Synthesis of novel quinoline-based thiadiazole, evaluation of their antileishmanial potential and molecular docking studies

Article abstract of DOI:10.1016/j.bioorg.2018.12.025

New series of quinoline-based thiadiazole analogs (1–20) were synthesized, characterized by EI-MS, ¹H NMR and ¹³C NMR. All synthesized compounds were subjected to their antileishmanial potential. Sixteen analogs 1–10, 12, 13, 16, 17,

Full text of DOI:10.1016/j.bioorg.2018.12.025

Accepted Manuscript
Synthesis of novel quinoline-based thiadiazole, evaluation of their antileishma-
nial potential and molecular docking studies
Noor Barak Almandil, Muhammad Taha, Fazal Rahim, Abdul Wadood, Syahrul
Imran, Mohammed A. Alqahtani, Yasser A. Bamarouf, Mohamed Ibrahim,
Ashik Mosaddik, Mohammed Gollapalli
PII:
S0045-2068(18)30104-4
DOI:
https://doi.org/10.1016/j.bioorg.2018.12.025
YBIOO 2689
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 February 2018
13 December 2018
19 December 2018
Please cite this article as: N. Barak Almandil, M. Taha, F. Rahim, A. Wadood, S. Imran, M.A. Alqahtani, Y.A.
Bamarouf, M. Ibrahim, A. Mosaddik, M. Gollapalli, Synthesis of novel quinoline-based thiadiazole, evaluation of
their antileishmanial potential and molecular docking studies, Bioorganic Chemistry (2018), doi: https://doi.org/
10.1016/j.bioorg.2018.12.025
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Synthesis of novel quinoline-based thiadiazole, evaluation of their antileishmanial potential and
molecular docking studies
a
Noor Barak Almandila, Muhammad Taha , Fazal Rahimb, Abdul Wadoodc, Syahrul Imrand,
Mohammed A. Alqahtanie, Yasser A. Bamaroufe, Mohamed Ibrahima, Ashik Mosaddika, Mohammed
Gollapallie,
aDepartment of clinical pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin
Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
bDepartment of Chemistry, Hazara University, Mansehra-21300, Pakistan
cDepartment of Biochemistry, Abdul Wali Khan University Mardan, Mardan-23200, Pakistan.
dAtta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus,
42300 Bandar Puncak Alam, Selangor D. E. Malaysia.
eCollege of Computer Science & Information Technology (CCSIT) Imam Abdulrahman Bin Faisal University P.O. Box
1982, Dammam 31441, Saudi Arabia.
Abstract:
New series of quinoline-based thiadiazole analogs (1-20) were synthesized, characterized by EI-MS,
13
1HNMR and CNMR. All synthesized compounds were subjected to their antileishmanial potential.
Sixteen analogs 1-10, 12, 13, 16, 17, 18 and 19 with IC50 values in the range of 0.04 ± 0.01 to 5.60 ±
0.21µM showed tremendously potent inhibition as compared to the standard pentamidine with IC50
value 7.02 ± 0. 09µM. Analogs 11, 14, 15 and 20 with IC50 8.20 ± 0.35, 9.20 ± 0.40, 7.20 ± 0.20 and
9.60 ± 0.40 µM respectively showed good inhibition when compared with the standard. Structure-
activity relationships have been also established for all compounds. Molecular docking studies were
performed to determine the binding interaction of the compounds with the active site target.
Keywords: Synthesis, quinoline, thiadiazole, antileishmanial, SAR, molecular docking studies
 Correspondence and reprints
E-mail: E-mail: taha_hej@yahoo.com and mtaha@uod.edu.saTel: 00966502057370

1. Introduction
The quinoline is an important heterocyclic moiety found in the basic skeleton of many natural products
[1]. Substituted quinolines are potentially important compounds as they have potent anti-inflammatory,
antiasthmatic, antibacterial, antimalarial activity and also have industrial applications [2-4].
Thiadiazole and their derivatives have been used from ancient time while their synthetic strategy,
physical and chemical properties have studied extensively. They have not only application in medicine
[5,6 ] and agriculture[7-10 ] but also widely used as proficient electron acceptor. Functional materials
play important role in the field of organic electronics, in which thiadiazole have been reported [11].
They have been used as ligands for the coordination of paramagnetic cations [12]. Some derivatives of
thiadiazole exhibit antiferromagnetic interactions while other also possesses photoconductivity [13-
15]. Thiadiazole derivative possesses strong biological activities and thus are extensively used in the
field of pesticides and medicine [16-18].
Leishmaniasis is a severing disease which is initiated by leishmania genus and belongs to family
Trypanosomatidea. This disease is categorized into three types: visceral commonly called Kala-azar,
mucocutaneous and Cutaneous [19-21]. The most dangerous form is visceral in which vital organs are
targeted by the parasite. Long time fever, hyper gammaglobulinemia, pancytopenia, and splenomegaly
are the properties of such severe visceral leishmaniasis. The patient is affected in very short span of
time and can cause death if untreated [22]. Leishmaniasis is transferred through female sandflies and
its bites can affect liver, spleen and bone marrow [23]. The parasites of leishmaniasis have two
morphological forms which are amastigotes and promastigotes [24]. Each year 1.5 million people
affected from cutaneous while 500,000 new cases appear from visceral leishmaniasis. Seventy (70)
countries of the world affected by cutaneous leishmaniasis and major cases occur in Afghanistan,
Pakistan, Saudi Arabia, Brazil and Syria [25, 26]. Sitamaquine (1) [27] Figure 1 (WR6026), an 8-
aminoquinoline derivative, has been shown to have antileishmanial activity in Phase II studies, but
confirmation of such activity during Phase III studies is still lacking.
Sitamaquine
Figure 1
Allopurinol [28] and rifampicin [29] showed activity in experimental systems, but proved
disappointing in clinical trials. Treatment of visceral leishmania is limited because of drug resistance
2

and keeping that in mind, quinoline based derivatives have been synthesized and evaluated for their
antileishmanial and found to be most active Figure 2 [30].
Figure 2
Quinoline-based gold complexes were synthesized, by Catherine Hemmert and subjected for
antileishmanial activity, which showed good in vivo activity Figure 3 [31].
Figure 3
A series of nitro-substituted thiadiazole derivatives Figure 4 were synthesized and evaluated for their
antileishmanial activity. Compound given has high potency when compared with other analogs [32].
Figure 4
Leishmaniasis can be treat by using tolerated drugs. Currently, glucantime, pentostam, pentamidine
and amphotericin are the drugs which are used for treatment of leishmaniasis [33,34]. However,
treatment with these current drugs suffers from numerous limitations like toxicity, cost, parenteral
administration, and banquet of drug resistance, and reverts in HIV–Leishmania co-infected patients.
Therefore, there is still a horrible need for novel effective and anodyne drugs in the absence of a
forthcoming vaccine.
Keeping in view the biological importance of these classes of heterocycles i.e quinoline and
thiadiazole, in this study we are going to report the synthesis of quinoline-based thiadiazole hybrid
analogs, their in vitro leishmanicidal activity and molecular docking.
2.1. Results and Discussion
The methyl 6-quinoline carboxylate I was refluxed with methylated hydrazine hydrate for 6 hours to
get compound II. The compound II was refluxed with Lawesson's reagent in toluene for 10 hours to
3

get compound III. The compound III was reacted with various aryl aldehyde in the presence of POCl3
and Pyridine to form compounds 1-20.
Structure of Basic skeleton
Table-1: Synthesis of quinoline based thiadiazole derivatives (1-20) and their antileishmanial potential
IC50 ± SEMa [M]
IC50 ± SEMa [M]
S.No.
R
S.No.
11
R
8.20 ± 0.35
0.04 ± 0.01
1
0.70 ± 0.1
4.68 ± 0.20
6.30 ± 0.30
2
3
12
13
0.08 ± 0.01
4

9.20 ± 0.40
0.90 ± 0. 10
14
4
7.20 ± 0.20
2.10 ± 0. 10
4.10 ± 0. 20
15
16
5
6
05.10 ± 0.25
5.60 ± 0.21
0.980 ± 0.02
3.60 ± 0.20
3.40 ± 0.20
1.18 ± 0.1
17
18
19
7
8
9
2.10 ± 0.15
3.20 ± 0.20
F
9.60 ± 0.40
20
10
7.02 ± 0. 09µM
Standard Pentamidine
2.2. Biological activity
Our group is continuous working on bioactive molecules [35]. New series of quinoline-based
thiadiazole analogs (1-20) were synthesized and evaluated for their antileishmanial activity. Out of
twenty analogs, sixteen analogs 1-10, 12, 13, 16, 17, 18 and 19 with IC50 values 0.04 ± 0.01, 0.70 ±
0.1, 0.08 ± 0.01, 0.90 ± 0.10, 2.10 ± 0.10, 4.10 ± 0.20, 3.40 ± 0.20, 1.18 ± 0.1, 2.10 ± 0.15, 3.20 ±
0.20, 4.68 ± 0.20, 6.30 ± 0.30, 05.10 ± 0.25, 5.60 ± 0.21, 0.980 ± 0.02 and 3.60 ± 0.20 µM
respectively showed excellent antileishmanial potential when compared with the standard drug
pentamidine (IC50 7.02 ± 0. 09µM). Analogs 11, 14, 15 and 20 with IC50 8.20 ± 0.35, 9.20 ± 0.40, 7.20
5

± 0.20 and 9.60 ± 0.40 µM respectively also showed good inhibitions when compared with the
standard. The structure-activity relationship was mainly based on substitution pattern on phenyl part
attached to thiadiazole. Observing the potency of the compounds, it was noticed that those analogs
having two hydroxyl groups present in phenyl ring i.e compounds 1, a 2,3-dihydroxy analog (IC50
value = 0.04 ± 0.01) 2, a 2,4-dihydroxy analog (IC50 value = 0.70 ± 0.1) 3, a 2,3-dihydroxy analog
(IC50 value = 0.08 ± 0.01) and 4, a 2,3-dihydroxy analog (IC50 value = 0.90 ± 0. 10) showed the
excellent inhibition. The greater potential shown by these compounds might be due to hydroxyl that
may be involved in hydrogen bonding. The small activity difference among these analogs might be due
to the position difference of the substituents. Those analogs having methoxy along with hydroxyl
groups present on the same phenyl ring at various positions also showed excellent inhibition such as
compounds 5, a 2-hydroxy-5-methoxy analog (IC50 value = 2.10 ± 0. 10) 6, a 2-hydroxy-4-methoxy
analog (IC50 value = 4.10 ± 0. 20) and 10, a 3-hydroxy-4-methoxy analog (IC50 value = 3.20 ± 0.20).
The decline in the inhibitory potential of these analogs from dihydroxy analog seems to due to bulky
methoxy group and less number of hydrogen bonding. All those analogs in which only one hydroxyl
group is present at different position also showed potent inhibition such as compounds 7, a 3-hydroxy
analog (IC50 value = 3.40 ± 0.20) 8, a 2-hydroxy analog (IC50 value = 1.18 ± 0.1) and 9 a 4-hydroxy
analog (IC50 value = 2.10 ± 0.15). The compound 8 showed greater potential then analog 7 and 9
which seems due to difference in position of hydroxyl group on phenyl ring. Compounds having
fluorine atom in phenyl ring at the the ortho, meta and para position also exhibit fantastic inhibition as
shown by compounds 17, a 3-flouro analog (IC50 value = 5.60 ± 0.21) 18, a 2-flouro analog (IC50 value
= 0.980 ± 0.02) and 19 a 4-flouro analog (IC50 value = 3.60 ± 0.20). The compound 18 was superior
then compound 17 and 19 which that substituent at ortho position plays a vital role in this inhibition.
Compounds having a nitro group in phenyl ring at ortho and para position also showed potent
inhibition as shown by compound 12, a 2-nitro substituted analog (IC50 value = 4.68 ± 0.20) and 13 a
4-nitro substituted analog (IC50 value = 6.30 ± 0.30) while the nitro group at 3 position also showed
good inhibition such as compound 11 (IC50 value = 8.20 ± 0.35). Pyridine nitrogen atom at the ortho,
meta, and para position of phenyl ring show good activity. Overall in this study, we observed that
either EDG or EWG on phenyl ring play an important role in inhibition but EDG are superior to some
extent. The position of substituents also played a vital role. The binding interactions of the compounds
were confirmed by molecular docking studies.
2.3. Molecular docking
The molecular docking procedure was used to predict the binding interaction of the compounds
in the binding pocket of the enzyme. The 3D crystal structure of the pteridine reductase 1 enzyme of L.
donovani (PDB ID: 2XOX) [36] was retrieved from the protein databank. All the ions and water
6

molecules were discarded, and the hydrogen atoms were added to the enzyme by the 3D protonation
using the MOE (Molecular Operating Environment) software. The enzyme was then energy minimized
by the default parameters of the MOE for the stability and further assessment of the enzyme. The
structures of the new series of quinoline-based thiadiazole compounds were built in MOE and energy
minimized using the MMFF94x forcefield and gradient: 0.05. The synthesized compounds were
docked into the active site of the target enzyme using MOE-Dock program with default parameters i.e.,
Placement: Triangle Matcher, Rescoring: London dG. For each ligand ten conformations were
generated. The top-ranked conformation of each compound was used for further analysis.
2.4. Docking studies
The molecular docking process was carried out in order to inspect the prospective interactions
between the quinoline based thiadiazole analogs and the active site of the pteridine reductase 1 (PTR1)
enzyme of L. donovani. The docking results showed that all the compounds were well accommodated
in the active site of Leishmania enzyme. From the docking conformation of the most potent
compounds, compound 1 (IC50 = 0.04 ± 0.01) was observed that this compound formed five hydrogen
bonds and one arene-cation contact with the active residues of the binding pocket. Two hydroxyl
groups attached to the phenyl ring of the compound formed H-bonds with the Arg-A17 and Asp-A181
and phenyl ring showed π interaction with the Arg-A17 residue. The –NH of the Arg-A17 interacts
through its H with the nitrogen of the 1, 3, 4-thiadiazole moiety of the compound as shown in the
Figure (5A). The strong bonding network of the compound with the residues of the active pocket
might be one of the reasons to show excellent biological activity.
The docking conformation of the second most active compound, compound 3 with IC50 value
of 0.08 ± 0.01, it was noticed that this compound has shown three polar interactions with the His-A38,
Arg-A39 and Ser-A40 residues as shown in the Figure (5B). The hydroxyl moieties of the phenyl ring
of the compound showed polar interactions with the –NH groups of the His-A38, Arg-A39 and Ser-
A40 residues. The good interactions of the compound with the residues might be due to the presence of
the electron donating groups (-OH). It seemed that the presence of the ortho-hydroxyl substituent on
the phenyl ring of compound 1 might be responsible for the additional interactions with the active site
of the enzyme. If we compare the compound 1 and 3, the only difference is in the position of the –OH
groups. The docking results showed that compound 2 (IC50 = 0.70 ± 0.1) exhibited good interactions
with the residues of the enzyme. This compound established two polar interactions, one arene-cation
and one arene-arene contact with the active residues His-A38, Arg-A39 and Ser-A146 of the active site
of the target protein as shown in the Figure (5C). His-A38 and Arg-A39 were observed making an
arene-arene linkage and arene-cation contact with the electronic cloud of the phenyl ring of the
compound. Arg-A39 formed a hydrogen bond with the nitrogen atom of the 1,3,4-thiadiazole. The
7

hydroxyl group of the phenyl ring interacts through its H with the oxygen atom of the –OH group of
the Ser-A146 residue. The good inhibitory activity of the compound might be due to the availability of
the ortho/para –OH groups of the phenyl ring enhancing the electronic density of the compound. The
compound 4 and compound 8 have shown moderate inhibitory activity as compared to compound 1, 3
and 2. The compound 4 (0.90 ± 0. 10) has two ortho hydroxyl groups while compound 8 (1.18 ± 0.1)
has only one ortho hydroxyl group so the one extra –OH moiety at the phenyl ring might be the reason
of the good biological activity of the compound 4. The docked conformation of the compound 4
showed two polar interactions, two arene-cation and two arene-arene interactions with the Arg-A17,
His-A38 and Arg-A39 residues as shown in the Figure (5D) while compound 8 exhibited three
interactions. Arg-A17 formed an arene-cation linkage with the π electrons of the quinoline moiety of
the compound 8 as shown in the Figure (6A).
Among the halogen-based derivatives, compound 18 showed good inhibitory activity with IC50 of
0.980± 0.02 and formed one hydrogen bond with the His-A38 as shown in the Figure (6B). The good
biological activity of the compound may be due to the existence of the ortho halogen group i-e fluorine
at the phenyl ring of the compound.
8

Figure 5: Docking conformation of compound 1 (A), 3 (B), 2 (C) and 4 (D) in the active site of
pteridine reductase 1 enzyme.
Figure 6: Docking conformation of compound 8 (A) and 18 (B) in the active site of pteridine
reductase 1 enzyme.
3.
Conclusion
It is concluded that a new series of quinoline based thiadiazole showed excellent antileishmanial
activity. Fourteen analogs 1-10, 12, 13, 16, 17, 18 and 19 with IC50 values 0.04 ± 0.01, 0.70 ± 0.1, 0.08
± 0.01, 0.90 ± 0.10, 2.10 ± 0.10, 4.10 ± 0.20, 3.40 ± 0.20, 1.18 ± 0.1, 2.10 ± 0.15, 3.20 ± 0.20, 4.68 ±
0.20, 6.30 ± 0.30, 05.10 ± 0.25, 5.60 ± 0.21, 0.980 ± 0.02 and 3.60 ± 0.20 µM respectively, showed
extremely potent inhibition as compared to the standard pentamidine with IC50 is 7.02 ± 0. 09µM.
Analogs 11, 14, 15 and 20 with IC50 8.20 ± 0.35, 9.20 ± 0.40, 7.20 ± 0.20 and 9.60 ± 0.40 µM
respectively also showed good inhibition.
9

4.
Acknowledgment:
The authors would like to acknowledge University of Dammam for the financial support. Syahrul
Imran would like to thank Universiti Teknologi MARA for the support under Bestari Perdana grant file
No. 600-IRMI/PERDANA 5/3 BESTARI (041/2018).
Experimental
General procedure
Synthesis of quinoline-6-carbothiohydrazide.
The 20 mmole (3.74g) quinoline-6-carbohydrazide was refluxed with 20 mmole (8.09g) Lawesson's
reagent in toluene for 10 hours to get quinoline-6-carbothiohydrazide. The crude product was washed
with diethyl ether and recrystallized in methanol to get pure quinoline-6-carbothiohydrazide with 90 %
(3.65 g).
General Procedure for the synthesis of quinoline based thiadiazole derivatives (1-20)
A mixture of quinoline-6-carbothiohydrazide (0.5 mmol) and various aromatic acid (0.5 mmol) in
POCl3 (5 ml) was refluxed for 4-6 hours. The mixture was cooled and poured onto crushed ice. It was
neutralized with NaHCO3 solution and the resulting solid mass precipitated out was filtered, dried, and
crystallized in methanol.
In vitro bioassay
The assay was carried out according to Seifert. Briefly, THP-1 cells (ATCC) were cultured in RPMI-
1640 (R5886 Sigma) supplemented with 1% L-glutamine and 10% HI-FBS (complete medium) before
harvested at 1.0 x 106 cells/mL. Cells were diluted to 2.0 x 105 cells/mL with the complete medium,
seeded in 16-well Lab Tek tissue culture chamber slide (Fisher Scientific) at a seeding density of
5.0x104 macrophage/well (100µL) and allowed to adhere by the addition of PMA (Phorbol -12
myristate Acetate P8139 Sigma) for 3 days at 37°C in a 5% CO2 – 95% air mixture. Macrophages were
then infected with long-slender (stationary stage) of Leishmania major promastigote (JISH118)
obtained from The London School of Hygiene and Tropical Medicine (LSHTM) United Kingdom,
which were cultured at 26°C in Schneiders Drosophila Medium (S0146 Sigma), at a macrophage-
10

promastigote ratio of 1:5. Infected macrophages were maintained at 34°C in a 5% CO2 – 95% air
mixture. After 48 hours, extracellular parasites were removed by substituting the overlay with new
fresh RPMI-1640 medium supplemented with 1% L-glutamine. Fresh drug and test compounds with
various concentrations were added and drug or compound activity was determined from the percentage
of infected cells in drug-treated cultures in relation to non-treated cultures using GraphPad Prism after
methanol fixation and Giemsa staining.
3-(5-(Quinolin-6-yl)-1,3,4-thiadiazol-2-yl)benzene-1,2-diol (1)
1
IR (KBr): 3306 (OH), 3070 (Ar CH), 1573 (C=N), 1230 (C-S-C); H NMR (500 MHz, DMSO-d6): 
11.11 (s, 1H, OH), 9.25 (s, 1H, OH), 9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.64 (d, 1H, J = 1.0 Hz), 8.56
(d, 1H, J = 8.0 Hz), 8.27 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.18 (d, 1H, J = 8.5 Hz), 7.67 (dd, 1H, J = 4.0, J
13
= 8.0 Hz), 7.03 (d, 1H, J = 7.0 Hz), 6.90(d, 1H, J = 7.5 Hz), 6.79 (t, 1H, J = 8.0, J = 15.5 Hz); C
NMR (125 MHz, DMSO-d6): δ 174.0, 174.0, 149.8, 148.4, 145.4, 143.8, 136.2, 134.2, 133.6, 129.2,
128.3, 127.1, 125.0, 123.1, 121.3, 121.3, 117.1; Anal. Calcd for, C17H11N3O2S: C, 63.54; H, 3.45; N,
13.08; Found C, 63.53; H, 3.43; N, 13.06; HR-ESI-MS: m/z calcd for C22H17N5O3, [M + H]+ 322.0650;
Found 322.0334.
4-(5-(Quinolin-6-yl)-1,3,4-thiadiazol-2-yl)benzene-1,3-diol (2)
1
IR (KBr): 3423 (OH), 3074 (Ar CH), 1588 (C=N), 1228 (C-S-C); H NMR (500 MHz, DMSO-d6): 
11.44 (s, 1H, OH), 9.99 (s, 1H, OH), 9.03 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.61 (d, 1H, J = 1.0 Hz), 8.54
(d, 1H, J = 8.0 Hz), 8.25 (dd, 1H, J = 2.0, J = 9.0 Hz), 8.16 (d, 1H, J = 9.0 Hz), 7.67 (dd, 1H, J = 4.5, J
= 8.5 Hz), 7.37 (d, 1H, J = 8.5 Hz), 6.40 (dd, 1H, J = 2.0, J = 8.5 Hz), 6.35 (d, 1H, J = 2.0 Hz); 13C
NMR (125 MHz, DMSO-d6):  174.2, 174.2, 159.8, 156.4, 149.6, 148.4, 136.2, 134.2, 133.6, 130.2,
129.3, 128.3, 127.1, 121.4, 116.3, 109.1, 105.3; Anal. Calcd for, C17H11N3O2S: C, 63.54; H, 3.45; N,
13.08; Found C, 63.52; H, 3.46; N, 13.09; HR-ESI-MS: m/z calcd for C22H17N5O3, [M + H]+ 322.0650;
Found 322.0564.
4-(5-(Quinolin-6-yl)-1,3,4-thiadiazol-2-yl)benzene-1,2-diol (3)
11

1
IR (KBr): 3260 (OH), 3075 (Ar CH), 1576 (C=N), 1224 (C-S-C); H NMR (500 MHz, DMSO-d6): 
9.34 (s, 2H, 2 x OH), 9.02 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.58 (d, 1H, J = 1.5 Hz), 8.54 (dd, 1H, J = 1.5,
J = 8.5 Hz), 8.23 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.15 (d, 1H, J = 8.5 Hz), 7.66 (dd, 1H, J = 4.0, J = 3.0
Hz), 7.29 (d, 1H, J = 2.0 Hz), 6.99 (dd, 1H, J = 2.0, J = 8.0 Hz), 6.82 (d, 1H, J = 8.0 Hz); 13C NMR
(125 MHz, DMSO-d6):  174.0, 174.0, 148.4, 145.7, 149.7, 147.1, 136.2, 134.2, 133.6, 129.3, 128.3,
127.1, 127.3, 116.0, 121.4, 114.2, 121.3; Anal. Calcd for, C17H11N3O2S; C, 63.54; H, 3.45; N, 13.08;
Found C, 63.51; H, 3.42; N, 13.06; HR-ESI-MS: m/z calcd for C22H17N5O3, [M+ + H]+ 322.0650;
Found 322.0370.
2-(5-(Quinolin-6-yl)-1,3,4-thiadiazol-2-yl)benzene-1,4-diol (4)
1
IR (KBr): 3520 (OH), 3070 (Ar CH), 1569 (C=N), 1232 (C-S-C); H NMR (500 MHz, DMSO-d6): 
10.35 (s, 1H, OH), 9.03 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.99 (s, 1H, OH), 8.63 (d, 1H, J = 2.0 Hz), 8.54
(d, 1H, J = 8.0 Hz), 8.27 (dd, 1H, J = 2.0, J = 9.0 Hz), 8.17 (d, 1H, J = 8.5 Hz), 7.67 (dd, 1H, J = 4.0, J
13
= 8.0 Hz), 7.04 (d, 1H, J = 2.5 Hz), 6.80 - 6.76 (m, 2H); C NMR (125 MHz, DMSO-d6):  174.0,
174.0, 150.2, 149.8, 148.4, 147.6, 136.3, 134.2, 133.6, 129.3, 128.3, 121.4, 127.1, 125.0, 117.4, 117.2,
114.2; Anal. Calcd for, C17H11N3O2S, C, 63.54; H, 3.45; N, 13.08; Found C, 63.52; H, 3.44; N, 13.05;
HR-ESI-MS: m/z calcd for C22H17N5O3, [M + H]+ 322.0650; Found 322.1098.
4-Methoxy-2-(5-(quinolin-6-yl)-1,3,4-thiadiazol-2-yl)phenol (5)
1
IR (KBr): 3366 (OH), 3074 (Ar CH), 1590 (C=N), 1231 (C-S-C); H NMR (500 MHz, DMSO-d6): 
10.66 (s, 1H, OH), 9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.63 (d, 1H, J = 1.0 Hz), 8.55 (d, 1H, J = 8.0
Hz), 8.27 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.17 (d, 1H, J = 9.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0 Hz),
7.18 (d, 1H, J = 3.0 Hz), 6.95 (dd, 1H, J = 2.5, J = 8.5 Hz), 6.90 (d, 1H, J = 9.0 Hz), 3.76 (s, 3H,
13
OCH3); C NMR (125 MHz, DMSO-d6):  174.0, 174.0, 153.6, 149.8, 148.4, 147.4, 136.2, 134.2,
133.6, 129.3, 128.3, 127.1, 124.5, 121.4, 117.2, 115.6, 112.4, 55.7; Anal. Calcd for, C18H13N3O2S, C,
64.46; H, 3.91; N, 12.53; Found C, 64.43; H, 3.90; N, 12.52; HR-ESI-MS: m/z calcd for C18H13N3O2S,
[M+H]+
336.0801;
Found
336.1090.
12

5-Methoxy-2-(5-(quinolin-6-yl)-1,3,4-thiadiazol-2-yl)phenol (6)
1
IR (KBr): 3430 (OH), 3071 (Ar CH), 1585 (C=N), 1234 (C-S-C); H NMR (500 MHz, DMSO-d6): 
11.59 (s, 1H, OH), 9.04 (dd, 1H, J = 1.5, J = 4.5 Hz), 8.62 (s, 1H), 8.55 (d, 1H, J = 8.0 Hz), 8.26 (dd,
1H, J = 2.0, J = 9.0 Hz), 8.17 (d, 1H, J = 8.5 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.5 Hz), 7.49 (d, 1H, J =
13
8.5 Hz), 6.57 (dd, 1H, J = 2.0, J = 8.5 Hz), 6.53 (d, 1H, J = 2.0 Hz), 3.80 (s, 3H, OCH3); C NMR
(125 MHz, DMSO-d6):  174.0, 174.0, 162.1, 156.1, 149.8, 148.5, 136.2, 134.2, 133.6, 129.8, 129.3,
128.3, 127.1, 121.4, 116.0, 107.3, 104.1, 55.6; Anal. Calcd for, C18H13N3O2S, C, 64.46; H, 3.91; N,
12.53; Found C, 64.45; H, 3.90; N, 12.52; HR-ESI-MS: m/z calcd for C18H13N3O2S, [M+H]+
336.0801; Found 336.0695.
3-(5-(Quinolin-6-yl)-1,3,4-thiadiazol-2-yl)phenol (7)
1
IR (KBr): 3417 (OH), 3067 (Ar CH), 1586 (C=N), 1237 (C-S-C); H NMR (500 MHz, DMSO-d6): 
9.66 (s, 1H, OH), 9.03 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.54 (d, 1H, J = 8.0 Hz), 8.43 (s, 1H), 8.25 (d, 1H,
J = 9.0 Hz), 8.16 (d, 1H, J = 9.0 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.30 (d, 1H, J = 7.5 Hz), 7.27
13
(d, 1H, J = 5.0 Hz), 7.15 (d, 1H, J = 7.5 Hz), 6.87(d, 1H, J = 7.0 Hz); C NMR (125 MHz, DMSO-
d6):  174.0, 174.0, 162.1, 156.1, 149.8, 148.5, 136.2, 134.2, 133.6, 129.8, 129.3, 128.3, 127.1, 121.4,
116.0, 107.3, 104.1, 55.6. Anal. Calcd for, C17H11N3OS, C, 66.87; H, 3.63; N, 13.76; Found C, 66.85;
H, 3.62; N, 13.73; HR-ESI-MS: m/z calcd for C18H13N3O2S, [M+H]+ 306.0696; Found 306.1070.
2-(5-(Quinolin-6-yl)-1,3,4-thiadiazol-2-yl)phenol (8)
1
IR (KBr): 3423 (OH), 3072 (Ar CH), 1584 (C=N), 1227 (C-S-C); H NMR (500 MHz, DMSO-d6): 
9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.64 (s, 1H, OH), 8.55 (d, 1H, J = 8.0 Hz), 8.41 (s, 1H), 8.27 (dd,
1H, J = 1.5, J = 8.5 Hz), 8.18 (d, 1H, J = 9.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.61 (d, 1H, J =
7.5 Hz), 7.35 (dd, 1H, J = 1.0, J = 8.0 Hz), 6.98 (dd, 2H, J = 8.0, J = 13.5 Hz); 13C NMR (125 MHz,
DMSO-d6):  174.0, 174.0, 162.1, 156.1, 149.8, 148.5, 136.2, 134.2, 133.6, 129.8, 129.3, 128.3, 127.1,
121.4, 116.0, 107.3, 104.1, 55.6. Anal. Calcd for, C17H11N3OS, C, 66.87; H, 3.63; N, 13.76; Found C,
13

66.85; H, 3.62; N, 13.74; HR-ESI-MS: m/z calcd for C18H13N3O2S, [M+H]+ 306.0696; Found
306.0432.
4-(5-(Quinolin-6-yl)-1,3,4-thiadiazol-2-yl)phenol (9)
1
IR (KBr): 3395 (OH), 3073 (Ar CH), 1583 (C=N), 1233 (C-S-C); H NMR (500 MHz, DMSO-d6): 
9.97 (s, 1H, OH), 9.02 (t, 1H, J = 2.5, J = 4.0 Hz), 8.53 (d, 1H, J = 8.0 Hz), 8.42 (s, 1H), 8.24 (t, 1H, J
= 8.0, J = 9.0 Hz), 8.15 (d, 1H, J = 8.5 Hz), 7.65 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.62 (d, 2H, J = 8.5 Hz),
6.88(d, 2H, J = 8.5 Hz); 13C NMR (125 MHz, DMSO-d6):  174.0, 174.0, 162.1, 156.1, 149.8, 148.5,
136.2, 134.2, 133.6, 129.8, 129.3, 128.3, 127.1, 121.4, 116.0, 107.3, 104.1, 55.6. Anal. Calcd for,
C17H11N3OS, C, 66.87; H, 3.63; N, 13.76; Found C, 66.85; H, 3.62; N, 13.75; HR-ESI-MS: m/z calcd
for C18H13N3O2S, [M+H]+ 306.0696; Found 306.0634.
2-Methoxy-5-(5-(quinolin-6-yl)-1,3,4-thiadiazol-2-yl)phenol (10)
1
IR (KBr): 3376 (OH), 3071 (Ar CH), 1590 (C=N), 1233 (C-S-C); H NMR (500 MHz, DMSO-d6): 
9.03 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.59 (s, 1H, OH), 8.54 (t, 1H, J = 7.5, J = 8.0 Hz), 8.36 (s, 1H), 8.24
(dd, 1H, J = 1.0, J = 8.5 Hz), 8.15 (d, 1H, J = 9.0 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.5 Hz), 7.32 (s, 1H),
13
7.11 (t, 1H, J = 6.5, J = 8.0 Hz), 7.01 (d, 1H, J = 8.5 Hz), 3.83 (s, 3H, OCH3); C NMR (125 MHz,
DMSO-d6):  174.0, 174.0, 162.1, 156.1, 149.8, 148.5, 136.2, 134.2, 133.6, 129.8, 129.3, 128.3, 127.1,
121.4, 116.0, 107.3, 104.1, 55.6; Anal. Calcd for, C18H13N3O2S, C, 64.46; H, 3.91; N, 12.53; Found C,
64.45; H, 3.90; N, 12.51; HR-ESI-MS: m/z calcd for C18H13N3O2S, [M+H]+ 336.0801; Found
336.0695.
4.5.11.
2-(3-Nitrophenyl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (11)
1
IR (KBr): 3076 (Ar CH), 1593 (C=N), 1538 (N-O), 1360 (N-O), 1237 (C-S-C); H NMR (500 MHz,
DMSO-d6):  9.04 (dd, 1H, J = 1.5 J = 4.0 Hz), 8.60 (s, 2H), 8.56 (t, 1H, J = 1.0, J = 8.5 Hz), 8.30 -
8.20 (m, 3H), 8.18 (d, 1H, J = 8.5 Hz), 7.81 (t, 1H, J = 8.0, J = 16.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.0
Hz); 13C NMR (125 MHz, DMSO-d6):  174.2, 174.2, 149.8, 148.3, 148.6, 137.1, 136.5, 134.5, 134.2,
14

133.8, 130.2, 129.5, 128.5, 127.1, 123.8, 122.9, 121.5. Anal. Calcd for, C17H10N4O2S, C, 61.07; H,
3.01; N, 16.76; Found C, 61.06; H, 3.01; N, 16.75. HR-ESI-MS: m/z calcd for C17H10N4O2S, [M+H]+
335.0592; Found 335.0998
2-(2-Nitrophenyl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (12)
1
IR (KBr): 3074 (Ar CH), 1591 (C=N), 1536 (N-O), 1356 (N-O), 1235 (C-S-C); H NMR (500 MHz,
DMSO-d6):  9.04 (d, 1H, J = 3.0 Hz), 8.65 (s, 1H), 8.56 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.27 (d, 1H, J
= 9.0 Hz), 8.20 (dd, 2H, J = 8.0, J = 12.5 Hz), 8.12 (d, 1H, J = 7.5 Hz), 7.88 (t, 1H, J = 7.0, J = 14.5
13
Hz), 7.73 (t, 1H, J = 7.0, J = 15.0 Hz), 7.68 (dd, 1H, J = 4.0, J = 8.0 Hz); C NMR (125 MHz,
DMSO-d6):  174.2, 174.2, 149.8, 148.3, 146.6, 136.5, 135.4, 134.4, 133.8, 131.7, 129.7, 129.6, 128.5,
128.5, 127.3, 124.5, 121.6. Anal. Calcd for, C17H10N4O2S, C, 61.07; H, 3.01; N, 16.76; Found C,
61.05; H, 3.01; N, 16.74. HR-ESI-MS: m/z calcd for C17H10N4O2S, [M+H]+ 335.0592; Found
335.0634
2-(4-Nitrophenyl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (13)
1
IR (KBr): 3075 (Ar CH), 1594 (C=N), 1534 (N-O), 1359 (N-O), 1233 (C-S-C); H NMR (500 MHz,
DMSO-d6):  9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.62 (s, 1H), 8.56 (dd, 1H, J = 1.5, J = 8.5 Hz), 8.34
(d, 2H, J = 8.0 Hz), 8.26 (d, 1H, J = 8.0 Hz), 8.20 (d, 1H, J = 9.0 Hz), 8.06 (d, 2H, J = 8.0 Hz), 7.68
13
(dd, 1H, J = 4.5, J = 8.5 Hz); C NMR (125 MHz, DMSO-d6):  174.2, 174.2, 149.8, 148.6, 147.8,
139.5, 136.5. 134.4, 133.8, 129.5, 128.6, 128.5, 128.5, 127.3, 124.5, 124.5, 121.6, Anal. Calcd for,
C17H10N4O2S, C, 61.07; H, 3.01; N, 16.76; Found C, 61.05; H, 3.01; N, 16.75; HR-ESI-MS: m/z calcd
for C17H10N4O2S, [M+H]+ 335.0592; Found 335.0498.
2-(Pyridin-3-yl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (14)
IR (KBr): 3084 (Ar CH), 1592 (C=N), 1236 (C-S-C); 1H NMR (500 MHz, DMSO-d6):  12.26 (s, 1H,
NH), 9.03 (dd, 1H, J = 1.5, J = 4.5 Hz), 8.91 (s, 1H, CH=N), 8.65 (d, 1H, J = 4.0 Hz), 8.62 (s, 1H),
8.57 (s, 1H), 8.55 (dd, 1H, J = 1.0, J = 8.0 Hz), 8.25 (d, 1H, J = 8.5 Hz), 8.20 (dd, 2H, J = 7.5, J =
15

16.0 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.53 (dd, 1H, J = 5.0, J = 7.0 Hz); 13C NMR (125 MHz,
DMSO-d6):  174.2, 174.2, 149.8, 148.8, 148.6, 147.7, 136.5. 134.4, 134.1, 133.8, 133.5, 129.5, 128.6,
127.3, 124.1, 121.4, Anal. Calcd for, C16H10N4S, C, 66.19; H, 3.47; N, 19.30; Found C, 66.18; H, 3.45;
N, 19.30. HR-ESI-MS: m/z calcd for C17H10N4O2S, [M+H]+ 291.0693; Found 290.0329.
2-(Pyridin-4-yl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (15)
IR (KBr): 3082 (Ar CH), 1590 (C=N), 1234 (C-S-C); 1H NMR (500 MHz, DMSO-d6):  12.37 (s, 1H,
NH), 9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.68 (s, 2H), 8.63 (s, 1H, CH=N), 8.56 (d, 1H, J = 8.0 Hz),
8.51 (s, 1H), 8.25 (d, 1H, J = 8.5 Hz), 8.17 (d, 1H, J = 9.0 Hz), 7.72 (s, 2H), 7.67 (dd, 1H, J = 4.0, J =
13
8.5 Hz); C NMR (125 MHz, DMSO-d6):  174.2, 174.2, 149.8, 149.9, 148.6, 149.7, 143.8, 136.5,
134.4, 133.8, 129.5, 128.3, 127.3, 121.6, 121.5, 121.4; Anal. Calcd for, C16H10N4S, C, 66.19; H, 3.47;
N, 19.30; Found C, 66.17; H, 3.45; N, 19.30; HR-ESI-MS: m/z calcd for C17H10N4O2S, [M+H]+
291.0693; Found 290.1004.
2-(Pyridin-2-yl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (16)
IR (KBr): 3080 (Ar CH), 1591 (C=N), 1234 (C-S-C); 1H NMR (500 MHz, DMSO-d6):  9.04 (dd, 1H,
J = 1.0, J = 4.0 Hz), 8.64 (s, 1H, , H-6), 8.57 (d, 2H, J = 10.0 Hz), 8.26 (d, 1H, J = 8.5 Hz), 8.18 (d,
1H, J = 9.0 Hz), 8.04 (d, 1H, J = 7.5 Hz), 7.93 (t, 1H, J = 7.5, J = 15.0 Hz), 7.67 (dd, 1H, J = 4.0, J =
8.5 Hz), 7.46 (t, 1H, J = 6.0, J = 11.5 Hz); 13C NMR (125 MHz, DMSO-d6):  174.2, 174.2, 157.5,
149.8, 149.3, 148.4, 136.5, 137.3. 134.4, 133.8, 129.3, 128.5, 127.3, 124.1, 123.7, 121.6; Anal. Calcd
for, C16H10N4S, C, 66.19; H, 3.47; N, 19.30; Found C, 66.18; H, 3.46; N, 19.30. HR-ESI-MS: m/z
calcd for C17H10N4O2S, [M+H]+ 291.0693; Found 291.0856.
2-(4-Fluorophenyl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (17)
IR (KBr): 3080 (Ar CH), 1588 (C=N), 1260 (F-C), 1234 (C-S-C); 1H NMR (500 MHz, DMSO-d6): 
12.11 (s, 1H, NH), 9.03 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.61 (s, 1H, CH=N), 8.54 (d, 1H, J = 1.0 Hz),
8.53 (d, 1H, J = 3.5 Hz), 8.25 (d, 1H, J = 8.5 Hz), 8.16 (d, 1H, J = 8.5 Hz), 7.85 (t, 2H, J = 7.5, J =
13.5 Hz), 7.66 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.34 (t, 2H, J = 9.0, J = 17.5 Hz); 13C NMR (125 MHz,
16

DMSO-d6):  174.2, 174.2, 162.8, 149.8, 148.6, 136.5, 134.4, 133.8, 129.2, 129.5, 129.2, 129.2,
128.5, 127.3, 121.6, 116.2, 116.1; Anal. Calcd for, C17H10FN3S, C, 66.43; H, 3.28; N, 13.67; Found C,
66.42; H, 3.26; N, 13.65; HR-ESI-MS: m/z calcd for C17H10N4O2S, [M+H]+ 308;0647 Found
308.0800
2-(2-Fluorophenyl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (18)
IR (KBr): 3078 (Ar CH), 1587 (C=N), 1258 (F-C), 1235 (C-S-C); 1H NMR (500 MHz, DMSO-d6): 
12.22 (s, 1H, NH), 9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.77 (s, 1H, CH=N), 8.63 (s, 1H), 8.55 (t, 1H, J
= 7.5, J = 8.5 Hz), 8.26 (d, 1H, J = 8.5 Hz), 8.17 (d, 1H, J = 9.0 Hz), 8.02 (t, 1H, J = 7.0, J = 14.0 Hz),
7.67 (dd, 1H, J = 4.5, J = 8.5 Hz), 7.55 (dd, 1H, J = 6.5, J = 13.5 Hz), 7.35 (dd, 2H, J = 7.0, J = 11.0
Hz); 13C NMR (125 MHz, DMSO-d6):  174.0, 174.0, 158.4, 149.7, 148.4, 136.5, 134.4, 133.8, 130.4,
129.5, 129.2, 128.6, 127.3, 124.9, 123.6, 121.6, 114.8; Anal. Calcd for, C17H10FN3S, C, 66.43; H, 3.28;
N, 13.67; Found C, 66.42; H, 3.26; N, 13.65; HR-ESI-MS: m/z calcd for C17H10N4O2S, [M+H]+
308;0647; Found 308.1073.
2-(3-Fluorophenyl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (19)
IR (KBr): 3083 (Ar CH), 1586 (C=N), 1261 (F-C), 1236 (C-S-C); 1H NMR (500 MHz, DMSO-d6): 
12.21 (s, 1H, NH), 9.04 (dd, 1H, J = 1.5, J = 4.0 Hz), 8.62 (s, 1H, CH=N), 8.56 (dd, 1H, J = 1.5, J =
8.5 Hz), 8.52 (s, 1H), 8.25 (d, 1H, J = 8.5 Hz), 8.17 (d, 1H, J = 9.0 Hz), 7.67 (dd, 1H, J = 4.0, J = 8.5
Hz), 7.63 (d, 1H, J = 7.5 Hz), 7.59 (d, 1H, J = 10.5 Hz), 7.55 (t, 1H, J = 6.5, J = 13.5 Hz), 7.32 (t, 1H,
13
J = 7.5, J = 15.5 Hz); C NMR (125 MHz, DMSO-d6):  174.0, 174.1, 162.1, 149.8, 148.4, 136.5,
135.2, 134.4, 133.8, 129.3, 128.5, 127.6, 127.3, 126.6, 121.6, 115.8, 115.6, Anal. Calcd for,
C17H10FN3S, C, 66.43; H, 3.28; N, 13.67; Found C, 66.42; H, 3.27; N, 13.65; HR-ESI-MS: m/z calcd
for C17H10N4O2S, [M+H]+ 308;0647; Found 308.0417.
2-(4-Chlorophenyl)-5-(quinolin-6-yl)-1,3,4-thiadiazole (20)
17

IR (KBr): 3077 (Ar CH), 1583 (C=N), 1233 (C-S-C), 747 (Cl-C); 1H NMR (500 MHz, DMSO-d6): 
9.00(t, 1H, J = 2.0, J = 4.0 Hz), 8.55 (d, 1H, J = 8.0 Hz), 8.40 (s, 1H), 8.21 (t, 1H, J = 8.0, J = 8.0 Hz),
8.12 (d, 1H, J = 8.0 Hz), 7.62 (dd, 1H, J = 4.0, J = 8.0 Hz), 7.60 (d, 2H, J = 8.0 Hz), 6.94 (d, 2H, J =
8.0 Hz); 13C NMR (125 MHz, DMSO-d6):  174.1, 174.0, 149.8, 148.4, 136.5, 134.4, 134.4, 133.8,
131.7, 129.5, 129.4, 129.2, 128.8, 128.8, 128.3, 127.3, 121.4, Anal. Calcd for, C17H10ClN3S, C, 63.06;
H, 3.11; N, 12.98; Found C, 63.05; H, 3.10; N, 12.97; HR-ESI-MS: m/z calcd for C17H10N4O2S,
[M+H]+ 324.0351; Found 324.0319.
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Highlights:
 Novel Quinoline based thiadiazole scaffold 1-20
Evaluation of antileishmanial potential
Identification of a new antileishmanial compounds
Molecular docking
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Graphical abstract
New series of quinoline based thiadiazole analogs (1-20) were synthesized and evaluated for antileishmanial Potential
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