Design, synthesis and biological evaluation of oxime lacking Psammaplin inspired chemical libraries as anti-cancer agents

Article abstract of DOI:10.1016/j.molstruc.2020.129173

In this study, we attempted the chemical simplification of Psammaplin (PsA), while retaining its activity in vitro. Inspired by the previous Structure Activity Relationship (SAR) studies on various PsA analogues and relying on the fact that oxime is metabolically unstable, we initially designed and synthesized a diverse library of PsA analogues and evaluated for cytotoxic activity. Among 32 compounds of Psammaplin analogues synthesized, the compound 10b was almost equally active as parent Psammaplin in vitro.

Full text of DOI:10.1016/j.molstruc.2020.129173

Journal of Molecular Structure 1225 (2021) 129173
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Design, synthesis and biological evaluation of oxime lacking
Psammaplin inspired chemical libraries as anti-cancer agents
Srinivas Lavanya Kumar Ma, Kasim Alia, Priyank Chaturvedib, Sanjeev Meenab,
Dipak Dattab, Gautam Pandaa,∗
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow 226031, UP, India
b Cancer Biology Division, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow 226031, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, we attempted the chemical simplification of Psammaplin (PsA), while retaining its activity
in vitro. Inspired by the previous Structure Activity Relationship (SAR) studies on various PsA analogues
and relying on the fact that oxime is metabolically unstable, we initially designed and synthesized a di-
verse library of PsA analogues and evaluated for cytotoxic activity. Among 32 compounds of Psammaplin
analogues synthesized, the compound 10b was almost equally active as parent Psammaplin in vitro.
Received 28 April 2020
Revised 24 August 2020
Accepted 26 August 2020
Available online 31 August 2020
Keywords:
© 2020 Elsevier B.V. All rights reserved.
Psammaplin
Colon cancer
Structure-activity relationship (SAR) study
Ideal reaction condition
Cytotoxic
1. Introduction
cause 50% inhibition of cell growth (EC50) by 0.48, 0.39, 1.83 and
3.76 μM to A549, SK-OV-3, HCT15 and HCT15/CL02 cancer cells, re-
Since inception, marine natural products (MNPs) have been a
constant source of antineoplastic drug discovery [1]. ‘Despite be-
ing taxonomically rich, bearing novel chemical signatures, ma-
rine ecosystems are largely underexplored for the drug discovery’.
MNPs have accelerated the drug discovery research providing more
than 8000 new chemical entities in the last decade itself [2]. MNPs
are new age arsenals of drug discovery for anti-cancer therapeu-
tics. Of the 7 clinically approved MNP based drugs, 4 are for an-
ticancer ailments [3]. One of the novel structural classes of MNPs
are bromotyrosine alkaloids. Initial reports on marine bromotyro-
sine derivatives can be dated back to 1913 [4] biological impor-
tance was established in 1967 on the alkaloids isolated from V. Fis-
tularis [5].
spectively’.
PsA was also demonstrated to be an epigenetic regulator
[13] and after careful analysis of previous SAR studies, it could
be stated that the indole derivatives of Psammaplin are more po-
tent modulators of epigenetic enzymes than the original natu-
ral product. Moreover, positional isomers at the bromoindole ring
also showed cell cycle block and apoptosis induction. Incorpora-
tion of an alcohol functional group in place of the putative thiol
afforded inactive compound. It is also revealed that C5-Br of in-
dole could be replaced by other halogens (F, Cl, I) or oxygen sub-
stituents (OMe, OBn) with retention of activity. Dimeric structure is
required for efficient inhibition, as monomeric analogues were in-
active and oxime group is not crucial for anti-cancer activity [14].
Declassifying the structural information [15] on the Psammaplin-A
(PsA) reveals that it’s a “cap-linker-chelator” model [16]. It is well-
known that many disulfide-like pharmacophores function as a pro-
drug. In a cellular environment, the reduced form of disulfide acts
as a chelator blocking the enzymatic activity [17] as evidenced in
the case of pre-treated PsA with H2O2 [18] and functionalising the
thiol to its ester [19]. Several libraries developed on PsA, explicate
the role of oxime and disulfide functionality for the activity (Fig. 1).
With the promising anticancer potency of PsA and in order to
address the concerns associated with the metabolic stability [20] of
the oxime functionality, [21] there has been a lot of interest gen-
erated in developing novel PsA analogues to improve its pharma-
Psammaplin A (PsA) is a bromotyrosine derived, symmetri-
cal bis-conjugate of cystamine which was first isolated from an
unidentified marine sponge in 1987 by Arabshahi and Schmitz [6],
by Quinoa and Crews [7] from Psammaplysilla sp., and by Ro-
driguez, Akee, and Scheuer [8] from Thorectopsamma xana. An-
timicrobial and anticancer activity of Psammaplin A (PsA) was
also established [9–12] and was proven to ‘retard the both bacte-
rial and tumourous cell growth with effective concentrations that
∗
Corresponding author.
E-mail address: gautam_panda@cdri.res.in (G. Panda).
https://doi.org/10.1016/j.molstruc.2020.129173
0022-2860/© 2020 Elsevier B.V. All rights reserved.

2
S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
2. Synthesis
Towards this end, we synthesized simplified analogues of PsA
bearing similar physical properties of PsA in order to retain the
pharmaceutical potency of the parent compound. Commercially
available cinnamic acids and phenyl propionic acid derived cys-
tamine conjugates were synthesized (Scheme 1). Attempting the
direct peptide coupling with the HCl salt of cystamine resulted in
moderate yields. Therefore, neutralizing and extracting [22] cys-
tamine from its commercially available salt, just before the reac-
tion followed by conventional peptide coupling procedures were
developed as ideal reaction conditions. Phenyl propanoic acid 1
was coupled with cystamine and diaminodisulfide groups leading
to 2 and 3. All the attempted cinnamic acids 5a-h were success-
fully coupled with cystamine in good to excellent yields. Even the
diaminodisulfide analogues were synthesised in 68% yield. Thus
psammaplin analogues 3, 4 (Scheme 1) were obtained having 4-
aminophenyl disulfide skeleton instead of cystamine. Commercially
available sulfonyl chlorides 7a-d when treated with the cystamine
is nicely precipitated out of the reaction mixture after adding Et3N
leading to the analogues 8a-8d (Scheme 1). Both electron rich and
deficient analogues were synthesized along with the unsubstituted
sulfonyl chlorides 7a-7d
Fig. 1. Structure of Psammaplin A (PsA).
2.1. Cytotoxic activity
Fig. 2. Approach towards designing of simplified PsA analogs.
We first investigated the anticancer activity of the PsA analogs
into various cell lines (MCF-7, DLD-1, HELA, FADU, A549, SKOV3).
Detailed results of these investigations in terms of percentage in-
hibition of cell growth at 10 μM are given in (Table 1).
ceutical profile. In the present study, a simplified PsA library has
been synthesised lacking the oxime functionality and attempted to
establish structure activity relationships (Fig. 2) in vitro.
After evaluating the biological profile of analogues 2, 3, 4, 6a-
h, 8a-d, we found that both the saturated analogues 2–3 ob-
Scheme 1. Synthetic scheme of Psammaplin analogues.

S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
3
Table 1
List of Psammaplin analogs with their biological properties against Breast MCF-7, Colon DLD-1, Cervical
HELA, Head & Neck FADU, Lung A549 and Ovary SKOV3 cell lines.

4
S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
Scheme 2. Synthesis Scheme of PsA analogs.
tained from phenyl propanoic acid showed moderate inhibition.
Analogues 6a-6h bearing unsaturation in linker didn’t show any
remarkable potency. Even the incorporation of chloro, bromo, flu-
oro, methyl and methoxy group into the benzene ring did not re-
sult into increase in activity. Even the sulfonamide analogues 8a-d,
diaminodisulfide based analogues 3 & 4 (Table 1) were not effec-
tive. At this point, we thought of impregnating the linker with het-
eroatoms such as O, N or S instead of bulky functional groups.
The synthesis of other analogues bearing heteroatoms in the
linker region involves the alkylation of respective phenols, thio-
phenols and anilines with either ethyl 2-bromoacetate or ethyl 2-
bromopropanoate initially. Direct AlMe3 (trimethylaluminum) me-
diated coupling of esters obtained with cystamine showed messy
reaction profile. Therefore, we thought of hydrolysing the ester to
its acid and was subjected to coupling with cystamine. Hydrolysis
was facilitated with LiOH. After consumption of esters in the reac-
tion, pH was acidified and solid obtained was filtered resulting in
the respective acids. Coupling of cystamine with respective acids
of 9a’-l’ (Scheme 2) was facilitated using the coupling conditions
mentioned above (Scheme 1) affording good yields without any
necessity of any further optimization. Compound 12 (Scheme 2)
was prepared from the coupling of previously developed acid (ob-
tained by hydrolysing ester 9a’) with commercially available 5-
amino-1,3,4-thiadiazole-2-thiol 11 (Table 2). Compounds 14a, 14b
(Scheme 2) can be conveniently prepared by alkylating respec-
tive thiophenol with ethyl bromoacetate, hydrolysing their esters
13a’-b’ to acids followed by coupling with cystamine. Analogue 16
(Scheme 2) was synthesized from benzyl cyanate. EDCI.HCl pro-
moted coupling of pyridine 3-propionic acid with cystamine re-
sulted in analogue 18 (Scheme 2).
3. Results and discussion
After synthesizing the second set of psammaplin analogues,
they were evaluated against only colon cancer cell lines DLD-1 as
the PsA itself is potent against colon cancer with 80.41% inhibi-
tion at MIC at 10 μM [23]. Cytotoxic activity of most Psammaplin
analogues were sensitive to substitution on aromatic pendant as
indicated in the (Table 2). Analogues 10a, 10k-m featuring NH and
N-alkylated substitution in linker didn’t show any remarkable po-
tency. Similarly, thio-alkylated analogues 14a-b also showed min-
imal inhibition. Similar to the analogues 3 and 4, any change in
the chelator functionality severely affects the activity once again
as proven in the case of analogue 12. Even the urea derivative 16
showed complete loss of activity. Of the all oxygen doped ana-
logues, 10b and 10c were potent and much precisely analogue
10b was as potent as the PsA. Surprisingly, other oxygen im-
pregnated analogues with aromatic substitutions such as tosyl,
dimethyl amino 10e-i (Table 2) were not active, Fig. 3.

S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
5
Table 2
List of Psammaplin analogs with their biological properties against Colon DLD-1 cell
lines.
Fig. 3. Structure-Activity relationship.
4. Conclusion
Inspired by previous Structure Activity Relationship studies on
various PsA analogues and relying on the fact that oxime is
metabolically unstable, we designed and synthesized an easily ac-
cessible diverse library of PsA like molecules and evaluated for
their cytotoxic activity. Among 32 compounds synthesized, the
oxygen impregnated compound 10b was as potent as the parent
Psammaplin in vitro. This finding may help to discover a promis-
ing Psammaplin based lead compound for further development as
anticancer agents and work towards this direction is currently un-
derway.
4.1. Experimental section
All the starting materials were obtained from commercial
sources and used as such. NMR spectrum were recorded on 300,
400 or 500 MHz spectrometer for 1H NMR, 75 or 100 or 125 MHz
for 13C NMR spectroscopy. Chemical shifts are reported relative
to the residual signals of either tetramethylsilane in CDCl3 or
deuterated DMSO for 1H and 13C NMR spectroscopy. Multiplici-
ties are reported as follows: singlet (s), broad singlet (bs), dou-
blet (d), doublet of doublets (dd), doublet of triplets (dt), triplet
(t), quartet (q), multiplet (m). HRMS were recorded by using Q-
TOF mass spectrometer. Column chromatography was performed
with silica gel (100–200 mesh) as the stationary phase. All reac-
tions were monitored by using TLC. The purity and characteriza-
tion of compounds were further established by using HRMS. HRMS
were recorded by using Q-Tof mass spectrometer. Melting points
are uncorrected and were determined in capillary tubes on SMP
10 melting point apparatus. Commercially available cystamine salt
was neutralized to cystamine using NaOH1 in MeOH. ethyl 2-(4-
(tosyloxy)phenoxy)acetate 8e’ was prepared from its tosyloxy phe-
nol using reported procedure2.
4.2. General procedures for the synthesis Psammalin inspired libraries
general procedure A for the preparation of cystamine conjugates:
To the solution of appropriate acid (1 equiv) in dry DMF was
added to freshly prepared cystamine (0.495 equiv) at 0°C followed
by EDCI.HCl (1.1 equiv) and HOBt (1.1 equiv) under nitrogen. Later
Et3N (3.0 equiv) was added drop-wise at same temp. The result-
ing mixture was shifted to RT and stirred overnight. Organic layer
was partitioned between saturated LiCl solution and EtOAc. Or-
ganic layer dried over Na2SO4 was concentrated and column chro-
matography was performed.
4.3. General procedure B for the preparation of p-amino
phenyldisulfide conjugates:
To the solution of appropriate acid (1 equiv) in dry DMF was
ꢀ
added 4,4 -disulfanediyldianiline (0.495 equiv) at 0°C followed by

6
S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
EDCI.HCl (1.1 equiv) and HOBt (1.1 equiv) under nitrogen. Later
Et3N (3.0 equiv) was added drop-wise at same temp. The result-
ing mixture was shifted to RT and stirred overnight. Organic layer
was partitioned between saturated LiCl solution and EtOAc. Or-
ganic layer was concentrated and column chromatography was
performed.
4.9. Spectral characterization of synthesized compounds ethyl
N-ethyl-N-phenylglycinate 9a’:
4.4. General procedure C for the preparation of sulfanamide
analogues:
Following the experimental proce-
dure E, glycinate ester 9a’ was obtained by refluxing N-ethyl ani-
line in the presence of ethyl bromoacetate as colourless sticky
Commercially available aryl sulfonyl chlorides was added to so-
lution of cystamine (0.495 equiv) in DCM at 0°C followed by Et3N
and stirred at RT for 2 h. After completion of reaction, it was
quenched with satd. NaHCO3 followed by its extraction with DCM.
Dried over Na2SO4 and concentrated to get off-white solids with-
out necessity of further purification.
liquid in 82% yield. Rf
=
0.60 (20% EtOAc/Hexane). 1H NMR
(400 MHz, CDCl3, 25°C): δH 7.23–7.18 (m, 2H), 6.71–6.68 (m, 1H),
6.65–6.62 (m, 2H), 4.18 (q, J =7.16 Hz, 2H), 3.40 (s, 2H), 3.45 (m,
2H), 1.25 (t, J =7.12 Hz, 3H), 1.20 (t, J =7.12 Hz, 3H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δC 171.43, 147.85, 129.26, 116.87,
112.09, 60.92, 52.36, 46.08, 14.24, 12.46 ppm. HRMS (M+H+) calcd
+
for C12H18 NO2 is 208.1332, Observed 208.1335.
4.5. General procedure D for the preparation of 2-phenoxy
acetate/propanotes or 2-phenyl acetate/propanotes:
To the solution of phenol (1 equiv) was added K2CO3 (2 equiv),
ethyl 2-bromo acetate/propanoate (1.5 equiv) in freshly distilled
acetone, was added a pinch of KI and refluxed overnight. After the
completion of reaction, acetone was distilled off and reaction mix-
ture was partitioned between saturated brine solution and ethyl
acetate. Organic layer was collected, dried over Na2SO4, concen-
trated and column chromatography was performed.
4.10. ethyl 2-(4-methoxyphenoxy)acetate 9b’:
4.6. General procedure E for the preparation of 2-phenyl amino
acetate/propanotes:
Following the experimen-
tal procedure D, aryloxy ester 9b’ was obtained by refluxing 4-
methoxy phenol in the presence of ethyl bromoacetate as oil in
91% yield. Rf = 0.5 (10% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3,
25°C): δH 6.89–6.82 (m, 4H), 4.57 (s, 2H), 4.27 (q, J= 7.14 Hz, 2H),
3.77 (s, 3H), 1.30 (t, J = 7.12 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δC 169.20, 154.56, 152.07, 115.90, 114.68, 66.38,
To the solution of amine (1 equiv) was added K2CO3 (2 equiv),
2-bromo acetate/propanoate (1.1 equiv) in freshly distilled acetone,
added a pinch of KI and refluxed overnight. After the completion of
reaction, acetone was distilled off and reaction mixture was parti-
tioned between saturated brine solution and ethyl acetate. Organic
layer was collected, dried over Na2SO4, concentrated and column
chromatography was performed.
+
61.26, 55.66, 14.16, ppm. HRMS (M+H+) calcd for C11 H15O4 is
211.0965, Observed 211.0970.
4.7. General procedure F for the hydrolysis of esters to acid:
4.11. ethyl 2-(4-bromophenoxy)acetate 9c’:
To the solution of acetate/propanoate in THF:H2O (1:1) was
added 2.0 equiv of LiOH, and stirred for 2–3 hrs. When the es-
ter was fully consumed, THF was evaporated and aq.NaHCO3 was
added and worked up with ethyl acetate. Organic layer was dis-
carded and the pH of aqueous layer was adjusted to 2. Then the
acid was extracted with ethyl acetate. Ethyl acetate extracts were
dried over sodium sulfate and was concentrated to give off-white
to white solids.
Following the experimen-
tal procedure D, aryloxy ester 9c’ was obtained by refluxing 4-
bromo phenol in the presence of ethyl bromoacetate as brown
color sticky liquid in 72% yield. Rf = 0.5 (8% EtOAc/Hexane). 1H
NMR (400 MHz, CDCl3, 25°C): δH 7.40–7.36 (m, 2H), 6.80–6.77 (m,
2H), 4.58 (s, 2H), 4.26 (q, J=7.12 Hz, 2H), 1.28 (t, J=7.16 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δC 168.55, 156.92, 132.39,
116.52, 114.03, 65.55, 61.47, 14.15, ppm. HRMS (M+H+) calcd for
4.8. General procedure G for the urea analogue 16:
To the solution of cystamine (0.5 equiv) in THF at 0°C was
added benzyl isocyanate (1 equiv) and allowed stir for 2 hrs at
the same temperature. Solid was precipitated out of the solution
which was filtered out and washed with DCM 2–3 times resulting
in white solid of urea analogue 16.
+
C10H12BrO3 is 260.1065, Observed 260.1049.

S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
7
4.12. ethyl 2-(4-(dimethylamino)phenoxy)acetate 9d’:
4.15. ethyl 2-(2-nitrophenoxy)acetate 9h’:
Following the experimental
procedure D, aryloxy ester 9h’ was obtained by refluxing 2-nitro-
phenol in the presence of ethyl bromoacetate as yellow amorphous
solid in 54% yield. M.P. 70°C. Rf = 0.65 (20% EtOAc/Hexane). 1H
NMR (400 MHz, CDCl3, 25°C): 7.84 (dd, J=1.24 Hz, 8.25 Hz, 1H),
7.53–7.49 (m, 1H), 7.11–7.07 (m, 1H), 7.00 (dd,J=0.94 Hz, 8.46 Hz,
1H), 4.76 (s, 2H), 4.25 (q, J =7.12 Hz, 2H), 1.27 (t, J=6.93 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δC 167.74, 151.25, 140.36,
134.07, 125.75, 121.70, 115.19, 66.50, 61.69, 14.03 ppm. HRMS
Following the experimental procedure
D, aryloxy ester 9d’ was obtained by refluxing 4-dimethylamino
phenol in the presence of ethyl bromoacetate as oil in 81% yield..
Rf = 0.4 (30% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3, 25°C): δH
7.12 (t, J= 8.15 Hz, 1H), 6.39–6.37 (m, 1H), 6.33 (t, J= 2.35 Hz, 1H),
6.22 (dd, J1= 2.19 Hz, J2 = 8.09 Hz, 1H), 4.60 (s, 2H), 4.26 (q, J=
7.24 Hz, 2H), 2.92 (s, 6H), 1.30 (t, J= 7.10 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δC 169.99, 158.76, 151.79, 129.53, 106.42,
101.34, 99.85, 65.27, 61.03, 40.28, 13.98 ppm. HRMS (M+H+) calcd
+
(M+H+) calcd for C10H12NO5 is 226.0710, Observed 226.0711.
+
for C12H18 NO3 is 224.1281, Observed 224.1276
4.16. ethyl 2-(2-bromo-4-methylphenoxy)acetate 9i’:
4.13. ethyl 2-(3,4,5-trimethoxyphenoxy)acetate 9f’:
Following the experimental
procedure D, aryloxy ester 9i’ was obtained by refluxing 2-bromo-
4-methyl-phenol in the presence of ethyl bromoacetate as yellow
oil in 76% yield. Rf = 0.4 (12% EtOAc/Hexane). 1H NMR (400 MHz,
CDCl3, 25°C): 7.36 (d, J= 1.16 Hz, 1H), 7.01 (dd, J1= 1.08 Hz, J2=
7.72 Hz, 1H), 6.72 (d, J= 6.68 Hz, 1H), 4.64 (s, 2H), 4.25 (q, J=
5.72 Hz, 2H), 2.26 (s, 3H), 1.28 (t, J= 5.72 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δC 168.57, 152.42, 134.05, 132.92, 128.82,
113.94, 112.22, 66.69, 61.39, 20.19, 14.14 ppm. HRMS (M+H+) calcd
Following the experimental pro-
cedure D, aryloxy ester 9f’ was obtained by refluxing trimethoxy
phenol in the presence of ethyl bromoacetate as white solid in
85% yield. M.p. 110 °C. Rf = 0.43 (30% EtOAc/Hexane). 1H NMR
(400 MHz, CDCl3, 25°C): δH 6.19–6.18 (m, 2H), 4.58 (s, 2H), 4.28
(q, J=7.20 Hz, 2H), 3.83 (s, 6H), 3.78 (s, 3H), 1.31 (t, J=7.12 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δC 168.86, 154.42, 153.73,
133.10, 92.75, 65.95, 61.39, 60.97, 56.11, 14.18 ppm. HRMS (M+H+)
+
+
calcd for C13H19O6 is 271.1176, Observed 271.1173.
for C11 H14 BrO3 is 273.0121, Observed 273.0119.
4.17. ethyl 2-(2-ethylphenoxy)acetate 9j’:
4.14. ethyl 2-(2-bromo-4-methoxyphenoxy)acetate 9g’:
Following the experimental pro-
cedure D, aryloxy ester 9g’ was obtained by refluxing correspond-
ing phenol in the presence of ethyl bromoacetate resulting oil
in 76% yield. Rf = 0.60 (30% EtOAc/Hexane). 1H NMR (400 MHz,
CDCl3, 25°C): δH 7.14–7.12 (m, 2H), 6.87–6.86 (m, 1H), 6.79 (dd,
J =8.84, 2.92 Hz, 1H), 4.64 (s, 2H), 4.31–4.25 (t, J=6.04 Hz, 2H),
3.78 (s, 3H), 1.41–1.22 (t, J=6.51 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δC 168.75, 155.12, 148.97, 120.05, 118.98, 116.02,
113.76, 67.64, 61.36, 55.87, 14.15 ppm. HRMS (M+H+) calcd for
Following the experimental
procedure D, aryloxy ester 9j’ was obtained by refluxing 2-ethyl-
phenol in the presence of ethyl bromoacetate as colourless oil in
81% yield. Rf = 0.6 (8% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3,
25°C): δH 7.17–7.09 (m, 2H), 6.93–6.89 (m, 1H), 6.70 (d, J= 8.16 Hz,
1H), 4.60 (s, 2H), 4.23 (q, J= 7.16 Hz, 2H), 2.71 (q, J= 7.52 Hz,
2H), 1.28–1.20 (q, 6H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δC
169.13, 155.80, 133.26, 129.36, 126.73, 121.59, 111.26, 65.64, 61.16,
+
23.32, 14.120, 14.14 ppm. HRMS (M+H+) calcd for C12H17 O3 is
+
C11 H14 BrO4 is 289.0070, Observed 289.0071.
209.1172, Observed 209.1169.

8
S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
4.18. ethyl (2-bromo-–4-methylphenyl)glycinate 9k’:
4.21. ethyl 2-(p-tolylthio)acetate 13a’:
Following the experimental proce-
dure D, arylthioacetate 13a’ was obtained by refluxing 4-methyl-
thiophenol in the presence of ethyl bromoacetate as yellow oil in
82% yield. Rf= 0.7 (10% EtOAc/Hexane). 1H NMsR (400 MHz, CDCl3,
25°C): δH 7.32 (d, J= 8.14 Hz, 2H), 7.10 (d, J= 8.14 Hz, 2H), 4.15 (q,
J= 7.15 Hz, 2H), 3.57 (s, 2H), 2.31 (s, 3H), 1.21 (t, J= 7.12 Hz, 3H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δC 169.60, 137.11, 130.77,
129.58, 61.22, 37.24, 20.83, 13.87 ppm. HRMS (M+H+) calcd for
C11 H15O2S+ is 211.0787; Observed 211.0792.
Following the experimental pro-
cedure E, arylamino ester 9k’ was obtained by refluxing 2-bromo-
4-methyl-amine in the presence of ethyl bromoacetate as yellow
oil in 76% yield. Rf = 0.4 (12% EtOAc/Hexane). 1H NMR (400 MHz,
CDCl3, 25°C): 7.28 (d, J= 1.4 Hz,1H), 6.99–6.96 (m, 1H), 6.42 (d,
J= 8.18 Hz, 1H), 4.79 (s,1H), 4.24 (q, J= 7.16, 2H), 3.91 (d, J=
5.27 Hz, 2H), 2.22 (s, 3H), 1.29 (t, J= 7.16 Hz, 3H), ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δC 170.61, 141.80, 132.99, 128.99, 111.38,
109.95, 61.39, 46.05, 20.01, 14.18 ppm. HRMS (M+H+) calcd for
+
C11 H15BrNO2 is 272.0281, Observed 272.0279.
4.22. ethyl 2-((4-hydroxyphenyl)thio)acetate 13b’:
4.19. ethyl (4-fluorophenyl)alaninate 9l’:
Following the experimental pro-
cedure D, arylthioacetate 13b’ was obtained by refluxing 4-
mercaptophenol in the presence of ethyl bromoacetate as colour-
less oil in 67% yield. Rf = 0.35 (50% EtOAc/Hexane). 1H NMR
(400 MHz, CDCl3, 25°C): δH 7.36–7.34 (m, 2H), 6.76–6.73 (d,
J=8.71 Hz, 2H), 5.06 (s, 1H), 4.17 (q, J=7.17 Hz, 2H), 3.51 (s,
2H), 1.25 (t, J=7.21 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δC 170.93, 156.79, 156.74, 134.68, 116.42, 61.72, 38.82,
14.06 ppm. HRMS (M+H+) calcd for C10H12O3S+ is 213.0580, Ob-
served 213.0578.
Following the experimental proce-
dure E, arylamino acetate of 9l’ was obtained by refluxing 4-
fluoroaniline in the presence of ethyl-2- bromopropanoate as oil
in 48% yield. Rf = 0.42 (50% EtOAc/Hexane). 1H NMR (400 MHz,
CDCl3, 25°C): δH 6.92–6.88 (m, 2H), 6.59–6.56 (m, 2H), 4.20 (q,
J=7.12 Hz, 2H), 4.07 (q, J=6.95 Hz, 2H), 1.47 (d, J=6.94 Hz, 3H),
1.26 (t, J=7.14 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δC
174.58, 157.47, 155.12, 143.02, 115.86, 115.64, 114.56, 114.48, 61.14,
+
52.77, 18.89, 14.17 ppm. HRMS (M+H+) calcd for C11 H15FNO2 is
212.1081 Observed 212.1075.
ꢀ
4.20. ethyl (4-methoxyphenyl)alaninate 9m’:
4.23. (2E,2 E)-N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
(3-(4-chlorophenyl) acrylamide) 6a:
Following the experimental proce-
dure E, arylamino acetate of 9m’ was obtained by refluxing 4-
methoxy aniline in the presence of ethyl-2- bromopropanoate as
oil in 68% yield. Rf = 0.32 (50% EtOAc/Hexane). 1H NMR (400 MHz,
CDCl3, 25°C): δH 6.76 (d, J=8.96 Hz, 2H), 6.58 (d, J=8.96 Hz, 2H),
4.16 (q, J=7.12 Hz, 2H), 4.04 (q, J=6.96 Hz, 1H), 3.73 (s, 3H),
1.44 (d, J=6.96 Hz, 3H), 1.23 (t, J=7.12 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δC 174.87, 152.72, 140.76, 115.08, 114.84,
60.96, 55.66, 53.13, 18.99, 14.15 ppm. HRMS (M+H+) calcd for
Following the experimental pro-
cedure A, psammaplin analogue 6a was obtained from the cou-
pling reaction between cinnamic acid 5a and cystamine as white
solid in 84% yield. M.P. 238 °C. Rf = 0.42 (70% EtOAc/Hexane).1H
NMR (400 MHz, DMSO-D6, 25 °C): δH 8.38 (t, J=5.66 Hz, 2H), 7.60–
7.57 (m, 4H), 7.47–7.40 (m, 6H), 6.67 (d, J=15.67 Hz, 2H), 3.49 (q,
J=6.45 Hz, 4H), 2.87 (t, J=6.76 Hz, 4H) ppm. 13C NMR (100 MHz,
DMSO-D6, 25 °C): δC 165.39, 137.99, 134.36, 134.29, 129+.70, 129.41,
123.26, 38.59, 37.77 ppm. m/z calcd for C22H29N2O2S2 [M+H]+:
417.1665, observed: 417.1662.
+
C12H18 NO3 is 224.1281, observed 224.1273.

S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
9
ꢀ
ꢀ
4.24. (2E,2 E)-N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
(3-(3-chlorophenyl) acrylamide) 6b:
4.27. (2E,2 E)-N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
(3-(4-bromophenyl) acrylamide) 6e:
Following the experimental pro-
Following the experimental
procedure A, psammaplin analogue 6e was obtained from the cou-
pling reaction between cinnamic acid 5e and cystamine as white
amorphous powder in 67% yield. M.P. 258 °C. Rf = 0.60 (65%
EtOAc/Hexane). 1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.35 (d,
J=5.49 Hz, 2H), 7.61–7.50 (m, 8H), 7.40 (d, J=15.91 Hz, 2H), 6.65
(d, J=15.91 Hz, 2H), 3.48 (q, J=5.74 Hz, 4H), 2.87 (t, J=6.44 Hz,
4H) ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C): δC 165.37, 138.11,
134.61, 132.34, 129.95, 123.28, 123.10, 38.59, 37.75 ppm. m/z calcd
cedure A, psammaplin analogue 6b was obtained from the cou-
pling reaction between cinnamic acid 5b and cystamine as white
solid in 71% yield. M.P. 149 °C. Rf = 0.40 (75% EtOAc/Hexane). 1H
NMR (400 MHz, DMSO-D6, 25 °C): δH 8.34 (t, J=5.59 Hz, 2H), 7.63
(bs, 2H), 7.55- 7.52 (m, 2H), 7.44–7.40 (m, 6H), 6.70(d, J=15.93 Hz,
2H), 3.49 (q, J=6.46 Hz, 4H), 2.88 (t, J=6.74 Hz, 4H) ppm. 13C
NMR (100 MHz, DMSO-D6, 25 °C): δC 165.26, 137.81, 137.65, 134.13,
131.20, 129.56, 127.66, 126.50, 124.12, 38.58, 37.71 ppm. m/z calcd
for C22H23Cl2N2O2S2 [M+H]+: 481.0573, observed: 481.0571.
+
+
for C22H23Br2N2O2S2 [M+H]+: 568.9562, observed 568.9581.
ꢀ
ꢀ
4.28. (2E,2 E)-N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
4.25. (2E,2 E)-N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
(3-(2-chlorophenyl) acrylamide) 6f:
(3-(4-fluorophenyl) acrylamide) 6c:
Following the experimental
procedure A, psammaplin analogue 6c was obtained from the cou-
pling reaction between cinnamic acid 5c and cystamine as white
solid in 64% yield. M.P. 187 °C. Rf = 0.55 (70% EtOAc/Hexane).
1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.32 (t, J=5.49 Hz, 2H),
7.62(q, J=5.60 Hz, 4H),7.43 (d, J=15.80 Hz, 2H), 7.23 (t, J=8.84 Hz,
4H), 6.59 (d, J=15.80 Hz, 2H),3.49 (q, J=6.29 Hz, 4H), 2.87 (t,
J=6.38 Hz, 4H) ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C): δC
165.52, 164.39, 161.93, 138.18, 131.95, 131.92, 130.19, 130.11, 122.32,
Following the experimental pro-
cedure A, psammaplin analogue 6f was obtained from the coupling
reaction between cinnamic acid 5f and cystamine as white powder
in 65% yield. Rf = 0.30 (70% EtOAc/Hexane). M.P. 149 °C. 1H NMR
(400 MHz, DMSO-D6, 25 °C): δH 8.46(t, J=5.65 Hz, 2H), 7.76–7.70
(m, 4H), 7.53–7.50 (m, 2H), 7.41–7.38 (m, 4H), 6.70 (d, J=15.62 Hz,
2H), 3.51 (q, J=6.38 Hz, 4H), 2.89 (t, J=6.80 Hz, 4H) ppm. . 13C
NMR (100 MHz, DMSO-D6, 25 °C): δC 165.10, 134.69, 133.77, 133.13,
131.39, 130.43, 128.21, 128.037, 125.48, 38.63, 37.66 ppm. m/z calcd
+
+
for C22H23Cl2N2O2S2 [M + H]+: 481.0573, observed 481.0571.
116.45, 116.23, 38.58, 37.78 ppm. m/z calcd for C22H23F2N2O2S2
[M+H]+: 449.1164, Observed 449.1159.
ꢀ
4.29. (2E,2 E)-N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
ꢀ
acrylamide) 6d:
(3-(2-methoxyphenyl) acrylamide) 6g:
4.26. (2E,2 E)-N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(3-(p-tolyl)
Following the experimental pro-
cedure A, psammaplin analogue 6 g was obtained from the cou-
pling reaction between cinnamic acid 5 g and cystamine as white
solid in 73% yield. M.p. 185 °C. Rf = 0.62 (75% EtOAc/Hexane). 1H
NMR (400 MHz, DMSO-D6, 25 °C): δH 8.27(t, J=5.10 Hz, 2H), 7.68
(d, J=15.87 Hz, 2H), 7.51 (d, J=7.37 Hz, 2H), 7.38–7.34 (m, 2H), 7.06
(d, J=8.22 Hz, 2H), 6.97 (t, J=7.60 Hz, 2H), 6.66 (d, J=15.81 Hz, 2H),
3.85 (s, 6H), 3.49 (q, J=6.28 Hz, 4H), 2.8 (t, J=6.89 Hz, 4H) ppm. 13C
NMR (100 MHz, DMSO-D6, 25 °C): δC 166.01, 158.04, 134.47, 131.32,
128.35, 123.77, 122.79, 121.15, 112.18, 56.03, 38.62, 37.85 ppm. m/z
Following the experimental
procedure A, psammaplin analogue 6d was obtained from the cou-
pling reaction between cinnamic acid 5d and cystamine as off-
white solid in 79% yield. M.P. 213 °C. Rf = 0.4 (75% EtOAc/Hexane).
1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.29 (t, J=5.67 Hz, 2H),
7.45–7.38 (m, 6H), 7.2 (d, J=8.06 Hz, 4H), 6.59 (d, J=15.87 Hz, 2H),
3.49 (q, J=6.45 Hz, 4H), 2.87(t, J=6.78 Hz, 4H), 2.31(s, 6H) ppm.
13C NMR (100 MHz, DMSO-D6, 25 °C): δC 165.75, 139.70, 139.33,
132.55, 129.98, 127.98, 121.37, 38.57, 37.84, 21.39 ppm. m/z calcd
for C24H29N2O2S2+ [M+H]+: 441.1665, observed 441.1659
+
calcd for C24H29N2O4S2 [M+H]+: 473.1563, observed 473.1565.

10
S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
ꢀ
ꢀ
4.30. (2Z, 2 Z)-N,N’-(disulfanediylbis(ethane-2,
1-diyl))bis(2-acetamido-3-phenylacrylamide) 6h:
4.33. (2E,2 E)-N,N’-(disulfanediylbis(4,1-phenylene))bis
(3-(3-chlorophenyl) acrylamide) 4:
Following the exper-
imental procedure A, psammaplin analogue was obtained
Following the experimental
4
procedure A, psammaplin analogue 6 h was obtained from the
coupling reaction between corresponding commercially available
cinnamic acid 5 h and cystamine leading to light yellow solid in
62% yield. M.P. 206 °C. Rf = 0.43 (80% EtOAc/Hexane). 1H NMR
(400 MHz, DMSO-D6, 25 °C): δH 9.42 (bs, 2H), 8.21(t, J=5.63 Hz,
2H), 7.53 (d, J=7.53 Hz, 4H), 7.41 (t, J=6.89 Hz, 4H), 7.34–7.30
(m, 2H), 7.04 (s, 2H), 3.45 (q, J=6.19 Hz, 4H), 2.85 (t, J=7.43 Hz,
4H), 1.99 (s, 6H) ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C): δC
169.91, 165.63, 134.65, 130.57, 129.80, 12+8.99, 128.11, 39.39, 37.44,
23.34 ppm. m/z calcd for C26H31N4O4S2 [M+H]+: 527.1781, ob-
served 527.1780.
from the coupling reaction between cinnamic acid 5b and 4-
aminophenyl disulfide as off-white solid in 58% yield. M.p. 255 °C.
Rf = 0.60 (65% EtOAc/Hexane). 1H NMR (400 MHz, DMSO-D6, 25
°C): δH 10.34 (s, 2H), 7.74–7.70 (m, 6H), 7.61–7.57 (m, 4H), 7.52–
7.47 (m, 8H), 6.87 (d, J=15.75 Hz, 2H) ppm. 13C NMR (100 MHz,
DMSO-D6, 25 °C): δC 163.78, 139.72, 139.35, 137.20, 134.20, 131.33,
130.45, 129.93, 1+27.92, 126.67, 124.19, 120.49 ppm. m/z calcd for
C30H23Cl2N2O2S2 [M+H]+: 577.0573, observed 577.0590.
4.34. N,N’-(disulfanediylbis(ethane-2,1-diyl))dibenzenesulfonamide 8a
4.31. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(3-phenylpropanamide)
2:
Following the experimental proce-
dure C, psammaplin analogue 8a was obtained from the coupling
reaction between the commercially available sulfonyl chloride 7a
and cystamine leading to white crystals in 71% yield. M.p. 95 °C.
Rf = 0.3 (10% Methanol/DCM).1H NMR (400 MHz, DMSO-D6, 25
°C): δH 7.89–7.87 (m, 4H), 7.62–7.57 (m, 2H), 7.56–7.49 (m, 4H),
5.18 (t, J=6.48 Hz, 2H), 3.25 (q, J=6.47 Hz, 4H), 2.71 (t, J=6.47 Hz,
4H) ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C): δC 139.76, 132.91,
Following the experimental proce-
dure A, psammaplin analogue 2 was obtained from the coupling
reaction between phenyl propionic acid and cystamine as white
solid in 76% yield. M.p. 128 °C. Rf = 0.52 (30% EtOAc/Hexane). 1H
NMR (400 MHz, CDCl3, 25°C): δH 7.27–7.25 (m, 4H), 7.20–7.17 (m,
6H), 6.23 (bs, 2H), 3.51 (q, J=6.38 Hz, 1H), 2.97 (t, J=7.35 Hz, /4H),
2.72 (t, J=6.39 Hz, 4H), 2.55–2.51 (m, 4H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δC 172.64, 140.77, 128.52, 128.36, 126.27, 38.35,
+
129.28, 127.03, 41.66, 37.94 ppm. m/z calcd for C16 H21N2O4S4
[M+H]+: 433.0379, observed 433.0378.
+
38.25, 37.75, 31.67 ppm. m/z calcd for C22H29N2O2S2 [M+H]+:
417.1665, observed: 417.1662.
4.35. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(4-(trifluoromethyl)
benzene sulfonamide) 8b:
4.32. N,N’-(disulfanediylbis(4,1-phenylene))bis(3-phenylpropanamide)
3:
Following the experimental
procedure C, psammaplin analogue 8b was obtained from
the coupling reaction between the commercially available 4-
(trifluoromethyl)benzene sulfonyl chloride 7b and cystamine lead-
ing to amorphous solid in 71% yield. M.p. 145 °C. Rf = 0.51
(8% Methanol/DCM).1H NMR (400 MHz, DMSO-D6, 25 °C): δH
8.12 (t, J=5.78 Hz, 2H), 8.03–7.98 (m, 8H), 3.06 (q, J=6.40 Hz,
4H), 2.69 (t, J=6.83 Hz, 4H) ppm. 13C NMR (100 MHz, DMSO-D6,
25 °C): δC 144.83, 133.19, 132.87, 132.55, 132.23, 127.92, 126.99,
126.95, 126.91, 125.32, 122.61, 42.08, 37.57 ppm. m/z calcd for
Following the experimen-
tal procedure A, psammaplin analogue
3
was obtained from
ꢀ
the coupling reaction between phenyl propionic acid and 4,4 -
disulfanediyldianiline as white solid in 68% yield. M.P. 201 °C.
Rf = 0.52 (56% EtOAc/Hexane).1H NMR (400 MHz, DMSO-D6, 25
°C): δH 10.06 (s, 2H), 7.62–7.58 (m, 4H), 7.45–7.41 (m, 4H), 7.30–
7.15 (m, 10H), 2.93–2.87 (m, 4H), 2.66–2.60 (m, 4H) ppm. 13C NMR
(100 MHz, DMSO-D6, 25 °C): δC 171.06, 141.55, 139.86, 130.60,
129.89, 128.78, 12+8.68, 126.42, 120.23, 38.40, 31.18 ppm. m/z calcd
for C30H29N2O2S2 [M+H]+: 513.1665, observed: 513.1665.
+
C18 H19 F6N2O4S4 [M+H]+: 569.0126, observed 569.0117.

S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
11
4.36. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
(2-bromobenzenesulfonamide) 8c:
4.39. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
(2-(4-methoxyphenoxy)acetamide) 10b:
Following the experimental procedure
Ester 9b’ was hydrolysed to its
acid following general procedure F. Acid obtained was directly
used for coupling with cystamine following the experimental pro-
cedure A resulting psammaplin analogue 10b which is of white
amorphous powder in 84% yield. M.P. 129 °C. Rf = 0.55 (60%
EtOAc/Hexane).1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.22 (t,
J=5.61 Hz, 2H), 6.93–6.85 (m, 8H), 4.43 (s, 4H), 3.69 (s, 6H), 3.43
(q, J=6.29 Hz, 4H), 2.8 (t, J=7.44 Hz, 4H) ppm. 13C NMR (100 MHz,
DMSO-D6, 25 °C): δC 168.52, 154.34, 152.18, 116.26, 115.05, 68.22,
C, psammaplin analogue 8c was obtained from the coupling re-
action between the commercially available 2-bromophenyl sul-
fonyl chloride 7c and cystamine leading to light yellow crystals
in 63% yield. M.P. 131 °C. Rf = 0.62 (8% Methanol/DCM). 1H NMR
(400 MHz, CDCl3, 25 °C): δH 8.13 (dd, J=7.63, 1.97 Hz, 2H), 7.74
(dd, J=7.77, 1.27 Hz, 2H), 7.50–7.41 (m, 4H), 5.55 (t, J=6.02 Hz,
2H), 6.45 (q, J=6.28 Hz, 4H), 2.69 (t, J=6.28 Hz, 4H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δC 138.64, 135.18, 133.93, 131.56,
+
127.94, 119.79, 41.58, 37.40 ppm. m/z calcd for C16 H19 Br2N2O4S4
[M+H]+: 588.8589, observed 585.8581.
+
55.84, 38.27, 37.49 ppm. m/z calcd for C22H29N2O6S2 [M+H]+:
481.1462, observed 481.1443.
4.40. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-(4-bromophenoxy)
acetamide) 10c
4.37. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
(2-bromobenzenesulfonamide) 8d:
Ester 9c’ was hydrolysed to its
acid following general procedure F. Acid obtained was directly used
for coupling with cystamine following the experimental procedure
A resulting psammaplin analogue 10c which is of amorphous solid
in 81% yield. M.p. 117 °C. Rf = 0.51 (50% EtOAc/Hexane). 1H NMR
(400 MHz, DMSO-D6, 25 °C): δH 8.28 (t, J=5.77 Hz, 2H), 7.46 (d,
J=9.06 Hz, 4H), 6.93 (d, J=9.00 Hz, 4H), 4.48 (s, 4H), 3.46–3.41 (m,
4H), 2.83 (t, J =6.84 Hz, 4H) ppm. 13C NMR (100 MHz, DMSO-
D6, 25 °C): δC 168.04, 157.43, 132.59, 117.55, 113.15, 67.55, 38.27,
Following the experimental
procedure C, psammaplin analogue 8d was obtained from
the coupling reaction between the commercially available 3-
methoxyphenyl sulfonyl chloride 7d and cystamine leading to
yellow oil in 85% yield. Rf = 0.45 (10% Methanol/DCM). 1H NMR
(400 MHz, CDCl3, 25 °C): δH 7.47–7.38 (m, 6H), 7.13–7.09 (m, 2H),
5.11 (t, J=6.20 Hz, 2H), 3.9 (s, 6H), 3.26 (q, J=6.36 Hz, 4H), 2.71 (t,
J=6.36 Hz, 4H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δC 160.07,
140.92, 130.33, 119.28, 119.15, 111.76, 55.74, 41.69, 38.01 ppm. m/z
+
37.46 ppm. m/z calcd for C20H23Br2N2O4S2 [M+H]+: 576.9461, ob-
+
calcd for C18 H25N2O6S4 [M+H]+: 493.0590, observed 493.0587.
served 576.9464.
4.41. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis
(2-(4-(dimethylamino)phenoxy)acetamide) 10d:
4.38. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-(ethyl(phen5yl)
amino)acetamide) 10a:
Ester 9d’ was hydrolysed to
its acid following general procedure F. Acid obtained was directly
used for coupling with cystamine following the experimental pro-
cedure A resulting psammaplin analogue 10d which is of amor-
phous yellow solid in 81% yield. M.P. 110 °C. Rf = 0.51 (50%
EtOAc/Hexane). 1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.22 (t,
J= 5.64 Hz, 2H), 7.07 (t, J= 8.16 Hz, 2H), 6.35 (dd, J1= 2.2 Hz,
J2= 8.24 Hz, 2H), 6.29 (t, J= 2.16 Hz, 2H), 6.25 (dd, J1= 2.28 Hz,
J2= 8.00 Hz, 2H), 4.26 (s, 4H), 3.44 (q, J= 6.44 Hz, 4H), 2.87–
2.82 (m, 16H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δC 169.13,
158.59, 152.23, 130.25, 106.99, 102.24, 99.59, 67.53, 40.69, 38.17,
Ester 9a’ was hydrolysed to its acid
following general procedure F. Acid obtained was directly used for
coupling with cystamine following the experimental procedure A
resulting psammaplin analogue 10a which is solid in 76% yield.
M.P. 108 °C. Rf = 0.40 (60% EtOAc/Hexane). 1H NMR (400 MHz,
DMSO-D6, 25 °C): δH 8.00 (t, J=5.49 Hz, 2H), 7.15 (t, J=7.53 Hz,
4H), 6.63–6.59 (m, 6H), 3.78 (s, 4H), 3.42–3.37(m, 8H), 2.75 (t,
J=6.76 Hz, 4H), 1.08 (t, J=6.96 Hz, 6H) ppm. 13C NMR (100 MHz,
DMSO-D6, 25 °C): δC 170.56, 148.40, 129.43, 116.54, 112.45, 54.27,
+
+
45.65, 38.38, 37.61, 12.05 ppm. m/z calcd for C24H35N4O2S2
[M+H]+: 475.2196, observed 475.2186.
37.80 ppm. m/z calcd for C24H35N4O4S2 [M+H]+: 507.2094, ob-
served 507.2096.

12
S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
4.42. ((((disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(2-
oxoethane-2,1-diyl))bis(oxy)) bis(4,1-phenylene)
bis(4-methylbenzenesulfonate) 10e:
4.45. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-(2-
nitrophenoxy)acetamide) 10h:
Ester 9h’ was hydrolysed to its
acid following general procedure F. Acid obtained was directly used
for coupling with cystamine following the experimental procedure
A resulting psammaplin analogue 10 h which is of yellow amor-
phous solid in 54% yield. M.P. 127 °C. Rf = 0.3 (60% EtOAc/ Hex-
ane). 1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.13 (t, J=5.59 Hz,
1H), 7.91 (dd, J=1.53 Hz, 8.12 Hz, 1H), 7.67–7.62 (m, 1H), 7.24 (d,
J=8.24 Hz, 1H), 7.18–7.12 (m, 1H), 4.72 (s, 2H), 3.46–3.42 (m, 2H),
2.81 (t, J=6.75 Hz, 2H) ppm. 13C NMR (100 MHz, DMSO-D6, 25
°C): δC 167.40, 151.19, 139.83, 135.09, 125.77, 121.78, 115.93, 68.20,
Ester 9e’ was hydrolysed to
its acid following general procedure F. Acid obtained was directly
used for coupling with cystamine following the experimental pro-
cedure A resulting psammaplin analogue 10e which is oil in 81%
yield. Rf = 0.42 (12% Methanol/DCM). 1H NMR (400 MHz, DMSO-
D6, 25 °C): δH 8.25 (t, J=5.66 Hz, 2H), 7.71 (d, J=8.30 Hz, 4H),
7.46 (d, J=8.30 Hz, 4H), 6.93 (s, 8H), 4.45 (s, 4H), 3.76–3.45 (m,
4H), 2.81 (t, J=6.80 Hz, 4H), 2.42 (s, 6H) ppm. 13C NMR (100 MHz,
DMSO-D6, 25 °C): δC 167.96, 156.79, 146.15, 143.32, 131.87, 130.64,
128.69, 123.58,+116.19, 67.64, 38.26, 37.45, 21.63 ppm. m/z calcd for
C34H37N2O10S4 [M+H]+: 761.1326, observed 761.1329.
+
38.16, 37.43 ppm. m/z calcd for C20H23N4O8S2 [M+H]+: 511.0952,
observed 511.0975.
4.46. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-(2-bromo-4-
methylphenoxy) acetamide) 10i:
4.43. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-(3,4,5-
trimethoxyphenoxy) acetamide) 10f:
Ester 9i’ was hydrolysed to its
acid following general procedure F. Acid obtained was directly used
for coupling with cystamine following the experimental proce-
dure A resulting psammaplin analogue 10i which is of white crys-
talline solid in 68% yield. M.p. 117 °C. Rf = 0.35 (40% EtOAc/ Hex-
ane). 1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.04 (t, J=5.70 Hz,
2H), 7.41–7.40 (m, 2H), 7.12–7.09 (m, 2H), 6.90 (d, J=8.16 Hz, 2H),
4.53 (s, 4H), 3.45 (q, J=6.74 Hz, 4H), 2.83 (t, J=6.90 Hz, 4H), 2.22
(s, 6H) ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C): δC 172.71,
157.21, 138.41, 137.45, 134.46, 119.46, 116.12+, 73.29, 42.84, 42.22,
24.85 ppm. m/z calcd for C22H27Br2N2O4S2 [M+H]+: 604.9774,
observed 604.9785.
Ester 9f’ was hydrolysed to
its acid following general procedure F. Acid obtained was directly
used for coupling with cystamine following the experimental pro-
cedure A resulting psammaplin analogue 10f which is of white
powder in 84% yield. M.P. 135 °C. Rf = 0.4 (8% Methanol/DCM). 1H
NMR (400 MHz, DMSO-D6, 25 °C): δH 8.25 (t, J=5.73 Hz, 2H), 6.31
(s, 4H), 4.46 (s, 4H), 3.75 (s, 12H), 3.58 (s, 6H), 3.49–3.41 (m, 4H),
2.85 (t, J=6.95 Hz, 4H) ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C):
δC 168.37, 154.58, 153.75, 132.56, 93.39, 67.86, 60.57, 56.30, 38.23,
37.49 ppm. m/z calcd for C26H37N2O10S2+: [M+H]+: 601.1884, ob-
served 601.1901.
4.47. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-(2-ethylphenoxy)
acetamide) 10j:
4.44. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-(2-bromo-4-
methoxyphenoxy) acetamide) 10g:
Ester 9g’ was hydrolysed to its
acid following general procedure F. Acid obtained was directly used
for coupling with cystamine following the experimental procedure
A resulting psammaplin analogue 10 g which is of white pow-
der in 68% yield. M.P. 114 °C. Rf = 0.5 (6% Methanol/DCM).1H
NMR (400 MHz, DMSO-D6, 25 °C): δH 8.06 (t, J=5.83 Hz, 2H), 7.19
(d, J=2.90 Hz, 2H), 7.02–6.98 (m, 2H), 6.91 (dd, J=8.93, 3.02 Hz,
2H), 4.50 (s, 4H), 3.72 (s, 6H), 3.46 (q, J=6.35 Hz, 4H), 2.85
(t, J=6.74 Hz, 4H) ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C):
δC 168.06, 154.84, 148.86, 118.76, 116.24, 114.58, 112.30, 69.31,
56.23, 38.10, 37.47 ppm. m/z calcd for C22H27Br2N2O6S2+: [M+H]+:
636.9672, observed 638.9657.
Ester 9j’ was hydrolysed to its acid
following general procedure F. Acid obtained was directly used for
coupling with cystamine following the experimental procedure A
resulting psammaplin analogue 10j which is of white crystalline
solid in 68% yield. M.p. 185 °C. Rf = 0.4 (20% EtOAc/ Hexane). 1H
NMR (400 MHz, DMSO-D6, 25 °C): δH 7.19–7.15 (m, 4H), 7.01–6.95
(m, 4H), 6.77 (d, J= 8.04, 2H), 4.49 (s, 3H), 3.70 (q, J= 6.17 Hz,
4H), 2.84 (t, J= 6.28 Hz, 4H), 2.70 (q, J= 7.59 Hz, 4H), 1.23 (t,
J= 7.56 Hz, 6H), ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C): δC
168.70, 154.96, 132.54, 129.43, 127.18, 122.12, 111.73, 6+7.55, 37.53,
37.45, 23.43, 14.28 ppm. m/z calcd for C24H33N2O4S2 [M+H]+:
477.1876, observed 407.1881.

S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
13
4.48. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-((2-bromo-4-
methylphenyl)amino) acetamide) 10k:
(100 MHz, CDCl3, 25 °C): δC 174.95, 151.73, 142.34, 114.93, 114.35,
55.76, 54.30, 38.19, 37.69, 19.49 ppm. m/z calcd for C24H35N4O4S2
[M+H]+: 507.2094, observed 507.2117.
+
4.51. 2-(ethyl(phenyl)amino)-N-(5-mercapto-1,3,4-thiadiazol-2-yl)
acetamide 12:
Ester 9k’ was hydrolysed
to its acid following general procedure F. Acid obtained was di-
rectly used for coupling with cystamine following the experimental
procedure A resulting psammaplin analogue 10k which is of brown
crystalline solid in 68% yield. M.p. 87 °C. Rf = 0.6 (50% EtOAc/ Hex-
ane). 1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.16 (t, J=5.64 Hz,
2H), 7.25 (d, J=1.44 Hz, 2H), 6.99–6.96 (m, 2H), 6.39 (d, J=8.23 Hz,
2H), 5.35 (t, J=5.18 Hz, 2H), 3.71 (d, J=4.90 Hz, 4H), 3.41–3.40
(m, 4H), 2.78 (t, J=6.61 Hz, 4H), 2.10 (s, 6H) ppm. 13C NMR
(100 MHz, DMSO-D6, 25 °C): δC 170.14, 142.88, 132.82, 129.57,
127.29, 112.02, 109.09, 47.22, 38.42, 37.59, 19.96 ppm. m/z calcd for
Ester 9a’ was hydrolysed to
its acid following general procedure F. Acid obtained was di-
rectly used for coupling with 5-amino-1,3,4-thiadiazole-2-thiol
11 (1equiv) following the experimental procedure
A resulting
psammaplin analogue 12 which is of white solid in 71% yield. M.P.
173 °C. Rf = 0.51 (85% EtOAc/Hexane).1H NMR (400 MHz, CDCl3,
25 °C): δH 14.07 (s, 1H), 12.52 (s, 1H), 7.17–7.13 (m, 2H), 6.64–
6.59(m, 3H), 4.22 (s, 2H), 3.46–3.41 (m, 2H), 1.10 (t, J=6.75 Hz,
3H). 13C NMR (100 MHz, CDCl3, 25 °C): δC 184.09, 171.09, 152.48,
147.98, 129.55, 116.58, 112.10, 52.93, 45.85, 12.55 ppm. m/z calcd
+
C22H29Br2N4O4S2 [M+H]+: 605.4275, observed 605.4273.
4.49. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-((4-fluorophenyl)
amino)propanamide) 10l:
+
for C12H15N4OS2 [M+H]+: 295.0682, observed 295.0680.
4.52. N, N’-(disulfanediylbis(ethane-2,1-diybl))bis(2-(p-tolylthio)
acetamide) 14a:
Ester 9l’ was hydrol-
ysed to its acid following general procedure F. Acid obtained was
directly used for coupling with cystamine following the exper-
imental procedure A resulting psammaplin analogue 10l which
Ester 13a’ was hydrol-
ysed to its acid following general procedure F. Acid obtained was
directly used for coupling with cystamine following the exper-
imental procedure A resulting psammaplin analogue 14a which
is of brown solid in 77% yield. M.P. 126 °C. Rf = 0.51 (40%
EtOAc/Hexane).1H NMR (400 MHz, DMSO-D6, 25 °C): δH 8.26 (t,
J=5.27 Hz, 2H), 7.25(d, J=8.00 Hz, 4H), 7.12 (d, J=8.00 Hz, 4H),
3.58 (s, 4H), 3.36–3.31(m, 8H), 2.72 (t, J=6.81 Hz, 4H), 2.26 (s,
6H) ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C): δC 168.56, 136.07,
132.68, 130.06, 129.25, 38.68, 37.52, 37.48, 20.99 ppm. m/z calcd
is oil in 68% yield. Rf
=
0.5 (50% EtOAc/ Hexane). 1H NMR
(400 MHz, DMSO-D6, 25 °C): δH 7.30–7.27 (m, 2H), 6.88 (t, J=
8.8 Hz, 4H), 6.54–6.50 (m, 4H), 3.74 (q, J= 6.89 Hz, 2H), 3.56–
3.43 (m, 4H), 2.78–2.61 (m, 4H), 1.48 (d, J= 7.00 Hz, 6H), ppm 13C
NMR (100 MHz, DMSO-D6, 25 °C): δC 174.25, 174.23, 157.55, 155.19,
142.65, 115.73, 115.51, 114.29, 114.26, 114.21, 114.19, 55.36, 55.34,
+
37.75, 37.46, 19.42 ppm. m/z calcd for C22H29F2N4O4S2 [M+H]+:
483.1695, observed 483.1675.
+
for C22H29N2O2S4 [M+H]+: 481.1106, observed 481.1106.
4.50. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-((4 methoxyphenyl)
amino) propanamide) 10m:
4.53. N,N’-(disulfanediylbis(ethane-2,1-diyl))bis(2-((4-hydroxyphenyl)
thio)acetamide) 14b:
Ester 9m’ was hydrol-
ysed to its acid following general procedure F. Acid obtained was
directly used for coupling with cystamine following the experi-
mental procedure A resulting psammaplin analogue 10 m which
is of white crystalline solid in 67% yield. M.P. 178 °C. Rf = 0.5
(10% Methanol/DCM). 1H NMR (400 MHz, CDCl3, 25 °C): δH 8.04
(t, J=5.74 Hz, 2H), 6.70 (d, J=8.81 Hz, 4H), 6.50 (d, J=8.81 Hz,
4H), 5.35 (d, J=6.60 Hz, 2H), 3.70–3.57 (m, 8H), 3.34–3.28 (m, 4H),
2.77–2.66 (m, 4H), 1.28 (t, J= 8.04 (t, J=5.74 Hz, 2H) ppm. 13C NMR
Ester 13b’ was hydrol-
ysed to its acid following general procedure F. Acid obtained was
directly used for coupling with cystamine following the experi-
mental procedure A resulting psammaplin analogue 14b which is
oil in 54% yield. Rf = 0.4 (10% Methanol/DCM). 1H NMR (400 MHz,
DMSO-D6, 25 °C): δH 9.63 (s, 2H), 8.17 (t, J=5.35 Hz, 2H), 7.24 (d,
J=8.60 Hz, 4H), 6.72 (d, J=8.76 Hz, 4H), 3.44 (s, 4H), 3.34–3.29

14
S.L. Kumar M, K. Ali and P. Chaturvedi et al. / Journal of Molecular Structure 1225 (2021) 129173
(m, 4H), 2.70 (t, J=2.70 Hz, 4H) ppm. 13C NMR (100 MHz, DMSO-
D6, 25 °C): δC 168.86, 158.08, 133.46, 123.19, 116.62, 39.64, 38.67,
Investigation. Sanjeev Meena: Investigation. Dipak Datta: Supervi-
sion. Gautam Panda: Conceptualization, Writing - review & edit-
ing, Supervision.
+
37.45 ppm. m/z calcd for C20H25N2O4S4 [M+H]+: 485.0692, ob-
served 485.0695.
Acknowledgments
ꢀ
4.54. 1,1 -(disulfanediylbis(ethane-2,1-diyl))bis(3-benzylurea) 16:
SLKM and KA thank CSIR and UGC for research fellow-
ship. Partial financial support from BRNS-BARC (3511410812018-
BRNS/35032), Mumbai to Dr. Panda is highly appreciated. Instru-
mental support from SAIF, CDRI is highly acknowledged. CDRI com-
munication no for this article is 10114.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2020.129173.
Isocyanate 15 was
made to react with Cystamine following the genereal procedure
G. The resulting psammaplin analogue 16 is off-white solid in
92% yield. M.p. 168 °C. Rf = 0.3 (10% Methanol/DCM). 1H NMR
(400 MHz, DMSO-D6, 25 °C): δH 7.32–7.28 (m, 4H), 7.23–7.19
(m, 6H), 6.51 (t, J=5.99 Hz, 2H), 6.20 (t, J=5.80 Hz, 2H), 4.18
(d, J=5.98 Hz, 4H), 3.34–3.29 (m, 4H), 2.76 (t, J=6.68 Hz, 4H)
ppm. 13C NMR (100 MHz, DMSO-D6, 25 °C): δC 158.40, 141.25,
128.66, 127.45, 127.60, 43.35, 39.05, 38.83, ppm. m/z calcd for
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Acid 17 was made to re-
act with Cystamine following the general procedure A. The re-
sulting psammaplin analogue 18 is off-white amorphous powder
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(400 MHz, DMSO-D6, 25 °C): δH 8.43 (d, J=5.96 Hz 4H), 7.54–
7.52 (m, 2H), 7.20 (dd, J1= 4.8 Hz, J2= 7.72 Hz, 4H), 6.86 (d,
J=5.48 Hz 4H), 3.50 (q, J=6.4 Hz 4H), 2.97 (d, J=7.44 Hz, 4H), 2.73
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+
38.43, 37.79, 137.46, 28.71 ppm. m/z calcd for C20H25N2O4S4
[M+H]+: 419.1570, observed 419.1563.
Supporting Information
Details of the experimental procedures and characterization
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Declaration of Competing Interest
[22] J. H.Kim, H. S.Shin, S. B.Kim, T. Hasegawa, Langmuir 20 (2004) 1674.
[23] S. Hong, Y. Shin, M. Jung, M. W.Ha, Y. Park, Y. J.Lee, J. Shin, K.B. Oh, S.K. Lee,
H.G. Park, Eur. J. Med. Chem. 96 (2015) 218.
There is no conflict of interest to declare.
CRediT authorship contribution statement
Srinivas Lavanya Kumar M: Methodology, Data curation, Writ-
ing - original draft. Kasim Ali: Methodology. Priyank Chaturvedi: