Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis, biological evaluation, molecular docking and in silico physico-chemical properties

Article abstract of DOI:10.1016/j.bmcl.2017.03.049

According to WHO, leishmaniasis is a major tropical disease, ranking second after malaria. Significant efforts have been therefore invested into finding potent inhibitors for the treatment. In this work, eighteen novel 1,2,3-triazoles appended with L-amin

Full text of DOI:10.1016/j.bmcl.2017.03.049

Accepted Manuscript
Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Syn-
thesis, biological evaluation, molecular docking and in silico physico-chemical
properties
Mir Mohammad Masood, Phool Hasan, Shams Tabrez, Md. Bilal Ahmad,
Umesh Yadava, Constantin G. Daniliuc, Yogesh A. Sonawane, Amir Azam,
Abdur Rub, Mohammad Abid
PII:
S0960-894X(17)30298-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.03.049
BMCL 24801
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
10 December 2016
17 March 2017
20 March 2017
Please cite this article as: Masood, M.M., Hasan, P., Tabrez, S., Ahmad, d.B., Yadava, U., Daniliuc, C.G., Sonawane,
Y.A., Azam, A., Rub, A., Abid, M., Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids:
Synthesis, biological evaluation, molecular docking and in silico physico-chemical properties, Bioorganic &
Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.03.049
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Bioorganic & Medicinal Chemistry Letters
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Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis,
biological evaluation, molecular docking and in silico physico-chemical properties
a,b
a,c
d
c
e
Mir Mohammad Masood , Phool Hasan , Shams Tabrez , Md. Bilal Ahmad , Umesh Yadava ,
f
g
b
d
a,g*
Constantin G. Daniliuc , Yogesh A. Sonawane , Amir Azam , Abdur Rub and Mohammad Abid
a
Medicinal Chemistry Lab, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
b
Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
c
Department of Chemistry, TNB College, TM Bhagalpur University, Bhagalpur 812007, Bihar, India
d
Infection and Immunity Lab, Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India
e
Department of Physics, Deen Dayal Upadhyay Gorakhpur University, Gorakhpur, UP 273009, India
f
Organisch-Chemisches Institut, Westfälische Wilhelm-Universität Münster, 48149, Germany
g
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
*
Corresponding author: Mohammad Abid; E-mail: mabid@jmi.ac.in; mobile: +91-8750295095; Fax: +91-11-26980229.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
According to WHO, leishmaniasis is a major tropical disease, ranking second after malaria.
Significant efforts have been therefore invested into finding potent inhibitors for the treatment.
In this work, eighteen novel 1,2,3-triazoles appended with L-amino acid (Phe/Pro/Trp) tail were
synthesized via azide-alkyne click chemistry with moderate to good yield, and evaluated for
their anti-leishmanial activity against promastigote form of Leishmania donovani (Dd8 strain).
Among all, compounds 40, 43, and 53 were identified with promising anti-leishmanial activity
with IC50 = 88.83 ± 2.93, 96.88 ± 12.88 and 94.45 ± 6.51 µM respectively and displayed no
cytotoxicity towards macrophage cells. Moreover, compound 43 showed highest selectivity
index (SI = 8.05) among all the tested compounds. Supported by docking studies, the lead
inhibitors (40, 43 and 53) showed interactions with key residues in the catalytic site of
trypanothione reductase. The results of pharmacokinetic parameters suggest that these selected
inhibitors can be carried forward for further structural optimization and pharmacological
investigation.
Keywords:
Click chemistry
1
,2,3-Triazole
Amino acid tail
Anti-leishmanial
Docking studies
Trypanothione reductase
Leishmaniasis is poverty related most neglected zoonotic
disease worldwide caused by protozoan parasites of the genus
Leishmania and spread by the bite of infected female
phlebotomine sandflies. Leishmaniasis is endemic in 98 countries
placing 350 million people at risk. An estimated 0.9 –1.3 million
new cases and 20 – 30 thousand deaths occur annually with many
cases going undiagnosed. Three main forms of leishmaniasis –
visceral (also known as kala-azar), cutaneous, and
mucocutaneous are observed. Of these, visceral leishmaniasis
amphotericin B, in spite of its adverse effects is the drug of
choice where resistance to pentavalent antimonial is developed.
Usefulness of second-line drugs such as paromomycin and
4
pentamidine
has
been
restricted.
Miltefosine
(hexadecylphosphocholine [HePC]), an alkyl phosphocholine
originally developed as anticancer agent, is widely used as an
5
,6
anti-leishmanial drug as it has a good oral profile, causes
7
apoptotic death and exhibits activity against various Leishmania
8
species. However, toxicity, appearance of drug resistance and the
(
VL) is fatal if left untreated, is endemic in the Indian
relapse of the disease in some cases, even after 10 months of a
full course of treatment with miltefosine prompted health
researchers to search for novel, safe and effective anti-
9
subcontinent and in East Africa. An estimated 0.2 to 0.4 million
new cases of VL occur worldwide each year.
1-2
leishmanial agents. In this regard, several studies with
Leishmaniasis control mainly depends on chemotherapy
Figure 1). The first-line therapy for leishmaniasis include
pentavalent antimonial drugs like sodium stibogluconate
heterocyclic compounds as anti-leishmanial agents have been
(
10-14
reported in the literature.
1,2,3-triazoles flanked on each side
by two randomized amino acids (peptidotriazoles) against L.
(
pentostam) and meglumine antimoniate (glucantime) being used
15
mexicana cysteine protease has also been reported (Fig.1).
for the last five decades. Unfortunately, about 60% of VL cases
in India alone become un-responsive to pentavalent antimonial
Peptidic compounds are susceptible to hydrolysis. However, the
combination of peptides with rigid and hydrophobic molecular
moieties can alter this process. Peptide based small molecules
3
due to developed resistance. Polyene antifungal drug

can provide inhibitors that bind to proteases as a natural peptide
substrate. These compounds are more resistant to hydrolysis
because of a structural mimetic within the peptide backbone and
rigidity of triazole pharmacophore and hydrophobic substituent.
Incorporation of triazoles into amino acids provides rationale for
the small, rigid, and aromatic structure capable of resistance to
enzymatic hydrolysis. We introduced phenyl ring in to our core
structure with triazole, in order to achieve rigidity. Considering
the present situation and in continuation to our search of potent
The structure of the compound 29 was unequivocally
established by X-ray crystallographic analysis. Single crystal of
29 was obtained through the slow evaporation of its hexane-
ethylacetate solution. A crystal of suitable size was mounted and
single-crystal data was collected at 223K.The crystal structure
2
0
was solved by direct methods using SHELXS-97 and refined
2
1
with SHELXL-97. The molecular graphics were prepared using
XP (Bruker AXS, 2000).The molecule crystallizes in the
monoclinic crystal system with P2 space group. The hydrogen
1
1
6-19
antimicrobial agents,
it is worthwhile to synthesize 1,2,3-
atoms were calculated and refined as riding atoms.The crystal
structure (unit cell diagram) and crystal data of the compound are
given in Figure 2 and Table 1 respectively. The crystal packing
structure of 29 and method of analysis is given in supplementary
information.
triazoles appended with L-amino acid tail (Phe/Pro/Trp) for their
anti-leishmanial activity and any possible cytotoxicity. In this
study, we aimed at exploiting the 1,2,3-triazole ring for the
development of novel anti-leishmanial pharmacophore.
Scheme 1: Synthesis of 1,2,3-triazole-amino acid hybrids. Reagents and
conditions: (a) propargyl bromide, DMF, K CO , 0 °C–rt, 18–24 h, 94–98%;
2 3
(
2 3 4 2
b) NaNO in HCl, NaN , 0 °C–rt, 2.5 h; (c) CuSO .5H O, sodium ascorbate,
THF/H O (1:2), rt, 22–24 h, 71–97%; (d) p-TSA, DCM, rt, 3–4 h, 53–98%.
2
Table 1. Crystal data and structure refinement details for 29.
Figure 1. (a) Commonly used anti-leishmanial drugs. (b) Model
for this study.
1
5
Identification code
CCDC number
29
1469760
The synthetic pathway to achieve title compounds 37–54 is
outlined in scheme 1. Boc protected L-amino acid (Phe/Pro/Trp)
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system, space group
20 26 4 5
C H N O
402.45
223(2) K
0.71073 Å
1
monoclinic, P2 (No. 4)
1
K
–3 were separately coupled with propargyl bromide using
CO in DMF to obtain their propargyl esters 4–6 in excellent
2
3
1
9
yield. On the other hand, phenyl azides (13–18) were prepared
by the diazotization of corresponding aniline 7–12 with NaNO
and HCl followed by the reaction with NaN in a single reaction
2
3
a = 5.7080(2), b = 17.1084(5),c
= 10.6589(5) Å, β = 92.741(1)°
Unit cell dimensions
vessel. Aniline and substituted anilines with electron donating as
well as electron withdrawing substituents were employed to
study their effect on biological activity. Finally, both alkyne and
azide components were reacted to obtain the intermediate
compounds 19–36 via Huisgen 1,3-dipolar cycloaddition reaction
3
Volume
1039.7(1) Å
-
3
Z, calculated density
Absorption coefficient
Crystal size
2, 1.286 gcm
0.094 mm
-1
0.14 x 0.12 x 0.03 mm
in the presence of CuSO
1:2) mixture. The key intermediates, 19–36 were deprotected
using p-toluene sulfonic acid in CH Cl to yield the title
4 2
and sodium ascorbate in THF:H O
Limiting indices
±h, ±k, ±l
(
Reflections collected/unique 6343/3154 [Rint = 0.040]
2
2
Absorption correction
Final R indices [I > 2s(I)]
Largest diff. peak and hole
0.987 ≤ T ≤ 0.997
R = 0.062, wR = 0.146
0.13 and -0.16 e.Å
compounds 37–54 in moderate to good yields (53–98%). All the
2
compounds and intermediates were confirmed by elemental
-3
1
13
analysis, FT-IR, H, C NMR and Mass spectral data. The
characterization data of all the intermediate and title compounds
along with some representative spectra are given in
supplementary information.

Figure 2. Crystal structure and unit cell diagrams of compound 29 (thermals ellipsoids are shown with 15% probability).
The title compounds (37–54) were subjected to their in vitro anti-leishmanial activity against L. donovani promastigotes (Dd8 strain)
and cytotoxicity towards THP-1 macrophages. The IC50 values in µM were estimated and the results are presented in Table 2. The
standard antileishmanial agent miltefosine was also screened under identical conditions for comparison. None of the compounds
showed better anti-leishmanial activity as compare to miltefosine (IC50 = 27.07±1.84µM). Moreover, compounds 40, 43 and 53 were
found better growth inhibitor with IC50 = 88.83 ± 2.93, 96.88 ± 12.88 and 94.45 ± 6.51 µM respectively with no cytotoxicity towards
macrophages. The percent cell viability of L. donovani and macrophages cells with increasing concentration of the selected inhibitors
(
40, 43 and 53) was also evaluated as shown in Figure 3 and 4, respectively. The results showed dose dependent killing of the
promastigotes of L. donovani. Even at 100 µM concentration of the inhibitor, no significant decrease in mammalian cell viability was
observed, indicating their non-cytotoxic nature.
Table 2. Anti-leishmanial activity of compounds (37–54) against L. donovani promastigotes.
a
IC50 (mean ± SD) µM
2
Selectivity Index
b
(SI)
Compound
R
R
THP-1
L. donovani
differentiated
macrophages
504.16 ± 90.10
388.76 ± 79.91
196.36 ± 12.20
291.56 ± 26.08
260.26 ± 25.57
promastigotes
3
3
3
4
4
7
8
9
0
1
H
Cl
F
163.33 ± 12.05
132.46 ± 2.48
132.96 ± 2.48
88.83 ± 2.93
144.33 ± 8.1
3.09
2.94
1.48
3.28
1.80
CH
OCH
3
3
4
2
NO
2
171.23 ± 16.26
179.86 ± 15.36
1.05
4
4
4
4
4
3
4
5
6
7
H
Cl
F
CH
OCH
96.88 ± 12.88
157.03 ± 3.69
121.7 ± 9.84
175.43 ± 7.48
103.50 ± 7.36
780.01 ± 92.61
346.16 ± 29.42
308.76 ± 15.18
420.63 ± 54.49
217.96 ± 18.81
8.05
2.20
2.54
2.40
2.11
3
3
4
8
NO
2
189.36 ± 8.84
343.73 ± 9.75
1.82
4
5
5
9
0
1
H
Cl
F
137.80 ± 7.1
129.1 ± 9.87
151.4 ± 4.34
190.96 ± 17.51
317.40 ± 15.26
352.10 ± 37.61
1.39
2.46
2.32
5
5
5
2
3
4
CH
OCH
NO
3
99.38 ± 6.09
94.45 ± 6.51
118.60 ± 3.08
27.07 ± 1.84
293.46 ± 30.50
194.66 ± 18.49
174.36 ± 21.39
54.08 ± 5.07
2.95
2.06
1.47
1.99
3
2
Miltefosine
a
b
SD: Standard Deviation; SI: The ratio of IC50 value on macrophage cell line to the IC50 value on L. donovani promastigotes.

Figure 3. Leishmanicidal effect of 40, 43 and 53 on promastigotes of L. donovani. L. donovani promastigotes were treated for 48 h with
increasing concentrations of three different compounds.
Figure 4. Toxic effect of the inhibitors on THP-1 macrophage. THP-1 macrophages were treated for 24 h with increasing
concentrations of the inhibitors and cell viability was assessed.
Compound 43 showed lowest cytotoxicity (IC50 = 780.01 ±
2.61 µM) against macrophages and found 14-fold less cytotoxic
Similarly, compounds 42, 48 and 54 with p-NO group were
found less effective than compounds 40, 47, 52 and 53 with
2
9
than miltefosine. Selectivity indices (SIs) (IC50 towards normal
cells/IC50 towards L. donovani) were calculated to guide the
selection of lead compound for further SAR and in vivo testing.
Compounds (40, 43 & 53) showed a better toxicity–activity
relation than miltefosine and compound 43 showed the highest
selectivity index (SI = 8.05) proving it as a good candidate
among all the tested compounds.
Structural-activity relationship (SAR) revealed that 1,2,3-
triazole pharmacophore flanked with three different amino acid
tail show varied antileishmanial activity (Table2). At one end,
modification with different amino acid tail (Phe/Pro/Trp) and
various substituents on phenyl ring such as halogen, methyl,
methoxy and nitro at para position at the other end were
performed to explore the SAR of the synthesized compounds 37-
electron donating substituent at phenyl ring. Though activity was
also related with the amino acid tail. The effect of phenyl
substituents was predicted by docking investigations. The
substituents on phenyl ring in compounds 40, 43 and 53 are
making hydrophobic interactions with hydrocarbon side chain of
non-polar Ile458.
Further to gain insights into the possible reasons for activity
and binding of the potent compounds 40, 43 and 53, we docked
them against three-dimensional trypanothione reductase (TryR)
of L. infantum. Since trypanothione is absent in humans and is
essential for survival of the parasitic protozoa like Leishmania
and Trypanosoma, the uniqueness of the parasite thiol
metabolism renders trypanothione reductase (TryR) as an
2
2
attractive target for the development of new antiparasitic drugs.
5
4. Amino acids selected for this study bear heterocyclic ring
The molecular docking was carried out using X-ray crystal
necessary for hydrophobic interactions as one of the driving force
for drug discovery. Among all the triazoles containing
structures of trypanothione reductase from L. infantum (PDB
23,24
code: 2jk6, resolution:2.95 Å).
as there is 98% similarity
phenylalanine tail (37-42), compound 40 with p-CH
phenyl group showed best antileishmanial activity (IC50= 88.83 ±
.93 µM), while compounds with unsubstituted phenyl ring (37)
and p-NO substituted phenyl (42) showed least activity among
3
substituted
between the trypanothione reductase of L. donovani and L.
2
3
infantum. Compound 40, 43 and 53 occupied a pocket near to
catalytic site (Cys52-His461-Cys57) and displayed strong
hydrogen bond of N-H in 40 and 53 and tertiary nitrogen of
triazole in 43 with Thr463. Compound 40 and 53 adopted similar
conformation, and shows π-π stacking of trizole with His461 and
hydrophobic interaction with Pro462, this stabilizes the structural
orientation of ligands in to the protein. Terminal aromatic ring is
showing hydrophobic interactions with Asn340, Arg472, and
Ile458. The three representative examples 40, 43, and 53
revealing the mode of interactions are provided in Figure 5.
Overall, these hypothetical docking observations indicate that the
compounds are showing sufficiently strong inhibition, which may
play important role against promastigotes of L. donovani.
2
2
them. Replacement of phenylalanine with proline tail in
compound 43with unsubstituted phenyl ring (43) showed good
antileishmanial activity (IC50= 96.88 ± 12.88 µM) followed by
p-OCH
NO shows least activity (IC50= 189.36 ± 8.84 µM) among them.
Among the compounds bearing tryptophan tail, 53 having p-
OCH on phenyl ring showed potent antileishmanial activity
IC50= 94.45 ± 6.51 µM) followed by p-CH 52 (IC50= 99.38 ±
.09 µM). As observed from the activity data, introduction of
3
47 (IC50= 103.50 ± 7.36 µM) while compound 48 with p-
2
3
(
3
6
halogen substituent (p-Cl or p-F) on phenyl ring did not showed
significant antileishmanial activity among all the compounds.

Figure 5. Predicted binding mode and docking in to the TryR homodimer. Ligands 40, 43, and 53 are shown in stick models (yellow
color). Hydrogen bonding interactions are shown as yellow dashes. Residues involved in hydrophobic interactions and hydrogen
bonding are represented in stick models.
The evaluation of important physico-chemical properties of drug
like molecules is an important step in the process of drug
discovery. Most of the drugs fail at clinical trial because of the
poor physico-chemical properties. This prediction became very
popular in drug discovery and designing process to screen out the
drug like molecules at an initial stage. Here, we did in silico
physico-chemical prediction for all the tested amino acid-triazole
hybrids (37-54) using QikProp version 3.2, Schrödinger software.
Along with Lipinski's parameters, the values for other important
physico-chemical parameters such as molecular weight (MW),
dipole moment (D), solvent accessible surface area (SASA), total
polar surface area (PSA), number of rotatable bonds (NRB),
predicted aqueous solubility (QP log S), prediction of binding to
human serum albumin (QP log Khsa), predicted brain/blood
partition coefficient (QP log BB) etc were also calculated and
found within the range with reference of 95% drugs. Aqueous
solubility, lipophilicity, polar surface area and molecular weight
are important parameters, which define absorption, movement
and action of drug molecule. The results of physico-chemical
properties showed that all the compounds have drug like
properties. All the eighteen compounds follow Lipinski's rule of
approach. All the newly synthesized intermediates and final
1 13
compounds were well characterized by H, C NMR, mass
spectroscopic techniques and elemental analysis. In the
pharmacological evaluation, compounds 40, 43 and 53 exhibited
good inhibitory activity against promastigote form of L. donovani
(Dd8 strain) with IC50 of 88.83 ± 2.93, 96.88 ± 12.88 and 94.45 ±
6.51 µM respectively. The lead inhibitors were also found non-
toxic against THP-1 macrophages using MTT assay. Selected
compounds showed a better toxicity–activity relation than
miltefosine. In docking study, we predicted that our compounds
might bind to the catalytic site of TryR and fit well into the
functional catalytic pocket with favorable hydrophobic and
hydrogen bonding interactions. In silico prediction of physico-
chemical properties for all the compounds was found within the
permitted range and no compound violate Lipinski's rule of 5.
The inhibitors 40, 43 and 53 with better IC50 and high selectivity
indices can be taken as lead for further development for the
search of better and safe anti-leishmanial agents.
Acknowledgments
5
. According to Lipinski rule of five, any orally active drugs
M. Abid gratefully acknowledges University Grants Commission
(UGC), Govt. of India for awarding RAMAN Postdoctoral
Fellowship in USA (F. No. 5-123/2016(IC)). M. M. Masood
acknowledges the financial support from University Grants
Commission (UGC), Govt. of India in the form of Teacher
Fellow (F. No. 27–109/2014 (TF/NRCB)).
should not violate more than one of its parameters. The important
Lipinski parameters are number of hydrogen bond acceptor HBA
(
not more than 10), number of hydrogen bond donor HBD (not
more than 5), molecular mass (< 500), octanol-water partition
coefficient (QP log Po/w) ≤ 5 and molar refractivity (in the range
of 40-130). No compound showed violation of Lipinski rule of 5.
Moreover, compounds 40, 43 & 53 have 78-84% predicted
bioavailability along with other favorable physico-chemical
properties. Therefore, these compounds have potential for
ensuing development as oral agents and can be potentially active
drug candidates after extended SAR and pharmacological
investigations. All the results of in silico physico-chemical
prediction are summarized in Table 4.
Conflict of interest
No conflict of interest.
Supplementary data
CCDC 1469760 (compound 29) contain the supplementary crystallographic
data for this Letter. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associated with
this article can be found, in the online version.
In conclusion, a series of eighteen new 1,2,3-triazole-amino
acid hybrids (37-54) were synthesized using click chemistry

Table 4. Physico-chemical parameters of compounds 37 – 54.
QPog
Kp
QP log
Po/w
QP log QP log
App.
App.
Comp
MW
D
SASA
PSA
NRB
HBD
HBA
QP logS
VLR5
%HOA
Khsa
BB
Caco-2 MDCK
(
cm/hr)
3
7
322.36
5.750
646.860
90.642
6.00
2.00
5.00
2.976
-3.95
0.329
-0.814
129
60
-3.979
0
82

3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
356.81
340.35
336.39
352.39
369.38
272.31
306.75
290.30
286.33
302.33
319.32
361.40
395.85
379.39
375.43
391.43
408.42
3.705
3.520
6.346
6.107
7.300
5.801
3.799
3.621
6.383
6.653
6.209
8.422
6.376
6.176
9.023
8.845
4.893
670.892
655.858
678.053
681.235
693.731
570.791
594.866
579.817
601.723
605.652
597.375
693.954
718.018
702.969
725.865
728.720
732.441
90.644
90.644
90.642
98.933
135.071
81.251
81.250
81.250
81.251
89.541
124.830
104.097
104.098
104.098
104.096
112.387
147.528
6.00
6.00
6.00
7.00
7.00
3.00
3.00
3.00
3.00
4.00
4.00
6.00
6.00
6.00
6.00
7.00
7.00
2.00
2.00
2.00
2.00
2.00
1.00
1.00
1.00
1.00
1.00
1.00
3.00
3.00
3.00
3.00
3.00
3.00
5.00
5.00
5.00
5.75
6.00
5.50
5.50
5.50
5.50
6.25
6.50
5.00
5.00
5.00
5.00
5.75
6.00
3.464
3.209
3.272
3.067
2.325
1.858
2.346
2.091
2.152
1.934
1.106
3.196
3.683
3.428
3.495
3.297
2.534
-4.679
-4.311
-4.491
-4.147
-4.282
-3.008
-3.737
-3.369
-3.544
-3.181
-2.949
-4.596
-5.323
-4.956
-5.146
-4.818
-4.810
0.440
0.369
0.478
0.343
0.330
0.006
0.118
0.047
0.155
0.006
-0.046
0.471
0.581
0.510
0.620
0.493
0.462
-0.668
-0.710
-0.849
-0.899
-1.993
-0.408
-0.258
-0.303
-0.439
-0.491
-1.410
-1.112
-0.970
-1.010
-1.155
-1.203
-2.253
129
129
129
129
15
148
108
60
60
5
-4.147
-4.114
-4.180
-4.089
-6.037
-4.657
-4.825
-4.791
-4.859
-4.765
-6.669
-4.322
-4.491
-4.457
-4.521
-4.431
-6.296
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
85
84
84
83
62
78
81
80
80
79
58
80
82
81
81
80
60
182
182
182
182
182
22
87
214
157
87
87
9
79
35
87
63
35
35
3
79
79
79
79
10
Abbreviations: Comp = compound; MW = molecular weight; D = dipole moment (D); SASA = solvent-accessible surface area; PSA = total polar surface area; NRB = number of rotatable bonds; HBD = hydrogen bond donor;
HBA = hydrogen acceptor; QP log P o/w = predicted octanol/water partition coefficient; QP log S = predicted aqueous solubility; QP log Khsa = prediction of binding to human serum albumin; QP log BB = predicted
brain/blood partition coefficient; App. Caco-2 = apparent Caco-2 cell permeability (nm/sec); App. MDCK = apparent MDCK cell permeability (nm/sec); QP log Kp = predicted skin permeability; VLR5 = violence of Lipinski
rule of 5; %HOA = % Human Oral Absorption.

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Graphical Abstract
.
Anti-leishmanial and cytotoxic activities of
amino acid-triazole hybrids: Synthesis,
biological evaluation, molecular docking and
in silico physico-chemical properties.
Leave this area blank for abstract info.
Mir Mohammad Masood, Phool Hasan, Shams Tabrez, Md. Bilal Ahmad, Umesh Yadava, Constantin G.
Daniliuc, Yogesh A. Sonawane, Amir Azam, Abdur Rub and Mohammad Abid.
Surface overlay of compounds 40 (cyancolor) and 53 (yellow color) with Trypanothione reductase.