Synthesis of symmetrical bis-Schiff base-disulfide hybrids as highly effective anti-leishmanial agents

Article abstract of DOI:10.1016/j.bioorg.2020.103819

Leishmaniasis has affected a wider part of population around the globe. Most often, the existing regiments to battle against leishmaniasis are inadequate and limited. In our ongoing efforts to develop new leishmanicidal agents, we have synthesized a serie

Full text of DOI:10.1016/j.bioorg.2020.103819

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Synthesis of Symmetrical bis-Schiff base-Disulfide Hybrids as Highly Effec-
tive anti-leishmanial Agents
Muhammad Taha, Amyra Amat Sain, Muhammad Ali, El Hassane Anoure,
Fazal Rahim, Nor Hadiani Ismail, Mohd Ilham Adenan, Syahrul Imran,
Ahmed Al-Harrasi, Fasial Nawaz, Naveed Iqbal, Khalid Mohammed Khan
PII:
S0045-2068(19)31962-5
DOI:
https://doi.org/10.1016/j.bioorg.2020.103819
YBIOO 103819
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
17 November 2019
1 March 2020
2 April 2020
Please cite this article as: M. Taha, A. Amat Sain, M. Ali, E. Hassane Anoure, F. Rahim, N. Hadiani Ismail, M.
Ilham Adenan, S. Imran, A. Al-Harrasi, F. Nawaz, N. Iqbal, K. Mohammed Khan, Synthesis of Symmetrical bis-
Schiff base-Disulfide Hybrids as Highly Effective anti-leishmanial Agents, Bioorganic Chemistry (2020), doi:
https://doi.org/10.1016/j.bioorg.2020.103819
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Synthesis of Symmetrical bis-Schiff base-Disulfide Hybrids as Highly Effective anti-
leishmanial Agents

a
b
c
d
e
Muhammad Taha , Amyra Amat Sain , Muhammad Ali , El Hassane Anoure , Fazal Rahim , Nor
f,g
f,g
f,g
c
h
Hadiani Ismail , Mohd Ilham Adenan , Syahrul Imran , Ahmed Al-Harrasi , Fasial Nawaz ,
Naveed Iqbal , Khalid Mohammed Khan
i
j
aDepartment of clinical pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O.
Box1982, Dammam 31441, Saudi Arabia.
b
Malaysian Institute of Pharmaceuticals and Nutraceuticals, National Institutes of Biotechnology Malaysia, Halaman Bukit Gambir, 11700,
Penang, Malaysia.
c
Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Birkat Al
Department of Chemistry, College of Science and Humanities, Prince Sattam bin Abdulaziz University, P.O. Box 83, Al Kharj 11942, Saudi Arabia
d
Mauz, Nizwa 616, Sultanate of Oman
e
Department of Chemistry, Hazara University, Mansehra-21300, Khyber Pakhtunkhwa, Pakistan.
f
Atta-ur-Rahman Institute for Natural Product Discovery, Aras 9 Bangunan FF3, UiTM Puncak Alam, 42300 Bandar Baru Puncak Alam,
Selangor, Malaysia.
g
Faculty of Applied Science, UiTM Shah Alam, 40450 Shah Alam, Selangor D.E., Malaysia.
Department of Chemistry, University of Wah, Quaid Avenue, Wah Cantt 47000, Pakistan
h
i
Department of chemistry University of poonch Rawalakot AJK.
h
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270,
Pakistan
Abstract
Leishmaniasis has affected a wider part of population around the globe. Most often, the existing
regiments to battle against leishmaniasis are inadequate and limited. In our ongoing efforts to
develop new leishmanicidal agents, we have synthesized a series of novel and symmetrical bis-
Schiff base-disulfide hybrids 1-27. Intermediate disulfide was synthesized from corresponding 2-
aminothiol followed by reacting the coupled adduct with various aromatic aldehydes. All these
compounds showed outstanding inhibition when compared with standard (Table 1). Out of twenty
seven analogues, twenty two analogues i.e. 1-5, 7-13, 17-21, 23-27 analogues showed excellent
inhibitory potential with EC values ranging from 0.010 ± 0.00 to 0.096 ± 0.01M while five
5
0
compounds i.e. 6, 14-16, and 22 showed good inhibitory potential with EC values ranging from
5
0
0
.10 ± 0.00 to 0.137 ± 0.01M when compared with the standard Amphotericin B. Structure-
activity relationship has been established while molecular docking studies were performed to pin
the binding interaction of active molecules. This study will help to develop new antileishmanial
lead compounds.
Keywords: Synthesis, disulfides, hybrids, leishmaniasis, molecular docking, structure-activity
relationship.

Correspondence and reprints
E-mail: E-mail: taha_hej@yahoo.com and mtaha@uod.edu.saTel: 00966502057370
1

1
. Introduction
Leishmaniasis is a infection that hit mainly economically less stable class of people, widespread
in 100 countries. Though an approximate 0·7–1 million additional cases of leishmaniasis per year
are registered from almost 100 endemic countries.
The number of registered visceral leishmaniasis cases has reduced significantly in the previous
decade as a consequence of improved admittance to analysis and dealing and stronger vector
control within a removal resourcefulness in Asia, even though natural cycles in transmission
strength might play a role. In east Africa nevertheless, the case statistics of this fatal infection
remain to be sustained. [1-3]. Leishmaniasis is a parasitic disease and exhibits four main clinical
syndrome representations; cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL),
visceral leishmaniasis/kala azar (VL), and post kala azar dermal leishmaniasis (PKDL). Nearly
9
3
0% of all VL cases occur in 3 endemic foci: 1. India, Bangladesh, and Nepal; 2. East Africa; and
. Brazil. Despite the astronomical occurrence, present regiments for treating leishmaniasis are
limited and imperfect. Standard therapy of leishmaniasis for several decades, the pentavalent
antimonial, have failed their effectiveness in Bihar (∼60% of VL cases worldwide) due to extensive
challenge to the drug. Countless ground-breaking VL therapies have existed during the last 10−15
years but each exemplified serious deficiencies, i.e. paromomycin (injectable, long therapy,
region-dependent efficacy), miltefosine (cost, teratogenicity, long treatment), and liposomal
amphotericin B (expense, hospitalization, region-dependent effectiveness). Another task that
arisen is characterized by patients with HIV/VL coinfections who are challengingly further
difficult to cure (lower initial and final cure rates). These patients have larger vulnerability to drug
harmfulness and have greater rates of death and relapse [4].
Therapy alternatives for the last 60 years against leishmaniasis persisted restricted to pentavalent
antimonial family agents, exemplified by sodium stibogluconate (Pentostam) and Meglumine
antimoniate (Glucantime). Pentamidine and amphotericin B presented second line of drugs, but
these drugs have not experienced widespread practice due to the severe toxicities and economic
in-viability [5]. For example, pentamidine presented numerous side effects, including renal and
hepatic toxicity, pancreatitis, hypotension, dysglycemia, and cardiac abnormalities. Amphotericin
B is, however, quite effective but very expensive against visceral leishmaniasis. Therefore, it does
not appear to be the suitable treatment of non-visceral diseases [6]. Added that no vaccine has been
approved for human utilization till date [7,8]. Consequently, there is an increasingly demand for
2

the development of new, low-priced, effective and harmless drugs for the treatment of
leishmaniasis.
The design of newly developed antileishmanial agents (Figure 1) is based on the concept molecular
hybridization. It is important to unlock the fact that molecular hybridization is a relatively newer
idea in drug developments that is based on the combination of pharmacophoric moieties of
different bioactive molecules to produce a new hybrid structure [9]. The concept has been
effectively utilized in our group to develop structural motifs of various biological interests [10].
Schiff bases have been found to possess diverse applications in medicinal chemistry because of
their pharmacological profiles [11]. These compounds and their metal complexes have been known
to possess a wide range of biological, physical, chemical, agricultural and industrial applications
[12]. On the other hand, disulfides, an important class of organic compounds has shown potential
for a biological hit. Ajoene, for example, is found in the garlic (Allium sativum) extract is an
extremely effective remedy for cutaneous leishmaniasis [13, 14]. Further, many synthetic origin
disulfides have been reported to possess antileishmanial potential [15].
Cl
S
N
S
O
B
A
Ic50 = 2.70 ± 0.01uM
Ic50 = 0.57 ± 0.11uM
Std Pentamine 5.51 ± 0.04 uM
Std Amphotericin B 0.56 ± 0.20uM
1,2-diphenyldisulfane
(
E)-N-(4-chlorobenzylidene)-4-
methoxybenzenamine
Molecular Hybridization for better effancies
R
N
N
S S
R
(
14E)-N-arylidene-2-(2-((E)-2-(arylideneamino)phenyl)disulfanyl)benzenamine
C
Newly Designed Molecular hybrids as Antilieshmanial Agents
3

Figure 1. Rational Design of New Molecular Hybrids as Novel Antileishmanial Agents
Compound A in figure 1 denotes good antileishmanial potential [16] while compound B, a
disulphide agent also possesses potentially high antileishmanial profiles [17] we desiged our
current study based on these results we synthesized hybrid C which having A and B and the activity
of C is far better than either A or B
Chemotherapy is the commanding arsenal to challenge the problem of Leishmaniasis. Many
commercially available regiments including pentavalent antimonials, amphotericin B,
pentamidine, aminosidine, miltefosine, llopurinol, some azole derivatives, sitamaquine and
immunomodulators are usual drugs to counter the infection [20] (Fig. 2). Nonetheless, drug
resistance in leishmanial infections is increasing and making it vital to foster newer remedies that
are economically and orally viable and safer. Molecules having highly electronegative atoms such
as nitrogen and oxygen on their backbone are considered to deter with polyamine metabolism and
disruption of mitochondrial membrane potential of the parasite [21].
Figure 2. (a) Spermidine, an agent that assists growth and survival of leishmanial parasites; (b)
Pentamidine, first-line antileishmanial drug belonging to diamidine class of compounds
A polyamine base such as spermidine plays a pivotal role in the growth and survival of leishmanial
parasite. These polyamine bases are synthesized in a metabolic process involving an enzyme
arginase (ARG) and polyamine precursors that are present in microenvironment using specific
transporters [22]. Since the toxicity of current regiments and their economically unviable costs
made these treatments to be replaced with newer, low-cost and more efficacious drugs, the quest
for searching newer and safer targets continues. Our search for the development of new
4

antileishmanial agents [23] lead us to design newer and unique structural motifs consisting of
disulfide linked bis-Schiff base hybrids 1-27. Composing two (2) antileishmanial pharmacophores
together, i.e. disulfides and bis-Schiff bases, synergized the antileishmanial potential of target
molecules many folds than their individual counterparts (Fig. 1). At the border of bio-inspired and
rational drug design, hybrid structures are anticipated with various modes of actions to conceive
newer and efficient pharmaceutical agents. These motifs with two or more structural entities may
occupy diverse biological roles and potentials, demonstrating the fact that hybrid structures act as
two distinctive pharmacophoric units [18].
Since both Schiff bases and disulfides are good individual leishmanicidals (vide supra), the newly
developed hybrid structures were found many times potent agents against leishmaniasis. Molecular
docking analysis were also performed to understand the mode of action of these compounds.
2
.0 Results and discussion
2
.1.0 Chemistry
In this study, disulfanediyldianiline had been synthesized by same protocol as we reported [19].
The disulfanediyldianiline (1 equiv, 0.5 mmol) were treated with different aryl aldehyde (1 equiv,
1
.0 mmol) in methanol and few drops of acetic acid (1-27). When the reaction completed, which
was confirmed via TLC, the solvent was evaporated, and crude product was washed with hexane.
The crude products were further recrystallized from methanol to afford pure compounds with the
yield between 80-88% (scheme 1).
R
R
H N
2
NH2
N
S
N
NH2
S
RCHO
S
SH H5IO6 /NaHSO3
rt, 3hrs
S
+
2
H , CH OH
3
H O
2
Scheme 1: Synthesis of disulfide Schiff base 1-27
5

2
.2.
In Vitro Antileishmanial Activity
All synthesized compounds (1-27) were screened for their leishmanial activity (Table-1) while all
these compounds showed outstanding inhibitory potential when compared with standard. Out of
twenty-seven analogues, twenty-two analogues i.e. 1-5, 7-13, 17-21, 23-27 showed excellent
inhibitory potential with EC values ranging from 0.010 ± 0.00 to 0.096 ± 0.01 µM while five
5
0
compounds i.e. 6, 14-16, and 22 showed good inhibitory potential with EC values ranging from
5
0
0
0
.010 ± 0.00 to 0.137 ± 0.01 µM when compared with standard Amphotericin B with EC values
50
.437 ± 1.06 µM.
Structure activity relationship has been established for all compounds. If we compare compound
(EC50 = 0.024 ± 0.00 µM) having hydroxy and methoxy groups on meta-para position
respectively with compound 3 (EC = 0.018 ± 0.00 µM) having hydroxy and methoxy groups on
1
5
0
para-meta position and compound 5 (EC = 0.041 ± 0.01 µM) with ortho-para position, analog 3
5
0
was found to be more potent. Furthermore, the hydroxyl group on meta position further enhance
the activity. If we compare the dihydroxy analogues 2, (EC = 0.036 ± 0.01 µM) 4 (EC = 0.043
5
0
50
±
0.01 µM), 9 (EC = 0.042 ± 0.00 µM), 10 (EC = 0.019 ± 0.00 µM) and 11 (EC = 0.017 ± 0.00
50 50 50
µM), the analog 11 was found to be more active. Comparing the p-nitro analogue 6 (EC = 0.124
5
0
±
0.01 µM) with o-nitro analogue 24 (EC = 0.057 ± 0.00 µM) and m-nitro analogue 25 (EC =
50 50
0
.062 ± 0.00 µM), the o-nitro analogue was found to be more superior than meta and para nitro
analogues. Comparing the monohydroxy analogues 8 (EC = 0.017 ± 0.00 µM), 26 (EC = 0.039
5
0
50
±
0.01 µM) and 27 (EC = 0.027 ± 0.00 µM), analogue 8 was found to be more potent than 26 and
50
2
7. This indicates that o-hydroxy analogue 8 interact better with enzyme than meta and para
hydroxy analogues 26 and 27. In case of methyl substituted analogues 12 (EC = 0.084 ± 0.00
5
0
µM), 13 (EC = 0.096 ± 0.01 µM) and 14 (EC = 0.10 ± 0.00 µM), the p-methyl analogue 12 was
5
0
50
more potent than o-methyl 13 and m-methyl analogue 14. The reason is the effective interaction
of p-methyl analogue with enzyme with minimum steric hindrance.
In case of chloro substituted analogues, p-chloro substituted analogue 20 (EC = 0.084 ± 0.01 µM)
5
0
was found more active than o-chloro analogue 15 ((EC = 0.15 ± 0.01 µM) and m-chloro analogue
5
0
6

1
6 (EC = 0.20 ± 0.01 µM) while p-fluoro analogue 19 (EC = 0.010 ± 0.01 µM) was found more
50 50
potent than o-fluoro analogue 17 (EC = 0.040 ± 0.01 µM) and m-fluoro analogue 18 (EC =
5
0
50
0
.030 ± 0.01 µM). p-fluoro analogue 19 was found to be the most potent in the series. It looks clear
that the presence of para- substituent on halogenated analogues in mandatory for activity. It is
further assessed from these findings that the presence of a strong electron withdrawing group such
as fluoro group is important in imparting such high activity when compared with a less
electronegative atom such as chlorine at the same position. Pyridine substituted analogues were
also evaluated which showed varying degree of potential. Overall majority of compounds in the
series exhibit better potency however the nature, number and position of electron donating and
electron withdrawing group on phenyl ring play a critical role in the inhibitory potential of the
synthesized analogues.
Table-1: Synthesis of disulfide based Schiff base analog (1-27) and their antilieshmanial
potential
S.
Structure
aAnti-
SIc
S.
Structure
aAnti-
SIc
N.o
leishmanial
Activity
NO.
leishmanial
Activity
(bEC , M)
( EC , M)
b
5
0
50
1
.
.
.
.
HO
0.024 ± 0.00
0.036 ± 0.01
0.018 ± 0.00
0.043 ± 0.01
4.0
3.6
4.5
6.0
14.
15.
16.
17.
0.10 ± 0.00
0.15 ± 0.01
0.20 ± 0.01
0.040 ± 0.01
10.10
6.2
O
Cl
2
3
4
HO
HO
Cl
7.0
O
HO
F
OH
OH
18.20
HO
O
F
F
5
6
.
.
0.041 ± 0.01
0.124 ± 0.01
5.0
3.0
18.
19.
0.030 ± 0.01
0.010 ± 0.01
16.0
21.01
O N
2
7

7
.
OH
0.037 ± 0.00
8.0
20.
0.084 ± 0.01
10.50
Cl
O
OH
N
8
9
.
.
0.017 ± 0.00
0.042 ± 0.00
7.0
4.2
21.
22.
0.030 ± 0.00
0.137 ± 0.01
11.60
9.60
OH
OH
N
N
1
1
0.
1.
HO
HO
0.019 ± 0.00
0.017 ± 0.00
4.0
5.0
23.
24.
0.088 ± 0.00
0.057 ± 0.00
12.40
4.20
OH
OH
NO2
O N
1
1
2.
3.
0.084 ± 0.00 12.0 25.
2
0.097 ± 0.01
0.09 ± 0.01
3.90
HO
0.096 ± 0.01 14.0
26
27
12.60
-
-
-
-
0.027 ± 0.00
11.50
HO
Standard Drug
Amphotericin B
0.437 ± 1.06
356.60
a
values were in  SEM of three independent experiments, quadruplicates each.
b
EC50; concentration at 50% inhibition of parasite infection, or the ability of compound(s) to clear intracellular parasites of host cells
Seifert et al., 2010).
(
c
SI value; IC50 value of cytotoxicity / EC50 value of antileishmanial
Conclusively, the inference may be drawn by the discussion (vide supra) that among
monosubstituted analogues, particularly, halogenated and hydroxy ones, presence of an atom is
crucial at para position, irrespective of the nature of group (electron withdrawing or donating,
either inductively or mesomerically). Among, halogenated analogue, substitution of fluorine at
para position played a crucial role and therefore, compound 19 among the current series found to
be the most active one.
We are currently working on the plausible mechanism of action of these compounds and expanding
our studies and scope of this biological activity. We are hopeful to showcase these findings in near
future.
8

2
.3.
Selectivity Index
Selectivity index (SI) of a compound determines or reflects the quantity of compound that is active
against the target but not toxic towards the host cell. It is the ratio of IC50 values of THP-1 cells to
that of antileishmanial EC50 values. Based on IC50 values, the selectivity index (SI) for each
compound has been determined separately for compounds 1-27 (Table 1). For simplicity of
analysis, compounds are grouped according the substitutions attached to the aromatic centres. The
most active compound (19) among the series with EC50 value of 0.010 ± 0.01 µm is a -para fluoro
analogue with SI value of 21.01. In a similar fashion, for compounds 17 and 18, which are -ortho
and -para analogues of flouro substituted compounds, the SI values were found to be 18.2 and 16,
respectively. According to definition, greater SI values shows the lesser toxicity the compound
has. Therefore, -para fluorinated analogue 19 is most active and least toxic among the fluorine
substituted compounds. Among chloro substituted derivatives 15, 16 and 20, again -para
substituted analogue 20 displayed highest value of SI showing again its potency. The trend of SI
values was found similar between flouro and chloro substituted analogues. Similarly, a systematic
trend of SI values was observed as depicted in Table 1. The nitro compounds 6, 24 and 25 showed
potent activity with low selectivity index. The methyl substituted compounds 12, 13 and 14 were
found be to be relatively low cytotoxic and similar results were obtained for methoxy and hydroxyl
substituted.
2
.4. Molecular docking results
Synthesized bis-Schiff base-disulfide hybrids were tested for the antileishmanial activity (Table
). The antileishmanial tests showed that the inhibitory potency of 1-27 is strongly related to their
1
structural geometries. The bis-Schiff base-disulfide hybrids differ by the number, position and type
of the substituent groups present on the aromatic ring of its basic skeleton. For instance, the
aromatic ring in subgroups (8, 26-27), (12-14), (15-16, 20) and (17-19) is mono-substituted with
hydroxyl, methyl, chlorine and fluorine groups at ortho, meta and para positions, respectively. 2,
4
, 9-11 are substituted with two hydroxyl groups in different positions to each other. To rationalize
the effect of hydroxylation, methylation and halogenation on the antileishmanial activity,
molecular docking study has been carried out to shed light on the binding modes between the
selected docked compounds and the active residues of the targeted trypanothione reductase from
9

L. infantum. The binding energies of the stable complexes ligand- trypanothione reductase, the
number of established intermolecular hydrogen bonds between the docked selected compounds (8,
2
6-7, 2, 4, 9-11, 13, 15 and 17) [24,25] and the active site residues of trypanothione reductase are
displayed in Table 2.
Table 2 Docking binding energies, number of hydrogen bonds and number of closest residues to
the docked compounds (8, 26-7, 2, 4, 9-11, 13, 15 and 17) within the active binding site of the
targeted trypanothione reductase.
Number of closest
residues to the
docked ligand into
Name of
synthesized
derivatives
Free binding
energy
(kcal/mol)
H-Bonds
IC ± SEM
5
0
(HBs)
the active site
8
-10.78
-11.21
-10.44
-11.08
-10.84
-11.18
-10.92
-11.31
-11.16
-11.45
-10.38
4
1
5
6
4
5
7
3
1
1
2
12
11
11
11
9
13
15
11
10
10
11
0.017 ± 0.00
-
2
2
6
7
0.027 ± 0.00
0.036 ± 0.01
0.043 ± 0.01
0.042 ± 0.01
0.019 ± 0.00
0.017 ± 0.00
0.096 ± 0.00
0.15 ± 0.00
0.040 ± 0.00
2
4
9
1
0
1
3
5
7
1
1
1
1
All complexes formed between the selected docked bis-Schiff base-disulfide hybrids (8, 26-7, 2,
, 9-11, 13, 15 and 17) into the active site of trypanothione reductase showed negative binding
4
energies, which indicates that the docking of the selected compounds is thermodynamically
favourable. The binding energies of the stable complexes are relatively close, which may not be
considered as a strong parameter in rationalizing the observed antileishmanial activities. Our
attempt will be on the rationalizing the effects of the substitution groups on the trypanothione
reductase inhibition, and the intermolecular interactions that can be formed between these
substitute groups and the closest residues of trypanothione reductase. It is obvious from docking
results in Table 2 and Figure X that the hydroxylation of the aromatic ring in bis-Schiff base-
disulfide hybrids increase the inhibition efficiency against trypanothione reductase, whereas the
methylation and halogenation induces a decrease of trypanothione reductase inhibition. The
increase of trypanothione reductase inhibition by hydroxylated bis-Schiff base-disulfide hybrids is
mainly refer to the number of hydrogen bonds that could form between these hydroxyl groups and
1
0

active residues of trypanothione reductase (Number of hydrogen bonds 3-7), while in methylated
and halogenated hydroxylated bis-Schiff base-disulfide hybrids the number of hydrogen bonds is
lower than 2 (Table 2 and Figure X).
8
1
0
1
1

1
3
1
5
1
7
Fig. X 3D (lfeft) and 2D (right) closest interactions between active residues of trypanothione
reductase and the selected docked synthesized derivatives 8, 10, 13 , 15 and 17
1
2

Conclusion
In the current study, we have identified new hybrids (1-27) structures as potent antileishmanial
scaffolds. It was found that the antileishmanial potential of hybrid analogs was much more
promising then the antileishmnial potentials of individual components such as Schiff base A and
the disulfide B. Based on EC values, the selectivity index (SI) for each compound has been
5
0
determined. The most active compound (19) among the series with EC value of 0.010 ± 0.01 µm
5
0
is a -para fluoro analogue with SI value of 21.01. According to definition, greater SI values shows
the lesser toxicity the compound has. The trend of SI values was found similar between flouro and
chloro substituted analogues. The nitro compounds 6, 24 and 25 showed potent activity with low
selectivity index. Further, molecular docking studies were performed to analyse the mode of action
of these potent analogues. We believe that our finding can helps to develop lead compounds against
leishmaniasis.
Acknowledgments:
Authors would thankful to MOE of Malaysia for Grant no: 600-RMI/frgs 5/3 (0065/2016)
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Synthesis of Symmetrical bis-Schiff base-Disulfide Hybrids as Highly Effective anti-leishmanial
Agents
Muhammad Taha*a, Amyra Amat Sainb, Muhammad Alic, El Hassane Anoured, Fazal Rahime,
Nor Hadiani Ismailf,g, Mohd Ilham Adenanf,g, Syahrul Imranf,g, Ahmed Al-Harrasic, Fasial
Nawazh, Naveed Iqbali, Khalid Mohammed Khanj
aDepartment of clinical pharmacy, Institute for Research and Medical Consultations (IRMC),
Imam Abdulrahman Bin Faisal University, P.O. Box1982, Dammam 31441, Saudi Arabia.
bMalaysian Institute of Pharmaceuticals and Nutraceuticals, National Institutes of
Biotechnology Malaysia, Halaman Bukit Gambir, 11700, Penang, Malaysia.
c Natural and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Birkat Al
dDepartment of Chemistry, College of Science and Humanities, Prince Sattam bin Abdulaziz
University, P.O. Box 83, Al Kharj 11942, Saudi Arabia
Mauz, Nizwa 616, Sultanate of Oman
eDepartment of Chemistry, Hazara University, Mansehra-21300, Khyber Pakhtunkhwa,
Pakistan.
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fAtta-ur-Rahman Institute for Natural Product Discovery, Aras 9 Bangunan FF3, UiTM Puncak
Alam, 42300 Bandar Baru Puncak Alam, Selangor, Malaysia.
gFaculty of Applied Science, UiTM Shah Alam, 40450 Shah Alam, Selangor D.E., Malaysia.
hDepartment of Chemistry, University of Wah, Quaid Avenue, Wah Cantt 47000, Pakistan
iDepartment of chemistry University of poonch Rawalakot AJK.
hH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi 75270, Pakistan
Highlights:
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Synthesis hybrid disulfide derivatives
In vitro antileishmanial activity
Identification of a new compounds of antileishmanial activity
Structure Activity Relationship established
Molecular docking
Selectivity index
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