the
existing drugs is totting up the concern of medicinal chemists. This has led to the abundant
structural and chemical modifications in the recognized drugs to give rise to a new generation
of antimicrobials that can combat the emergence of multidrug resistance [32]. In view of this,
the synthesised multicomponent motifs were evaluated against six strains of bacteria and
seven strains of fungi and compared with the standard drugs Rifampicin and Amphotericin B
respectively. The subsequent antibacterial and antifungal results are detailed in Table 2 and 3
respectively. It is worth mentioning that despite their moderate activity, synthesised silatranes
were found to be effective against all the tested bacterial strains. However, these were
comparatively more vigorous against numerous strains of fungi. This observation entails that
the assembled unit provides a broad spectrum of antibacterial and antifungal conduct, though
further research is required to improve their activity profile. So, auxiliary structural
modifications like the introduction of new substituents at the chalcone or the ferrocene ring
that can enhance their microbial potency is our ongoing topic of research.
Among the evaluated bacterial strains, L. monocytogens was the most resistant one to
ferrocenyl derivatives. In contrast, the best potency was shown against E. faecalis strain of
11

bacteria. FCTSa 9 was the most effective derivative against the bacterial strains. As a general
view, ortho derivatives were more active than the ones in which silatrane is present at the
para position. Considering fungal strains, C. albicans was the most affected while C. kusei
was the least bothered fungal strain. FCTSa 10 was found to be most effective against C.
albicans while FCTSa 8 displayed the highest activity against C. tropicalis fungi both
divulging the IC50 value of 31.25 μM. Amongst all silatranes, FCTSa 7 was the most potent
compound against all strains of fungi. Further optimizations on this structural outfit may
eventually lead to the innovation of more potential therapeutic agents.
Table 2. Antibacterial activity of silatranes 7-12 (IC50 values in µM).
FCTSa
E. coli
S. aureus E. faecalis V. cholera H.influenza L. monocytogens
7
250
250
125
250
n.d.
125
7.60
125
250
>250
>250
125
125
>250
>250
>250
n.d.
>250
>250
125
250
>250
250
8
9
250
10
11
>250
n.d.
125
125
>250
n.d.
n.d.
n.d.
12
>250
1.90
125
>250
62.50
>250
62.50
>250
125
Rifampicin
62.50
*n.d.: Not determined due to solubility reasons
Table 3. Antifungal activity of silatranes 7-12 (IC50 values in µM).
FCTSa
C. kusei
C. albicans C. tropicalis C. parapsolsis C. kyfer C. neoformans
C. glabrata
7
8
250
>250
>250
>250
n.d.
125
62.50
62.50
31.25
n.d.
125
31.25
>250
>250
n.d.
62.50
>250
>250
>250
n.d.
62.50
>250
>250
>250
n.d.
62.50
>250
>250
>250
n.d.
125
>250
>250
>250
n.d.
9
10
11
12
>250
125
125
>250
>250
>250
>250
12

Amphotericin B
0.78
0.78
0.78
0.78
1.25
0.195
0.78
*n.d.: Not determined due to solubility reasons
2.4.2. Antiparasitic Assay
Parasitic diseases are causing a serious health dilemma affecting both plants and animals. Of
these, giardiasis caused by protozoan parasite G. lamblia is the most important one
distressing around 280 million people, especially children, around the world [33]. Giardiasis
is often manifested by clinical symptoms like malabsorption, diarrohea, abdominal pain,
nausea and negative impact on overall growth and development [34]. Another important
parasitic disease is trichomoniasis caused by the flagellated protozoan parasite T. vaginalis.
Sexually transmitted diseases caused by this parasite are long been posing a serious threat to
mankind affecting nearly 340 million people every year [35]. Trichomoniasis infected
patients are posed to serious threats of cervical cancer and HIV transmission [36]. The
existing drugs either show low efficacy or are associated with adverse effects and are often
coupled with augmentation of resistant strains thus prompting efforts to develop new
therapeutics [37].
Consequently, organosilatranes FCTSa 7-12 were assayed against G. lamblia and T. vaginalis
and the results revealed that all the organosilatranes exhibited higher potency against G.
lamblia compared to T. vaginalis with IC50 values ranging from 0.57-113.8 µM against
giardial parasites. FCTSa 11 was the most promising candidate displaying the phenomenal
activity against G. lamblia on the exposure of parasites for 24 h while increasing this time to
48 h, FCTSa 7 exhibited best response against this parasite. In general, FCTSa 8 presented
good potency against both the parasites. Biological assay results against T. vaginalis showed
that most of the compounds exhibited comparatively low bioactivity with IC50 ranging from
13

22.90-116.9 µM. FCTSa 10 was the least effective organosilatrane against both the parasites
and at both time points.
Table 4. Antiparasitic activity of silatranes 7-12.
Compounds
G. lamblia
T. vaginalis
IC50 (µM) 24 h
IC50 (µM) 48 h
IC50 (µM) 24 h
IC50 (µM) 48 h
7
8
113.8
6.27
1.57
10.89
9.18
130
115.7
57.72
82.65
116.9
68.10
102.2
38.81
22.90
n.d.
9
17.77
n.d.
10
11
12
81.74
n.d.
0.57
n.d.
87.04
4.25
n.d.
*n.d.: Not determined due to solubility reasons
2.4.3. Antioxidant Assay
The antioxidant effect can be estimated from the ability to scavenge radicals and inhibit
oxidation of biological species [38]. As literature reports, radical scavenging efficacy of
ferrocenyl chalcones is higher than the chalcone itself [39], so synthesised ferrocenyl
chalcones are investigated for their antioxidant activity in aid of which stable radical like
ABTS is used to test the ability of an antioxidant to reduce radicals. The redox action of
Fe(II)/Fe(III) present in ferrocene moiety counts for its abundant antioxidant activity [40].
The Total Antioxidant Activity (TAA) results revealed FCTSa 10 to show the best activity
among all the silatranes while FCTSa 9 was the least effective one.
Table 5. Total Antioxidant Activity expressed in equivalents of ascorbic acid (mM) per mg
of the compounds (7-12).
14

S. No.
TAA (eq.asc) mM mg NP
7
8
7.4±1.5
10.3±0.8
23.0±0.5
5.00±0.07
n.d.
9
10
11
12
15.8±0.3
*n.d.: Not determined due to solubility reasons
3. Experimental
3.1. Chemistry
3.1.1. Starting Material
Propargyl bromide (80% in toluene) (Aldrich), o/p-hydroxyacetophenones (AVRA),
potassium carbonate (Thomas), sodium hydroxide (LOBA Chemie), sodium sulphate (Finar),
sodium
azide
(AVRA),
3-chloropropyltriethoxysilane
(Aldrich),
Bromotris(triphenylphosphine)copper(I) [CuBr(PPh3)3] (Aldrich), triethanolamine (LOBA
Chemie), potassium hydroxide (Finar) were used as received. The organic solvents were
dried according to standard procedures. 3-azidopropyltriethoxysilane (3-AzPTES) was
synthesized from 3-chloropropyltriethoxysilane by known procedure from literature (SI) [41].
3.1.2. Measurements
Infrared spectrum was obtained as Neat on a Thermo Scientific Fischer spectrometer. The
NMR spectra (1H and 13C) were recorded on a JEOL (AL 300 MHz) and BRUKER (400
MHz) spectrometer using CDCl3 as internal reference and chemical shifts were reported
relative to tetramethylsilane. J values are given in Hz. The following abbreviations are used:
s, singlet; d, doublet; q, quartet; t, triplet; m, multiplet. Melting points were measured in a
Mel Temp II device using sealed capillaries and were uncorrected. CHN analysis was
15

obtained on Perkin Elmer Model 2400 CHNS elemental analyzer and Thermo Scientific
Flash 2000 organic elemental analyzer. Mass spectral measurements (TOF MS ESþ 1.38 eV)
were carried out on Waters Q–TOF Micro Mass Spectrometer. Column chromatography was
performed with E. Merck silica gel (Kieselgel 60, 230-400 mesh). Analytical thin layer
chromatography was performed employing 0.2 mm coated commercial silica gel plates (E.
Merck, DC-Aluminium sheets, Kieselgel 60 F254).
3.1.3. General procedure for the synthesis of ferrocenyl chalcone appended triazole allied
triethoxysilanes (1-6)
Acetylinic ferrocene appended chalcones were synthesised following literature reports [42].
(1.0 equiv) of this acetylene was added to 1:1 THF/Et3N solvent mixture taken in a two-neck
round bottomed flask and the mixture was stirred for 15 min at room temperature. Then, slow
addition of AzPTES (1.0 equiv) was done followed by catalyst [CuBr(PPh3)3] (0.01 mmol)
loading and the mixture was stirred at 60 °C for 8-10 h. The reaction was then brought to
room temperature. The solvents were evaporated under reduced pressure followed by the
addition of hexane. The reaction mixture was then filtered and concentration of filtrate under
reduced pressure afforded the viscous red silane in excellent yield (82 to 94%). The
characterization data of all the synthesised silanes was found to be as per the literature
upholdings [42].
3.1.4. General procedure for the synthesis of ferrocenyl chalcone appended triazole allied
organosilatranes (7-12)
1 equiv of organotriethoxysilane (1-6) is taken in a two necked round bottomed flask fitted
with a Dean-Stark assembly followed by the addition of 20 ml toluene, 1 equiv of
triethanolamine and catalytic amount of KOH. The reaction mixture was then refluxed for 4
h. Thereafter, the solvent was evaporated under vacuum and on slow addition of hexane (10
ml), solid precipitated out. The solid so obtained was left for overnight stirring and then
16

filtered under nitrogen and dried under vacuum resulting into desired organosilatranes 7-12 in
excellent yields. The structures of the synthesised hybrids have been detailed in Table 6.
3.1.4.1.
Synthesis
of
(E)-1-(ferrocenyl)-3-(2-((1-(3-(silatranyl)propyl)-1H-1,2,3-
triazol-4-yl)methoxy)-phenyl)prop-2-en-1-one (7): The quantities used were as: 1 (1.00 g,
1.62 mmol), triethanolamine (0.24 g, 1.62 mmol). Dark red solid, Yield: 0.90 g, 89 %. M.P.:
Charring at 110 °C. Anal. Calcd. for C31H36FeN4O5Si: C, 59.23; H, 5.77; N, 8.91. Found: C,
59.19; H, 5.71; N, 8.84. IR (neat, cm-1): 482 (Fe-Cp), 538 (N→Si), 798, 1075 (Si-O), 1235,
1
1376 (CpC=C), 1646 (C=O), 2968 (C=C-H). H NMR (300 MHz, CDCl3, 25 °C): δ 0.37 (s,
2H, -SiCH2-), 1.96 (s, 2H, -CCH2C-), 2.72 (s, 6H, -CH2N-), 3.67 (s, 6H, -OCH2-), 4.09 (s,
5H, FcH), 4.30 (s, 2H, -N3CH2-), 4.47 (s, 2H, FcH), 4.69 (s, 2H, FcH), 5.25 (s, 2H, -OCH2-),
6.95-7.08 (m, 2H, H2, H4), 7.40-7.51 (m, 3H, Hα, H3, H5), 7.60 (s, 1H, Tz-H), 7.89 (d, J =
15.7 Hz, 1H, Hβ). 13C NMR (101 MHz, CDCl3): δ = 12.9 (SiCH2), 26.1 (CCH2C), 49.9
(CH2CH2N), 53.4 (N3CH2), 56.5 (OCH2CH2), 61.3 (OCH2), 69.1, 69.9, 71.6, 80.5 (Fc-C),
113.2 (C3), 116.8 (C5), 122.3, 141.6 (Tz-C), 124.9 (Cα), 127.5 (C1), 131.0 (C4), 131.1 (C6),
135.4 (Cβ), 157.8 (C2), 192.5 (C=O). MS: m/z 629 [M + H]+.
3.1.4.2.
Synthesis
of
(E)-1-(ferrocenyl)-3-(4-((1-(3-(silatranyl)propyl)-1H-1,2,3-
triazol-4-yl)methoxy)-phenyl) prop-2-en-1-one (8): The quantities used were as: 2 (1.00 g,
1.62 mmol), triethanolamine (0.24 g, 1.62 mmol). Dark red solid, Yield: 0.88 g, 87 %. M.P.:
Charring at 180 °C. Anal. Calcd. for C31H36FeN4O5Si: C, 59.23; H, 5.77; N, 8.91. Found: C,
59.16; H, 5.69; N, 8.87. IR (neat, cm-1): 482 (Fe-Cp), 538 (N→Si), 796, 1074 (Si-O), 1254,
1
1377 (CpC=C), 1648 (C=O), 2973 (C=C-H). H NMR (300 MHz, CDCl3, 25 °C): δ 0.35 (s,
2H, -SiCH2-), 1.92 (s, 2H, -CCH2C-), 2.74 (s, 6H, -CH2N-), 3.68 (s, 6H, -OCH2-), 4.14 (s,
5H, FcH), 4.51 (s, 2H, -N3CH2-), 4.68 (s, 2H, FcH), 4.83 (s, 2H, FcH), 5.17 (s, 2H, -OCH2-),
13
6.96 (s, 2H, H2, H6), 7.40 (s, 1H, Hα), 7.54 (s, 2H, H3, H5), 7.67 (s, 2H, Tz-H, Hβ). C
NMR (101 MHz, CDCl3): δ = 13.7 (SiCH2), 26.2 (CCH2C), 51.5 (CH2CH2N), 53.0 (N3CH2),
17

56.6 (OCH2CH2), 61.1 (OCH2), 69.7, 70.1, 72.7, 80.7 (Fc-C), 115.3 (C3, C5), 122.9, 135.2
(Tz-C), 129.9 (Cα), 131.5 (C2, C6), 132.2 (C1), 136.1 (Cβ), 163.3 (C4), 189.7 (C=O).
Synthesis
of
(E)-1-(ferrocenyl)-3-(4-((1-(3-(silatranyl)propyl)-1H-1,2,3-triazol-4-
yl)methoxy)-3-methoxyphenyl)prop-2-en-1-one (9): The quantities used were as: 3 (1.00 g,
1.54 mmol), triethanolamine (0.23 g, 1.54 mmol). Dark red solid, Yield: 0.84 g, 83 %. M.P.:
Charring at 136 °C. Anal. Calcd. for C32H38FeN4O6Si: C, 58.36; H, 5.82; N, 8.51. Found: C,
58.27; H, 5.81; N, 8.46. IR (neat, cm-1): 483 (Fe-Cp), 540 (N→Si), 796, 1074 (Si-O), 1254,
1
1378 (CpC=C), 1644 (C=O), 3072 (C=C-H). H NMR (300 MHz, CDCl3, 25 °C): δ 0.42 (s,
2H, -SiCH2-), 1.97 (s, 2H, -CCH2C-), 2.51 (s, 6H, -CH2N-), 3.75 (s, 6H, -OCH2-), 3.97 (s,
3H, -OCH3), 4.21 (s, 5H, FcH), 4.58 (s, 2H, -N3CH2-), 4.83 (s, 2H, FcH), 4.92 (s, 2H, FcH),
5.25 (s, 2H, -OCH2-), 7.00 (s, 2H, Hα, H5), 7.10-7.16 (m, 2H, H2, H6), 7.46 (s, 1H, Tz-H),
7.71 (d, J = 15.7 Hz, 1H, Hβ). 13C NMR (101 MHz, CDCl3): δ = 13.4 (SiCH2), 27.4
(CCH2C), 49.8 (CH2CH2N), 53.7 (N3CH2), 56.1 (OCH2CH2), 56.7 (OCH3), 60.8 (OCH2),
69.7, 70.1, 72.7, 80.7 (Fc-C), 111.2 (C2), 113.9 (C5), 121.5 (C1), 121.8 (C6), 122.2, 140.8
(Tz-C), 124.0 (Cα), 134.2 (Cβ), 148.6 (C4), 151.8 (C3), 193.0 (C=O). MS: m/z 659 [M +
H]+.
3.1.4.3.
Synthesis
of
(E)-1-(ferrocenyl)-3-(3-((1-(3-(silatranyl)propyl)-1H-1,2,3-
triazol-4-yl)methoxy)-4-methoxyphenyl)prop-2-en-1-one (10): The quantities used were as: 4
(1.0 g, 1.54 mmol), triethanolamine (0.23 g, 1.54 mmol). Dark red solid, Yield: 0.85 g, 84 %.
M.P.: Charring at 122 °C. Anal. Calcd. for C32H38FeN4O6Si: C, 58.36; H, 5.82; N, 8.51.
Found: C, 58.25; H, 5.76; N, 8.43. IR (neat, cm-1): 473 (Fe-Cp), 539 (N→Si), 797, 1074 (Si-
O), 1258, 1376 (CpC=C), 1645 (C=O), 2961 (C=C-H). 1H NMR (300 MHz, CDCl3, 25 °C): δ
0.30 (s, 2H, -SiCH2-), 1.90 (s, 2H, -CCH2C-), 2.69 (s, 6H, -CH2N-), 3.63 (s, 6H, -OCH2-),
3.85 (s, 3H, -OCH3), 4.16 (s, 5H, FcH), 4.25 (s, 2H, -N3CH2-), 4.48 (s, 2H, FcH), 4.89 (s, 2H,
FcH), 5.23 (s, 2H, -OCH2-), 7.05-7.12 (m, 3H, Hα, H2, H3), 7.25 (s, 1H, H6), 7.55-7.62 (m,
18

2H, Tz-H, Hβ). 13C NMR (75 MHz, CDCl3): δ = 13.2 (SiCH2), 26.4 (CCH2C), 51.0
(CH2CH2N), 53.5 (N3CH2), 56.0 (OCH2CH2), 57.6 (OCH3), 61.8 (OCH2), 69.8, 70.2, 72.8,
80.8 (Fc-C), 111.4 (C2), 117.1 (C5), 119.9, 140.7 (Tz-C), 121.3 (C1), 123.2 (C6), 128.6 (Cα),
134.1 (Cβ), 148.0 (C3), 152.9 (C4), 193.1 (C=O).
3.1.4.4.
Synthesis
of
(E)-3-(ferrocenyl)-1-(2-((1-(3-(silatranyl)propyl)-1H-1,2,3-
triazol-4-yl)methoxy)-phenyl)prop-2-en-1-one (11): The quantities used were as: 5 (1.00 g,
1.62 mmol), triethanolamine (0.24 g, 1.62 mmol). Yellow solid, Yield: 0.84 g, 83 %. M.P.:
Charring at 128 °C Anal. Calcd. for C31H36FeN4O5Si: C, 59.23; H, 5.77; N, 8.91. Found: C,
59.17; H, 5.68; N, 8.83. IR (neat, cm-1): 479 (Fe-Cp), 539 (N→Si), 792, 1074 (Si-O), 1256,
1
1376 (CpC=C), 1648 (C=O), 2958 (C=C-H). H NMR (300 MHz, CDCl3, 25 °C): δ 0.38 (s,
2H, -SiCH2-), 1.97 (s, 2H, -CCH2C-), 2.74 (s, 6H, -CH2N-), 3.68 (s, 6H, -OCH2-), 4.10 (s,
5H, FcH), 4.30 (s, 2H, -N3CH2-), 4.48 (s, 2H, FcH), 4.70 (s, 2H, FcH), 5.25 (s, 2H, -OCH2-),
6.98-7.07 (m, 2H, H3, H5), 7.41 (s, 2H, Hα, H4), 7.48 (s, 1H, Tz-H), 7.60 (s, 2H, H6, Hβ).
13C NMR (101 MHz, CDCl3): δ = 13.0 (SiCH2), 26.0 (CCH2C), 51.1 (CH2CH2N), 53.1
(N3CH2), 56.6 (OCH2CH2), 61.4 (OCH2), 69.7, 70.1, 72.7, 80.7 (Fc-C), 115.9 (C3), 121.8
(C5), 122.2, 140.8 (Tz-C), 125.8 (Cα), 128.6 (C6), 129.3 (C1), 135.6 (C4), 136.8 (Cβ), 161.2
(C2), 191.4 (C=O).
3.1.4.5.
Synthesis
of
(E)-3-(ferrocenyl)-1-(4-((1-(3-(silatranyl)propyl)-1H-1,2,3-
triazol-4-yl)methoxy)-phenyl)prop-2-en-1-one (12): The quantities used were as: 6 (1.00 g,
1.62 mmol), triethanolamine (0.24 g, 1.62 mmol). Yellow solid, Yield: 0.86 g, 85 %. M.P.:
138 °C. Anal. Calcd. for C31H36FeN4O5Si: C, 59.23; H, 5.77; N, 8.91. Found: C, 59.19; H,
5.65; N, 8.84. IR (neat, cm-1): 479 (Fe-Cp), 538 (N→Si), 799, 1075 (Si-O), 1257, 1368
1
(CpC=C), 1640 (C=O), 2960 (C=C-H). H NMR (300 MHz, CDCl3, 25 °C): δ 0.38 (s, 2H, -
SiCH2-), 1.97 (s, 2H, -CCH2C-), 2.73 (s, 6H, -CH2N-), 3.68 (s, 6H, -OCH2-), 4.10 (s, 5H,
FcH), 4.30 (s, 2H, -N3CH2-), 4.48 (s, 2H, FcH), 4.70 (s, 2H, FcH), 5.25 (s, 2H, -OCH2-), 6.96
19

-7.06 (m, 2H, H3, H5), 7.40 (s, 1H, Tz-H), 7.48 (s, 1H, Hα), 7.60 (s, 2H, H2, H6), 7.93 (s,
13
1H, Hβ). C NMR (101 MHz, CDCl3): δ = 12.2 (SiCH2), 25.3 (CCH2C), 50.0 (CH2CH2N),
52.5 (N3CH2), 56.5 (OCH2CH2), 61.3 (OCH2), 68.8, 69.1, 71.8, 79.6 (Fc-C), 115.4 (C3, C5),
122.4, 136.6 (Tz-C), 127.6 (Cα), 131.0 (C2, C6), 131.1 (C1), 139.5 (Cβ), 162.4 (C4), 189.0
(C=O).
Table 6. List of ferrocene appended chalcone linked orgnaosilatranes.
O
O
O
N
O
Si
O
N
N
O
O
Si
O
N
N
N
O
Fe
O
N
N
8
Fe
7
O
O
O
O
CH3
O
N
Si
N
Fe
O
O
O
Fe
O
CH3
O
N
N
Si
9
O
N
O
10
N
N
N
O
O
O
N
Si
O
O
N
N
O
O
Si
O
N
Fe
N
O
O
N
N
N
12
Fe
11
3.2. Biological Assays
3.2.1. Antiparasitic Assay
The Giardia lamblia strain Portland 1 (Pl) and Trichomonas vaginalis 413 strain was
maintained axenically on Diamond’s modified TYI-S-33 medium by incubating it at 37 °C.
Drug sensitivity was performed by using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-
20

diphenyltetrazolium bromide, a tetrazole) assay for all Compounds. The highest drug
concentration in each row was 100 μg /ml and then doubling dilutions of the drug were
performed. The plates were incubated at 37 °C for 24 h and 48 h. Following incubation at 37
°C for 24 h and 48 h, the optical density (OD) was measured in an ELISA recorder at 570
nm. IC50 value was calculated using Graph Pad Prism version 6.
3.2.2. Antibacterial and Antifungal Assay
The bacterial and fungal strains used in the study were procured from National Collection of
Pathogenic Fungi (NCPF), Post Graduate Institute of Medical Education and Research
(PGIMER), Chandigarh and Institute of Microbial Technology (MTCC-IMTECH),
Chandigarh. Human embryonic kidney cells (Hek-293) were obtained from American type
culture collection (ATCC-CRL1573). The pathogenic bacterial strains Escherichia coli (E.
coli) MTCC2961, Staphylococcus aureus (S. aureus) MTCC3160, Enterococcus faecalis (E.
faecalis) MTCC 439, Vibrio cholera (V. cholera) MTCC 3906, Streptococcus pyogenes (S.
pyogens) MTCC 442, Listeria monocytogens (L. monocytogens) MTCC839 were cultured in
Muller Hinton broth (MHB, HiMedia, India). The pathogenic fungal strains Candida albicans
(C. albicans) NCPF400034, Candida glabrata (C. glabrata) MTCC3019, Candida krusei (C.
krusei) NCPF44002, Candida parapsilosis (C. parapsilosis) NCPF450002, Candida keyfer
(C. keyfer) NPCPF410004, Candida tropicalis (C. tropicalis) NPCPF420007, Cryptococcus
neoformans (C. neoformans) NCPF250316 were cultured in Yeast Extract-Peptone-Dextrose
(YEPD broth, HiMedia, India) and RPMI 1640 media (HiMedia, India). For agar plates,
bacteriological agar (2.5% w/v, HiMedia, India) was added to the medium. The strains were
stored with glycerol (15%) at -80 °C as frozen stocks. The cells were freshly revived on
respective agar plates from the stock before each experiment.
3.2.3. Total Antioxidant Activity (TAA)
21

TAA was measured in particles using the method of Arnao, Cano and Acosta [43], which is
based on the ability of the antioxidants in the sample to reduce the radical cation of 2,2’-
azino-bis-3-(ethylbenzothiazoline-6-sulphonic acid) (ABTS), determined by the
decolouration of ABTS·+, and measuring the quenching of the absorbance at 730 nm. The
number of single electron in ABTS trapped by anantioxidant can be estimated by means of
chemical kinetics [44]. Furthermore, some new ferrocenylbase are described as novel
antioxidant to protect DNA against oxidation damage [45]. To do the assay, a solution
containing ABTS 2 mM, horseradish peroxidase 0.25 µM and H2O2 35 µM was prepared.
The particles were dissolved in PBS 50 mM pH= 7.5 and 50 µL of the suspension, containing
1 mg 100 µL-1 was added to 950 µL of the ABTS solution. The change of absorbance was
followed at 730 nm for five minutes. This activity is calculated by comparing the values of
the sample with a standard curve of ascorbic acid and expressed as ascorbic acid equivalents
(mmol) per milligram of particle. All the samples were measured per triplicate.
4. Conclusion
The idea of inculcating the active functionality of contrasting agglomerates in a single
chemical coliseum has lead to the revelation of hybrids with broad spectrum of activity
profile. The synthesised ferrocene conjoined chalcone appended triazole linked
organosilatranes were although only passably active against a range of bacterial and fungal
strains but have shown admirable response against precarious giardial and trichomonal
parasites. Ancillary to this is the antioxidant assay that has professed the tested compounds to
array excellent radical scavenging efficacy. Further, peculiar substitutions may be trialled to
augment the biological portrayal of the synthesised composites.
Acknowledgements
22

Aanchal Arora would like to thank CSIR, New Delhi for providing financial support (in the
form of Junior and Senior Research Fellowships). Special thanks to Mr. Avtar Singh, SAIF,
Panjab University, Chandigarh for NMR studies.
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