Design, synthesis, docking and biological evaluation of chalcones as promising antidiabetic agents

Article abstract of DOI:10.1016/j.bioorg.2019.103527

Diabetes mellitus (DM) is a serious chronic metabolic disorder which occurs due to dysfunction of insulin and therapeutic approaches are poor. It is an under estimation that 387 million people currently suffering globally with diabetic and more than 592 m

Full text of DOI:10.1016/j.bioorg.2019.103527

Journal Pre-proofs
Design, synthesis, docking and biological evaluation of chalcones as promis-
ing antidiabetic agents
Aluru Rammohan, Baki Vijaya Bhaskar, Nagam Venkateswarlu, Wei Gu,
Grigory V. Zyryanov
PII:
S0045-2068(19)31339-2
DOI:
https://doi.org/10.1016/j.bioorg.2019.103527
YBIOO 103527
Reference:
To appear in:
Bioorganic Chemistry
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Revised Date:
Accepted Date:
15 August 2019
25 October 2019
19 December 2019
Please cite this article as: A. Rammohan, B. Vijaya Bhaskar, N. Venkateswarlu, W. Gu, G.V. Zyryanov, Design,
synthesis, docking and biological evaluation of chalcones as promising antidiabetic agents, Bioorganic Chemistry
(2019), doi: https://doi.org/10.1016/j.bioorg.2019.103527
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Design, synthesis, docking and biological evaluation of chalcones as promising antidiabetic
agents
Aluru Rammohana, b*, Baki Vijaya Bhaskarc, f, Nagam Venkateswarlud,, Wei Guc, Grigory V.
Zyryanova,e
aCenter for Chemical and Pharmaceutical Technology, Ural Federal University, 19 Mira, Yekaterinburg 620002,
Russian Federation
bNatural Products Division, Department of Chemistry, Sri Venkateswara University, Tirupati, India.
cDepartment of Pathophysiology, The Key Immunopathology Laboratory of Guangdong Province, Shantou
University Medical College, Shantou, Guangdong, China-515031.
dState Key Laboratory of Microbial Technology, Shandong University, Qingdao 266200, China.
eUral Division of the Russian Academy of Sciences, I. Ya. Postovskiy Institute of Organic Synthesis, 22 S.
Kovalevskoy Street, Yekaterinburg, Russian Federation
fDepartment of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24060,
United States of America.
*E-mail: rammohan4ever@gmail.com

Abstract
Diabetes mellitus (DM) is a serious chronic metabolic disorder which occurs due to
dysfunction of insulin and therapeutic approaches are poor. It is an under estimation that 387
million people currently suffering globally with diabetic and more than 592 million people may
be affected by 2030. It makes an urgent necessity to discover novel drugs to control amplified
diabetic populations. In this study, amino chalcones (3a-j) were synthesized and hydroxy
chalcones (3g-j) were isolated from natural source such as Sophora interrupta, Clerodendrum
phlomidis and Andrographis macrobotrys. Structural elucidation was carried out using Mass, 1H
13
and C NMR Spectra. In vivo studies were carried out with alloxan induced diabetic rats (100
mg/kg) which reveals compounds 3c, 3a and 3h have significant antidiabetic efficacy with
decreased blood glucose levels in the diabetic rats while compared with control rats. Besides,
docking studies with aldose reductase, dipeptidyl peptidase, PPAR and glucosidase were
monitored which accomplishes that the compounds 3c, 3i, 3a and 3d have eloquent binding
affinity (kcal/mol) with aldose reductase, besides the chalcones 3c, 3b, 3d, 3e and 3i were also
showed inhibition with DPP-IV, PPAR- and -glucosidase. Also, these compounds explicated
distinct interactions i.e., -, -cationic, polar, electrostatic and hydrophobic bonds were
observed with key residues of binding pockets. Bioavailability is disclosed with Lipinski rule of
five and the design pharmacokinetic as well as pharmacodynamic properties are reliable.
Therefore, chalcones were implied as antidiabetic leads for in further studies and could be
worthwhile for the development of new classes of effective antidiabetic agents.
Keywords: Diabetes mellitus, chalcones, docking, ADME

1. Introduction
Diabetes mellitus (DM) is a serious chronic metabolic disorder, categorized in to two types
namely DM-I which is generated by dysfunction of -pancreatic cells, whereas DM-II is caused
from impairment of insulin secretion due to insulin resistance and occurs perturbations in the
glucose homeostasis. This leads to originate several disorders like cardiovascular risks,
blindness, skin infections and renal failure [1]. International Diabetes Federation (IDF) reported
that 366 million people are currently suffering with DM and 552 million people will be affected
by 2030 [2]. Now, biguanides, sulfonyl urease inhibitors, DPP4 inhibitors, trajenta, onglyza and
Nesina, SGLT2 inhibitors, thiazolidinediones and -glucosidase inhibitors are using in the
diabetes clinical practices. However, several adverse effects have been reported such as
diarrhea, liver diseases, renal failure, respiratory tract infections, musculoskeletal pain, enlarged
urination and urinary tract infections [3, 4, 5]. In addition, passable remedial findings are also
not optimistic. Therefore, there must be enormous contemplation is desired to deliberate
peculiar antidiabetic agents with improved steered pharmacological action without adverse
effects.
Chalcones are important classes of open chain flavonoids, essentially synthesized by plants
and numerous synthetic methods also available [6]. Chalcone comprises two aromatic rings are
united by three carbon system i.e., ,  unsaturated carbonyl system. It exhibits a wide range of
therapeutic activities for instance, anticancer, antioxidants [7], anti-inflammatory [8],
antihypertensive [9], antimalarial [10], antiulcer [11], antiviral [12], antiprotozoal [13], and
antimutagenic [14]. Chalcone is a versatile molecule and easily allow to cyclize forming
flavonoid structure. It is an isomeric key step for skeletal modification of biosynthetic pathway.
Based on this feature, several synthetic attempts have been made to produce a new class of
compounds, for example, azachalcones [15], oxazoles [16], pyrazoles [17] and indole grounded
chalcones [18]. Also, amino chalcones were reported as anti-inflammatory and antimicrobial
however antidiabetic activity has not yet been reported [19, 20]. So far, several chalcones have
been rationalized that how their inhibitory modulation deliberates with essential
pharmacological targets such as PPAR-g, DPP-4, a-glucosidase, PTP1B and aldose reductase in
the diabetic clinical management [21]. In the current study, amino and hydroxy chalcones were
achieved and examined their antidiabetic activity with alloxan induced diabetic rats through in
vivo experiments. In addition, in silico studies were conducted with specific molecular targets of
diabetes to confirm the chalcone structural significances for further comprehensive studies.
2. Material and methods
2.1. Chemistry
Chemicals and solvents were purchased from Merck, India and utilized in the present
investigations. Melting points were recorded with Kofler hot stage apparatus and are
uncorrected. The reactions were assessed by thin layer chromatography (TLC) on silica gel F254
1
plates. H and 13C NMR spectra were documented on Bruker Avance spectrophotometer
operating at 600 and 400 MHz (1H); 150 and 75 MHz (13C) using DMSO-d6 and CDCl3 with
TMS as an internal standard. Mass spectra was recorded on Micro Mass VG-7070H mass
spectrometer for ESI and API Q-STAR PULSA i of applied bio-system in positive mode was
used for ESI-TOFMS. The microanalyses were performed on Perkin-Elmer 240C elemental
analyzer and Catalyst -4R microwave oven was used for synthesis reactions. Alloxan

monohydrate was obtained from HIMEDIA Ltd, India. The Accu Chek (Roche diabetes care,
USA), glucometer and strips were purchased from local pharmacy.
2.2. Synthesis of amino chalcones
The preparation of amino chalcones was accomplished by microwave assisted synthesis
[22]. An equimolar ratio of 4-aminoacetophenone (1 mmol) and aromatic aldehyde (1 mmol)
were dissolved in 95% ethanol with catalytic quantity of NaOH (1-2 pellets). Further, the
reaction mixture was irradiated under 180 microwave radiations for 10-15 mins and the progress
of the reaction was confirmed with TLC using n-hexane-ethyl acetate (7:3). Subsequently, the
reaction mixture was cooled at room temperature and poured into ice water. The solid was
separated, filtered and recrystallized using ethanol (neutralize with dil. HCl, if precipitate is not
appeared).
2.3. Natural chalcones
Hydroxy chalcones (3g-3j) were isolated from the medicinal plants such as 3g from
Sophora interrupta [23], 3h and 3i from Clerodendrum phlomidis [24] and 3j from Andrographis
macrobotrys [25] and were reported from our research laboratory. Therefore, these compounds
were used in the present study to evaluate their antidiabetic activity.
2.3a.(E)-1-(4-Aminophenyl)-3-(3,5-dimethoxy,4-hydroxyphenyl) prop-2-en-1-one (3a)
Pale Yellow Solid, Yield 71 %, M.P: 101C; 1H NMR (CDCl3, 400 MHz) : 3.91 (6H, s, 3 and
5 OCH3 ), 4.17 (2H, s, NH2), 6.69 (2H, d, J = 9.6 Hz, H-3and H-5), 6.85 (2H, s, H-2 and H-6),
7.41 (1H, d, J=15.6 Hz, H), 7.74 (1H, d, J=15.6 Hz, H ), 7.91 (2H, d, J =8.6 Hz, H-2and H-6);
13C NMR (CDCl3, 75 MHz) : 189.7, 162.6, 160.2, 150.7, 138.8, 130.9, 130.6, 120.4, 117.6,
113.8, 112.8,105.5, 98.6, 55.6, 55.5; ESI-MS (m/z); 322 for [M+Na]+; Anal. calcd. for
C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.15; H, 5.70; N, 4.59.
2.3b.(E)-1-(4-Aminophenyl)-3-(4-dimethylaminophenyl) prop-2-en-1-one (3b)
1
Pale Yellow Solid, Yield 87 %, M.P: 169C; H NMR (CDCl3, 400 MHz) : 3.08 (6H, s, N,N
CH3), 4.11 (2H, s, NH2), 6.77 (2H, d, J = 7.8 Hz, H-3 and H-5), 7.01 (2H, d, J = 8.6 Hz, H-3and
H-5), 7.46 (1H, d, J = 15.2 Hz, H), 7.67 (2H, d, J = 7.8 Hz, H-2 and H-6), 7.81 (1H, d, J = 15.2
Hz, H), 7.97 (2H, d, J = 8.6 Hz, H-2and H-6);13C NMR (CDCl3, 75 MHz): 188.8, 151.9,
145.7, 137.7, 131.0, 129.5, 127.3, 127.1, 121.4, 115.4, 110.7, 40.0; ESI-MS (m/z); 267 for
[M+H]+; Anal. calcd. for C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found: C, 76.62; H, 6.77; N,
10.49.
2.3c.(E)-1-(4-Aminophenyl)-3-(4-isopropylphenyl) prop-2-en-1-one (3c)
1
Pale Yellow Solid, Yield 82 %, M.P: 143C, H NMR (CDCl3, 400 MHz) : 1.29 (6H, J = 7.0
Hz, 2 CH3), 2.90-2.99 (1H, m), 4.12 (2H, s, NH2), 7.01 (2H, d, J = 8.6 Hz, H-3and H-5), 7.15
(2H, d, J = 8.0 Hz, H-3 and H-5), 7.36 (1H, d, J = 15.6 Hz, H), 7.55 (2H, d, J = 8.0 Hz, H-2 and
13
H-6), 7.80 (2H, d, J = 8.6 Hz, H-2and H-6), 8.07 (1H, d, J = 15.5, H ), C NMR (CDCl3, 75
MHz) : 188.3, 153.7, 152.2, 143.4, 133.7, 131.1, 128.6, 128.3, 126.0, 121.3, 114.5, 34.7, 23.6,
ESI-MS (m/z); 266 for [M+H]+; Anal. calcd. for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found:
C, 81.44; H, 7.17; N, 5.19.
2.3d. (E)-1-(4-Aminophenyl)-3-(4-fluorophenyl) prop-2en-1-one (3d)

Pale Yellow Solid, Yield 91 %, M.P: 143C; 1H NMR (CDCl3, 400 MHz) : 4.16 (2H, s, NH2),
6.63 (2H, d, J=8.6 Hz, H-3 and H-5), 7.01 (2H, d, J = 8.3 Hz, H-3 and H-5), 7.36 (1H, d,
J=15.4 Hz, H), 7.51 (2H, d, J =8.6 Hz, H-2 and H-6), 7.64 (1H, d, J=15.4 Hz, H ), 7.82 (2H, d,
J = 8.6 Hz, H-2and H-6);13C NMR (CDCl3, 75 MHz): 188.2, 162.3, 151.0, 141.5, 131.0,130.9,
129.9, 128.8, 128.1,119.8, 114.4, 113.9; ESI-MS (m/z): 264 for [M+Na]+; Anal. calcd. for
C15H12FNO: C, 74.67; H, 5.01; N, 5.81. Found: C, 74.62; H, 4.97; N, 5.79.
2.3e. (E)-1-(4-Aminophenyl)-3-(pyridin-2-yl) prop-2-en-1-one (3e)
1
Pale Yellow Solid, Yield 78 %, M.P: 146C; H NMR (CDCl3, 400 MHz) : 4.12(2H, s, NH2),
6.68 (2H, d, J = 8.6 Hz, H-3and H-5), 7.21-7.25 (2H, m, H-4 and Hα), 7.63-7.68 (2H, m, H-3
and H-5), 7.87 (2H, d, J = 8.6 Hz, H-2and H-6), 8.01 (1H, d, J=15.4 Hz, H), 8.55 (1H, d, J =
7.3, H-6);13C NMR (CDCl3, 75 MHz) :187.0, 152.7, 150.3, 149.0, 140.1, 135.9, 130.3, 127.1,
124.2, 124.1, 123.0, 111.8; ESI-MS (m/z); 225 for [M+H]+; Anal. calcd. for C14H12N2O: C,
74.98; H, 5.39; N, 12.49. Found: C, 74.87; H, 5.37; N, 12.44.
2.3f. (E)-1-(4-Aminophenyl)-3-(thiophen-2-yl) prop-2-en-1-one (3f)
1
Pale Yellow Solid, Yield 66 %, M.P: 119C; H NMR (CDCl3, 400 MHz) : 4.12(2H, s, NH2),
6.78 (2H, d, J = 8.6 Hz, H-3and H-5), 7.03 (1H, t, J = 4.5 Hz, H-6), 7.31- 7.37 (2H, m, H-3 and
H), 7.85-7.96 (4H, m, H-4, H-2, H-6 and H),13C NMR (CDCl3, 75 MHz) : 186.25, 152.73,
140.09, 133.72, 131.51, 130.88, 129.11, 128.16, 124.87, 120.56, 112.51; ESI-MS (m/z); 252 for
[M+Na]+; Anal. calcd. for C13H11NOS: C, 68.09; H, 4.84; N, 6.11. Found: C, 68.01; H, 4.79; N,
5.09.
2.3g. (E)-1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-(2,4,5-trimethoxyphenyl) prop-2en-1-one (3g)
Yellow amorphous solid (Me2CO), M.P: 184oC; 1H NMR: (DMSO-d6, 600 MHz)  13.68 (1H, s,
OH-2'), 7.89 (1H, d, J=15.7 Hz, H-β), 7.73 (1H, s, H-α),7.19 (1H, s, H-6), 6.74 (1H, s, H-3), 6.13
(1H, d, J=2.3 Hz, H-3), 6.10 (1H, d, J=2.3 Hz, H-5), 3.88 (3H, s, OMe-2), 3.87 (3H, s, OMe-
6), 3.86 (3H, s, OMe-4), 3.80 (3H, s, OMe-4), 3.77 (3H, s, OMe-5);13C NMR: (DMSO-d6, 150
MHz)  191.9, 165.5, 165.1, 161.7, 154.2, 152.7, 143.1, 138.0, 124.8, 114.4, 111.7, 106.4, 97.8,
93.9, 91.0, 57.0, 56.2, 56.0, 55.8, 55.6; ESITOFMS (m/z) : 375.1430 for [M+H]+; Anal. calcd.
for C20H22O7: C, 64.16; H, 5.92. Found: C, 64.13; H, 5.91.
2.3h. (E)-1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-(3-hydroxyphenyl) prop-2en-1-one (3h)
1
Pale yellow solid (Me2CO), M.P: 147°C; H NMR (DMSO-d6, 600 MHz):  13.50 (1H, s, OH-
2), 9.65 (1H, s, OH-3), 7.69 (1H, d, J = 15.7 Hz, H-), 7.55 (1H, d, J = 15.7 Hz, H-β), 7.24 (1H,
dd, J = 7.9, 7.8 Hz, H-5), 7.12 (1H, brd, J = 7.8 Hz, H-6), 7.06 (1H, dd, J = 2.0, 1.7 Hz, H-2),
6.84 (1H, ddd, J = 7.9, 2.0, 0.9 Hz, H-4), 6.12 (1H, d, J = 2.3 Hz, H-5), 6.15 (1H, d, J = 2.3 Hz,
13
H-3), 3.89 (3H, s, OMe-6), 3.81 (3H, s, OMe-4); C NMR (DMSO-d6, 150 MHz):  192.4,
165.6, 165.7, 161.9, 157.8, 142.5, 136.0, 130.1, 127.2, 119.7, 117.7, 114.4, 106.2, 93.9, 91.2,
56.2, 55.7; ESI-TOFMS (m/z): 301.0991 for [M+H]+; Anal. calcd. for C17H16O5: C, 67.99; H,
5.37. Found: C, 67.93; H, 5.30.
2.3i. (E)-1-(2,3-Dihydroxy-4-methoxyphenyl)-3-(3-hydroxyphenyl) prop-2en-1-one (3i)
1
Orange yellow solid (Me2CO), M.P: 129°C; H NMR (DMSO-d6, 600 MHz):  12.97 (1H, s,
OH-2), 9.65 (1H, s, OH-3), 8.69 (1H, s, OH-3), 7.90 (1H, d, J = 15.4 Hz, H-), 7.84 (1H, d, J =

9.2 Hz, H-6), 7.72 (1H, d, J = 15.4 Hz, H-β), 7.32 (1H, m, H-6), 7.26 (1H, m, H-5), 7.24 (1H, m,
H-2), 6.88 (1H, dd, J = 8.0, 1.7 Hz, H-4), 6.67 (1H, d, J = 9.2 Hz, H-5), 3.88 (3H, s, OMe-4);
13C NMR (DMSO-d6, 150 MHz):  192.6, 157.8, 153.6, 152.2, 144.2, 135.8, 133.8, 129.9,
122.4, 121.2, 120.1, 118.0, 115.5, 114.9, 103.5, 56.0; ESI-TOFMS (m/z): 287.0880 for [M+H]+;
Anal. calcd. for C16H14O5: C, 67.13; H, 4.93. Found: C, 67.11; H, 4.89.
2.3j. (E)-1-(2-Hydroxy-4-methoxyphenyl)-3-(2,3-dimethoxyphenyl) prop-2en-1-one (3j)
Yellow solid (CHCl3), M.P: 185°; 1H NMR : (DMSO-d6, 400 MHz)  13.40 (1H, s, OH-2), 8.21
(1H, d, J = 9.0 Hz, H-6), 8.07 (1H, d, J = 15.7 Hz, H-), 7.93 (1H, d, J = 15.7 Hz, H-), 7.65
(1H, dd, J = 9.0, 2.0 Hz, H-6), 7.12 (1H, dd, J = 9.0, 9.0 Hz, H-5), 7.08 (1H, dd, J = 9.0, 2.0 Hz,
H-4), 6.54 (1H, dd, J = 9.0, 2.4 Hz, H-5), 6.49 (1H, d, J = 2.4 Hz, H-3), 3.82 (6H, s, OMe-3,
13
4), 3.79 (3H, s, OMe-2); C NMR : (DMSO-d6, 75 MHz)  191.8, 166.0, 165.7, 152.7, 148.3,
137.9, 132.6, 128.0, 124.2, 121.9, 119.3, 115.1, 113.9, 107.4, 100.9, 61.0, 55.7; ESITOFMS
(m/z): 315.1206 for [M + H]+; Anal. cald. for C18H18O5: C, 68.78; H, 5.77. Found: C, 68.73; H,
5.69.
2.4. In vivo studies
2.4.1. Animals
Wistar male albino rats (180-200 g) were utilized in the present study and ethical
committee clearance (No.27/2012-2013/(i)/a/CPCSEA/IAEC/SVU/CAR-MSA) was approved
from Sri Venkateswara Univeristy, Tirupati, India. The rats were maintained under standard
laboratory conditions at 25ºC with 12 hours light and dark by giving standard pelleted as feed
and water with not more than five animals per cage.
2.4.2. Experimental design and induction of diabetes
The antidiabetic evaluation of chalcones (3a-3j) was performed according to the
experimental design described by Satyanarayana, et. al., 2004 [26]. The animals were randomly
divided into ten groups and each group consists of five rats. Group-I is treated as normal control
and given normal diet and water throughout the experiment. Group-II is treated with simply
alloxan monohydrate and treated as positive control. Group-III is preserved as negative control
and treated with alloxan monohydrate followed by 0.025 units of insulin (1 IU/kg body weight).
The groups IV-XIII are consisting of diabetic induced arts and monitored with chalones (3a-3j).
The rats were fasted for 10-12 hrs and alloxan monohydrate (150 mg/kg body weight) was
administered intraperitoneally to induce the diabetes [26]. Subsequently, animals were feed with
on standard pellets and water. The blood glucose levels of the rats were monitored by tail tipping
method using glucometer. After two days, the blood glucose levels were predicted and are
considered as diabetic rats if blood glucose is above 200 mg/dl and conducted further studies.
2.4.3. Blood sampling and blood glucose determination
The portion of albino rat tail was wiped off with warm water, subsequently with 10%
alcohol nipping, squeeze gently to collect the blood drops at specific time intervals. The rat tail
was sterilized by swabbing with 70% alcohol and the blood glucose levels were measured with a
glucose analyzer model (Accu Chek, Roche diabetes care, USA) and were calculated according
to AUC method and expressed results in percentage (%).

2.5. Statistical analysis
All the experiments were carried out in triplicates and calculated using SPSS v16. The
data was expressed as Mean±Standard error of the mean (SEM) and analyzed by one-way
analysis of variance (ANOVA) followed by student t test and statistically significant findings
were considered as P-value is <0.05.
2.6. In silico studies
2.6.1. Protein preparation
Crystal structures of aldose reductase (PDBID:4GCA) [27], DPP-IV (PDBID:4N8D)
[28], PPAR- (PDBID:1K7L) [29] and -glucosidase (PDBID:5NN5) [30] were retrieved from
Protein Data Bank (PDB). Co-crystal ligands, water and ions were removed and hydrogens were
added. Energy minimization was employed using steepest descent algorithms [31, 32].
2.6.2. Binding cavity volume and shape calculations
CastP was employed to determine binding cavities, volume and key residues of targets
[33]. Shape analysis of binding cavity of the protein was achieved with Metapocket2.0 [34].
2.6.3. Ligand preparation
Chalcones and reference inhibitors were drawn in 3D and optimized using Marvin Skech.
The hydrogens were added and energy minimized molecules were used for docking studies.
2.6.4 Molecular docking
Auto Dock Vina 4.05 was used to dock into active site of the proteins [35, 36]. Ligand
molecules were uploaded and energy minimized with universal force field using conjugate-
gradient algorithm with 200 run iterations and converted as PDBQT files. Docking grid box was
prepared and positioned to cover binding pockets according to the location of key residues
(Table 1). The grid box and sizes were followed as aldose reductase (center_x = -9.1, center_y =
4, center_z = 4.3; size_x = 26.2, size_y = 24.6 and size_z = 25.9), DPPIV (center_x = 13.6,
center_y = 26.4, center_z =55.8; size_x = 25, size_y = 25 and size_z = 25), PPAR- (center_x =
-20.6, center_y = -12.5, center_z = -2.8; size_x = 25.0, size_y = 25.0) and -glucosidase
(center_x = -8.9, center_y = -34.9, center_z = 94.4; size_x = 25.0, size_y = 25.0, size_z = 25.0
and size_z = 25.0) and exhaustiveness was set to 8. Moreover, Lamarckian genetic algorithm
was used for docking with following parameters: the number of individuals in the population was
150; the maximum number of energy evaluations was 25,000; and the maximum number of
generations was 27,000. Top individuals to survive to next generation were 1; Gene mutation
rate was 0.02; Crossover rate was 0.8; Cauchy beta was 1.0 and genetic algorithm window size
was set to 10.0. The best docked ligand conformations, bond angles, bond lengths and bonding
interactions were analysed using PyMOL [37].
2.6.5. Bioavailability
Molecular properties, Lipinski rule of five, ADME (absorption, distribution, metabolism
and excretion) and drug likeness of chalcones were appraised using Molsoft molecular property
prediction and Swiss ADME server [38].

3. Results and discussion
3.1. Chemistry
Synthesis of amino chalcones (3a-f) were achieved by microwave irradiation of 4-
aminoacetophenone with the corresponding aryl aldehydes with varied substituents, resulting
moderate to high yields of 66-91% (Figure 1a). Natural hydroxy chalcones (3g-j) were isolated
from various medicinal plants and represented in Figure 1b. The structural elucidation of
chalcones was employed by Mass, 1H and 13C NMR spectra. A characteristic pair of doublets of
olefinic double bond protons with coupling constant ranges from 15.2 to 15.7 Hz indicating that
the two aryl rings in the chalcone moiety were in trans configuration.13C NMR spectra reveals
chemical shifts ranging from 192.6 to 186.3 ppm which attributed to carbonyl group of prop-2-
enone bridge and are the evidence for the formation of open chain chalcone structures.
3.2. In vivo studies
In vivo studies were carried out with alloxan induced diabetic wistar male albino rats to
evaluate the antidiabetic activity of chalcones. Initially, diabetes was induced with alloxan (100
mg/kg) and found that blood glucose levels are high in group II i.e., 301.12±1.85, 286.00±1.20
and 265.42±2.10 mg/dL at various time intervals (1, 2 and 3 hours) when compared with normal
control group I rats 84.78 ±0.78, 81.45±0.58 and 78.12±1.25 mg/dL, respectively. Further,
acute antidiabetic activities of chalcones (3a-j) were assessed by perceiving lower the blood
glucose levels in diabetic rats in the range of 50-29% (Figure 2). The compound 3c significantly
inhibited 50 of blood glucose levels (150.60±1.50 mg/dL) in the diabetic rats when compared
with control rats. Amino chalcone 3c possesses amphipathic properties owing to presence of
isopropyl and amino phenyl group which could able to implicate formation of hydrophilic and
hydrophobic bonds with targets. Another amino chalcone 3a is having amino phenyl, one
hydroxyl and two methoxy groups which contributed to reduce 41% blood glucose
(156.50±1.30 mg/dL). Further, compound 3e showed moderate antidiabetic activity with 39%
glucose inhibition (160.60±1.58 mg/dL) due to its hydrophobic property. In addition, 3d, 3b and
3f compounds conferred sensible antidiabetic activity by decreasing blood glucose with
percentage of 35 (170.60±1.44 mg/dL), 33 (176.40±1.90 mg/dL) and 31 (181.10±2.40
mg/dL), respectively. Also, the hydroxyl chalcone 3h has two methoxy, two hydroxy and one
carbonyl as function groups and able to reduce excess blood glucose levels (158.60±1.58
mg/dL) to 40% in alloxan induced diabetic rats. Another chalcone 3g revealed considerable
blood glucose inhibition with 33% percentage when compared with control diabetic rats. The
hydroxyl chalcone 3i has three hydroxy, one methoxy and one carbonyl group functions which
showed moderate activity. While the chalcone 3j has three methoxy, one hydroxy and one
carbonyl group which showed 29% of glucose inhibition with least antidiabetic activity.
Diabetic drug targets
Earlier reports have shown that chalcones are potent inhibitors of several key enzymes
such as aldose reductase, dipeptidyl peptidase-IV, peroxisome proliferator activated receptor-g
and -glucosidase with reference to diabetic complications [21]. Henceforth, in the present study
intended to in silico studies of chalcones to ascertain the active diabetic target(s). Hence, binding
pockets, volume, shape, key residues and docking with chalcones will be discussed more details
in below.

3.3. Volumetric evaluation of binding cavities
Volumetric analysis for aldose reductase, dipeptidyl peptidase-IV, and peroxisome
proliferator activated receptor-, and -glucosidase were assessed. It is a reliable approach to
distinguish binding cavity volumes to identify the related ligands (Figure 3). DPP-IV has largest
binding cavity volume (9903.2 Å) and area (4530.9) with predicted key residues such as Glu205,
Glu206, Arg358, Phe357, Tyr547, Tyr585, Tyr666, Tyr662. PPAR pocket has volume of 470.2
Å and area is 884.7, aligned with Phe351, Ile354, Phe243, His440, Phe318, Tyr314, Tyr646,
Cys275, Ala333 and Thr279. Aldose reductase pocket has 228.7 Å volume and area is 443.9 that
formed with critical residues of Thr113, Trp111, His110, Tyr48, Trp20, Tyr209, Leu300 and
Cys303. -Glucosidase pocket has smallest binding cavity volume is 216.1 Å and area is 195.1
including key residues of Trp376, Asp404, Ile441, Met519, Asp518, Trp516, Arg600, Trp613,
Asp616, His674, Phe649 (Table 1).
3.4.
Redocking and validation
The docking method is necessary to be validated by reproducing and hence co-crystal
ligands from the targets were retracted and redocked into specific identified binding pockets.
RMSD was computed with overlay of best docked pose with crystal pose of ligand. RMSD of
docked pose is within 2.0 Å that denoting reliable docking that helps in the endorsement of
consistency and reproducibility. Redocking studies explicated that IDD1219 has volume is 312
A3 and showed binding energy of -11.0 kcal/mol. RMSD was measured to be 1.0 Å with crystal
pose of aldose reductase. Syn-7aa is a crystal inhibitor of DPP-IV has volume of 351.15 A3 that
showed binding energy of -8.5 kcal/mol and RMSD was calculated as 1.8 Å with crystal pose.
DW409544 is a bound inhibitor of PPAR and has volume of 537.24 A3. It showed binding
energy -9.7 kcal/mol and measured RMSD of 1.2 Å. -Glucosidase has bound crystal inhibitor
1-deoxynojirimycin and has volume of 142.95 A3. Docking study showed binding affinity -4.5
kcal/mol and calculate RMSD was found to be 1.7 Å with crystal pose (Figure 4). Based on this
result, further we carried out docking by using reproducible protocol.
Protein-chalcone interactions
Docking experiment was assessed with aldose reductase, DPP-IV, PPAR and -
glucosidase and chalcones, and depicted binding affinities in Table 2. Chalcones interacted
through a variety of interfaces i.e., hydrogen bonds, hydrophobic and - interactions. Aldose
reductase is belonging to the aldo-keto reductase superfamily and involved in polyol pathway.
Chalcones were docked into binding pocket of energy minimized aldose reductase and measured
binding affinities (kcal/mol). The best docked conformation of chalcone was exposed and
extracted critical interaction with key residues in the pocket (Figure 5). Compound 3c showed
binding interactions with Thr113 (2.9 Å), the ring A of 3c formed - bond with Trp111 and
isopropyl forms - bonds with Trp20 (3.9 Å and 3.7 Å). Similarly, chalcone 3d bonds with
Thr113 (2.8 Å), ring A forms - bond with Trp111 (2.7 Å) and fluorophenyl exhibited - and
polar bonds with Trp20 (4.0 Å and 4.1 Å). While, 3a compound exerted four bonds such as one
bond with Thr113 (2.8 Å), - bond with Trp111 (2.7 Å), 5-methoxy phenyl formed two bonds
i. e., - and polar bonds with Trp20 (3.9 Å and 3.0 Å). Likewise, the chalcone 3b showed bonds
with Thr113 (2.8 Å), ring A forms - bond with Trp111 (3.6 Å), amino phenyl formed two
bonds such as - and polar bonds with Trp20 (4.1 Å and 4.0 Å). The compound 3e

demonstrated one bond with Thr113 (2.8 Å), ring A and pyridine forms - interactions with
Trp111 (3.7 Å) and Trp20 (4.0 Å). Whereas the chalcone 3f showed interactions such as, one
bond with Thr113 (3.1 Å), ring A and thiophene ring forms - bonds with Trp111 (3.8 Å) and
Trp20 (3.6 Å). The compound 3i with Thr113 (2.5 Å) and Trp111 (3.7 Å) through di-hydroxy
phenyl bonds with Tyr48 (3.4 Å), forms - and polar bonds with Trp20 (3.8 Å, 3.2 Å). 3h
exhibited bonding with Thr113 (4.3 Å) and Trp111 (3.7 Å), 2-hydroxy, 4, 6-dimethoxy phenyl
ring bonds with Tyr48 (3.3 Å), - and polar bond with Trp20 (3.9 Å and 4.7 Å) and Tyr209
(4.9 Å). Chalcone 3j showed one bond each with Cys303 (4.3 Å) and Trp111 (3.8 Å) and, 2-
hydroxy phenyl formed - and polar bonds with Trp20 (3.1 Å and 4.1 Å), respectively.
In addition, docking studies for DPP4 revealed that compounds 3c and 3i have revealed
highest binding energies and oriented in the S1 binding pocket (Figure 6). Chalcone 3c
illustrated binding interactions via isopropyl formed two -cation interactions with Tyr547 and
Glu206 (3.3 Å and 3.3 Å), polar bonds with Tyr666 and Tyr662 (3.3 Å and 3.4 Å) and carbonyl
group showed two bonds with Arg358 (2.8 Å). The amino group of 3c bonds with Tyr585 (4.7
Å) and phenyl formed - bond with Phe357 (3.8 Å). Similarly, 3i compound formed - bond
with Phe357 (3.8 Å), OH with Arg358 (3.1 Å), 17OH with Glu206 (2.8 Å), 21OH with Glu205
(2.7 Å), 16MeO with Tyr662 (4.3 Å) and one -cationic bond with Tyr547 (3.5 Å). Also, the
chalcone 3a made - bond with Phe357 (3.8 Å), carbonyl with Arg358 (3.9 Å), dimethyl with
Glu205 (3.4 Å) and 4-OH with Tyr662 (3.2 Å). Another chalcone 3d displayed two - bonds
with Phe357 (3.5 Å) and Arg358 (4.2 Å), carbonyl with Glu206 (3.2 Å), -cationic interaction
with Tyr662 (3.5 Å). The compound 3b formed - and polar bonds with Tyr585 (4.3 Å),
carbonyl with Arg358 (2.8 Å) and methyl amine bonds with Tyr666 (4.0 Å) and Tyr662 (3.7 Å).
In the same way, the compound 3e showed interactions with Phe357 (3.7 Å), carbonyl with
Arg358 (3.3 Å) and pyridine with Tyr666 (4.0 Å) and Tyr662 (3.5 Å). The chalcone 3f exhibited
bonds with Phe357 (3.8 Å), carbonyl with Arg358 (3.3 Å) and thiophene with Tyr666 (3.8 Å)
and Tyr662 (3.4 Å).
Further, the molecular docking of chalcones 3d, 3b, 3e and 3i exhibited best binding
energy with PPAR and explicate interactions with key residues and, depicted in Figure 7. 3d
compound showed - and polar bonds with Phe351 (3.3 Å) and Ile272 (3.7 Å) and,
fluorophenyl formed - and polar bonds with Tyr314 (3.1 Å) and Tyr464 (3.7 Å). The
compound 3b presented two bonds with Cys275 (4.3 Å) and Thr279 (3.7 Å) and, one - bond
with Phe318 (4.2 Å). Whereas, chalcone 3e showed polar bond with Tyr314 (3.0 Å), carbonyl
with Ile354 (4.3 Å) and pyridine with Phe351 (3.4 Å). Also, 3i compound disclosed - bond
with Phe351 (3.7 Å), -cationic bond with Phe273 (2.9 Å), 3OH with Tyr464, 4OH with Tyr314
and -cationic bond with Phe318. Furthermore, binding interactions of 3g, 3h, 3c, 3a, 3f and 3j
compounds with PPAR were also depicted.
The -glucosidase is a member of exo-acting enzyme which is actively involved in the
carbohydrate metabolism and regulation. Hence, the docking studies of chalcones revealed that
the compounds 3c, 3i and 3b showed best binding energies with significant binding interaction
with key residues of -glucosidase (Figure 8). The chalcone 3c displayed crucial interactions -
bond with Trp376 (3.4 Å). Another chalcone 3i formed four bonds i.e., polar bond with Asp616
(3.3 Å), - bond with Phe649 (3.5 Å) and Trp376 (3.6 Å). Further, 3b compound exhibited two
bonds such as one polar bond with Asp616 (4.1 Å) and one - bond with Phe376 (3.5 Å).

Likewise, the chalcones 3a, 3d, 3e, 3f, 3g, 3h and 3j formed bonds with Asp616, Trp376, Phe649
and Asp518.
3.7. Molecular properties, Lipinski rule and ADME
Pharmacokinetic and pharmacodynamic properties are playing an important role in the
optimization of lead molecules and in the drug discovery process which minimizes the
pharmacokinetic failures at various clinical phases. In this perspective, in silico prediction is an
effective alternative approach for prediction of ADME (Absorption, Distribution, Metabolism
and Elimination) to experimental estimations. Bioavailability radar hat denotes reliable drug-
likeness by considering lipophilicity (-0.7-+0.5), size (150g/mol >500g), polarity (20A-130A),
solubility (<6), flexibility (<9) and saturation (0.25<1) and shown in Figure 9. Further,
Lipinski’s rule of five (molecular weight (<500), H-bond donor (<5), H-bond acceptor (<10) and
cLogP (<5)) are specifically describing the relationships between physicochemical and
pharmacokinetic properties and were establish to be satisfied (Table 3). Similarly, lipophilicity is
calculated to be less than five. Solubility is another majorly concerning property about the
absorption of drug by assessing either drug to be soluble or moderately soluble. Further,
pharmacokinetic property evaluation revealed the skin permeability, gastrointestinal absorption
and blood brain barrier (BBB) permeability and interactions with different isoform of
cytochrome p450 which play a key role in the drug elimination. Based on the bioavailability,
clearly drug likeness could be deliberated as oral drug from the analysis of Lipinski rule, Ghose
(Amgen), Veber (GSK), Egan (Pharmacia) and Muegge (Bayer) (Table 4). Therefore, these
optimized chalcones could be recommended for further studies and ratified as anti-diabetes
agents.
3.8. Structure Activity Relationship (SAR) Studies
Chalcones possess broad spectrum therapeutic profiles which are believed to be owing to
their structural substitutions on the ring A and B. It is a fascinating note to mention that the
chalcones having electron releasing groups such as dimethyl amino, alkyl and amino groups at
C-4 position of either on the ring A or the ring B flourished extensive pharmacological activities
than heteroaryl chalcones. In case of 3c, amino and isopropyl groups act as electron donors and
substituted at para position incite electron delocalization and implicates stabilization of the
molecule. Also, the 2-hydroxyl group is an essential feature that deliberates the significant
biological activity and retains the structural stability. Furthermore, the chalcones having either
2-hydroxylation or 2,3-dihydroxylation substitution pattern exhibits augmented inhibitory
activities. Especially, 2-hydroxylation is in chelation with carbonyl group, is greatly enhances
the biological activities [39, 40]. Thus, the chalcone 3i showed effective diabetic activity is
believed due to the presence of 2, 3-dihydroxylations on the ring A. Similarly, the antidiabetic
activity of chalcone 3a may be assumed due to the unique tri-oxygenation in the ring B.
4. Conclusions
In conclusion, the present study discloses the antidiabetic activity of chalcones. The
results revealed that the chalcones 3c, 3a, 3e, 3h and 3i were presented significant antidiabetic
properties. In addition, the molecular docking studies reveal the target specificity with aldose
reductase. Hence, these findings would be helpful for the further in vitro studies with quantified
target. Furthermore, these molecules might be endorsed as plausible antidiabetic agents and to
ensure therapeutic profiles must be evaluated in the subsequent clinical phases for the effective
treatment of diabetes.

Conflict of Interest
All the authors declare no conflict of interest.
Acknowledgement
The author AR thankful to the Center for Chemical and Pharmaceutical Institute, Ural federal
University, Russia for providing laboratory facilities.
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a).
O
H2N
EtOH, NaOH
MW
CH3
Ar
+
Ar
CHO
2
H2N
O
3 a-f
1
OCH3
Ar
Ar
F
3d:
3a:
OH
OCH3
CH3
CH3
3e:
3f:
N
3b:
3c:
N
CH3
CH3
S
b).
R6
H3CO
R2
R5
R1
R4
OH
O
R3
3g R1=R4=H, R2=OCH3, R3=R5=R6=OCH3
3h R1=R3=R5=R6=H, R2=OCH3, R4=OH
3i R1=R4=OH, R2=R3=R5=R6=H
3j R1=R2=R5=R6=H, R3= R4=OCH3
Fig. 1. a). Synthesis of amino chalcones (3a-3f); b). natural hydroxy chalcones (3g-3j) were
isolated from medicinal plants.

a)
control
Alloxan
Insulin
3a
350
300
250
200
150
100
50
3b
3c
3d
3e
3f
0
1
3
5
Time (hours)
b)
Control
Alloxan
Insulin
3g
3h
350
300
250
200
150
100
50
3i
3j
0
1
3
5
Time (hours)
Fig. 2. a). Antidiabetic activity of amino chalcones (3a-3f); b). hydroxy chalcones (3g-3j). The
data are presented as means  SD from three independent experiments: p <0.05 as determined by
Student’s t test.

a).
b).
c).
d).
Fig. 3. Binding pocket volumes and shapes of a). Aldose reductase, b). DPP-IV, c). PPAR and
d). -Glucosidase.

a).
b).
c).
d).
Fig. 4. Binding pocket residues of putative drug targets of diabetes such as a). aldose reductase,
b). dipeptidyl peptidase-IV, c). PPAR and d). -glucosidase. Critical residues are rendered as
sticks with labeling and crystal ligands (white) and docked poses were overlaid.

a).
3a
3b
3e
3c
3f
3d
b).
3g
3h
3i
3j
Fig. 5. a). Amino chalcones (3a-3j) and b). hydroxy chalcones (3g-3j) binding interactions and
distances with active site residues of aldose reductase.

a).
b).
Fig. 6. 3c and 3i binding interactions and distances with key residues of DPP-IV.
a).
b).
e).
i).

Fig. 7. a). 3d, b). 3b, c). 3e and d). 3i binding interactions and bond distances with pocket
residues of PPAR.
a).
b).
c).
Fig. 8. a). 3c, b). 3i and c). 3b binding interaction and distances with active site residues of -
glucosidase.

3a
3e
3i
3b
3f
3j
3c
3g
3d
3h
Fig. 9. Drug-likeness of chalcones were predicted using Bioavailability radar. The pink is
depicted optimal range of each property (Lipo:Lipophilicity, Size:Molecular weight, POLAR:
Total Polar Surface Area, INSOLU: Insolubility, INSATU: Insaturation, FLEX: Flexibility).

Table 1. Binding pocket residues, volume and area of diabetic drug targets.
S. No
1
Targets
PDBID
Key Residues
Volume
(Å)
228.7
Area (SA)
Aldose reductase
4GCA
Thr113,
Trp111,
443.9
His110, Tyr48, Trp20,
Tyr209,
Cys303
Leu300,
DPP-IV
2
3
4N8D
1K7L
E205, E206, R358,
F357, Y547, Y585,
Y666, Y662
9903.2
470.2
4530.9
884.7
PPAR-
Phe351,
Ile354,
His440,
Tyr314,
Cys275,
Phe243,
Phe318,
Tyr646,
Ala333, Thr279
4
5NN5
Trp376,
Ile441,
Asp518,
Arg600,
Asp616,
Phe649
Asp404,
Met519,
Trp516,
Trp613,
His674,
216.1
195.1
-Glucosidase

Table 2. Binding energies of chalcones with diabetic drug targets.
Binding affinity G (kcal/mol)
Chalcones
IUPAC name
Aldose reductase
(PDBID:4GCA)
DPP-IV
PPAR
-Glucosidase
(PDBID:4N8D)
(PDBID:1K7L)
(PDBID:5NN5)
3a
(E)-1-(4´-aminophenyl)-3-(4-
hydroxy-3,5
-7.4
-6.8
-10.0
-7.5
dimethoxyphenyl) prop-2-en-1-
one
3b
3c
3d
3‐[4‐(dimethylamino)cyclohexyl]‐
1‐(4‐iminocyclohexyl)propan‐1‐o
ne octadecahydrogen
(E)-1-(4´-aminophenyl)-3-(4-
isopropylphenyl)prop-2-en-1-on
-7.9
-7.5
-7.1
-7.5
-9.6
-7.2
-8.6
-10.7
(E)1-(4´-aminophenyl)-3-(4-
fluorophenyl)-2-propen-1-one
-8.3
-7.9
-6.6
-6.9
-10.0
-9.2
-7.5
-7.1
3e
3f
(E)-1-(4´-aminophenyl)-3-(pyridin-
2-yl)prop-2-en-1-one
(E)-1-(4-aminophenyl)-3-
(thiophen-2-yl)prop-2-en1-one
-5.8
-6.2
-6.8
-8.7
-9.2
-9.3
-6.4
-7.2
-7.8
-7.3
-7.8
3g
3h
(E)-(1-(2-hydroxy, 4,6-
dimethoxyphenyl)-3-(2,4,5-
trimethoxyphenyl)prop-2-en1-
one)
(E)-1-(2-hydroxy,4,6-
dimethoxyphenyl)-3-(3-
hydroxyphenyl)prop-2-en1-one)
-7.8

3i
3j
(E)-1-(2,3-dihydroxy,4-
methoxyphenyl)-3-(3-
hydroxyphenyl)prop-2-en1-one)
(E)-1-(2-hydroxy,4-
methoxyphenyl)-3-(2,3-
dimethoxyphenyl)prop-2-en1-
one)
-7.9
-7.3
-7.2
-6.8
-10.3
-8.7
-8.5
-7.3
-9.7
-4.5
-11.0
-8.5
2,6-dimethyl-5-
[(4,5,7-trifluoro-1,3- {[(2E)-3-
benzothiazol-2-
yl)methyl]pyridin-3-
yl}acetic acid
(2x9)
1-(cis-1-phenyl-4- 2-(1-methyl-3-
oxo-3-phenyl-
phenylprop-2-en- propylamino)-3-
1- {4-[2-(5-methyl-2-
yl]oxy}cyclohexyl phenyl-oxazol-4-
1-deoxynojirimycin
(NOJ)
Cocrystal ligand
) methanamine
yl)-ethoxy]-
phenyl}-propionic
acid
(syn-7aa)
(GW409544)

Table 3. SMILES, Lipinski rule of five and drug likeness of chalcones.
S.
No
SMILES
Molecular properties
Drug likeliness
Chalcones
Molecular formula: C17 H17 NO4
Molecular weight: 299.12
Number of HBA: 4
Number of HBD: 3
MolLogP : 3.12
COC1=C(O)C(=CC(
=C1)\C=C\C(=O)C2
=CC=C(N)C=C2)O
C
1
3a
MolLogS : -3.79 (in Log(moles/L)) 48.50 (in
mg/L)
MolPSA : 64.76 A2
MolVol : 301.62 A3
Drug-likeness score: 0.37
Number of stereo centers: 0
Molecular formula: C17 H18 N2O
Molecular weight: 266.14
CN(C)C1=CC=C(\C Number of HBA: 1
=C\C(=O)C2=CC=C Number of HBD: 2
2
3b
(N)C=C2)C=C1
MolLogP : 3.56
MolLogS : -4.59 (in Log(moles/L)) 6.83 (in
mg/L)
MolPSA : 36.82 A2
MolVol : 277.23 A3
Number of stereo centers: 0
Drug-likeness score: -0.64

Molecular formula: C18 H19 N O
Molecular weight: 265.15
Number of HBA: 1
Number of HBD: 2
MolLogP : 4.56
CC(C)C1=CC=C(\C
=C\C(=O)C2=CC=C
(N)C=C2)C=C1
3
3c
MolLogS : -5.50 (in Log(moles/L)) 0.84 (in
mg/L)
MolPSA : 34.02 A2
MolVol : 280.74 A3
Drug-likeness score: -0.05
Number of stereo centers: 0
Molecular formula: C15 H12 F N O
Molecular weight: 241.09
NC1=CC=C(C=C1) Number of HBA: 1
C(=O)\C=C\C2=CC Number of HBD: 2
4
3d
=C(F)C=C2
MolLogP : 3.71
MolLogS : -4.78 (in Log(moles/L)) 4.02 (in
mg/L)
MolPSA : 34.02 A2
MolVol : 233.59 A3
Number of stereo centers: 0
Drug-likeness score: -0.54
Molecular formula: C14 H12 N2 O
NC1=CC=C(C=C1) Molecular weight: 224.09
C(=O)\C=C\C2=CC Number of HBA: 2
=CC=N2
Number of HBD: 2
5
3e
MolLogP : 2.50
MolLogS : -3.26 (in Log(moles/L)) 123.40
(in mg/L)
MolPSA : 43.56 A2
MolVol : 223.12 A3
Number of stereo centers: 0
Drug-likeness score: -0.00

Molecular formula: C13 H11 N O S
Molecular weight: 229.06
Number of HBA: 2
NC1=CC=C(C=C1)
C(=O)\C=C\C2=CC
=CS2
Number of HBD: 2
MolLogP : 3.31
6
3f
MolLogS : -4.01 (in Log(moles/L)) 22.44
(in mg/L)
MolPSA : 35.04 A2
MolVol : 225.89 A3
Drug-likeness score: -0.17
Number of stereo centers: 0
Molecular formula: C20 H22 O7
Molecular weight: 374.14
Number of HBA: 7
Number of HBD: 1
MolLogP : 3.59
COC1=CC(O)C(C=C1)C(
=O)\C=C\C2=C(OC)C(=
CC=C2)OC
7
3g
MolLogS : -3.78 (in Log(moles/L)) 61.63
(in mg/L)
MolPSA : 67.83 A2
MolVol : 390.54 A3
Number of stereo centers: 0
Drug-likeness score: -0.35
Molecular formula: C17 H16 O5
Molecular weight: 300.10
Number of HBA: 5
Number of HBD: 2
MolLogP : 3.18
COC1=CC(=C(C(=
C1)O)C(=O)\C=C\C
2=C(O)C=CC=C2)
OC
8
3h
MolLogS : -3.35 (in Log(moles/L)) 134.02
(in mg/L)
MolPSA : 61.48 A2
MolVol : 307.19 A3
Drug-likeness score: 0.08
Number of stereo centers: 0

Molecular formula: C16 H14 O5
Molecular weight: 286.08
Number of HBA: 5
COC1=CC=C(C(=C
1O)O)C(=O)\C=C\C
2=CC(=CC=C2)O
Number of HBD: 3
MolLogP : 2.83
9
3i
MolLogS : -3.28 (in Log(moles/L)) 150.91 (in
mg/L)
MolPSA : 69.42 A2
MolVol : 283.18 A3
Number of stereo centers: 0
Drug-likeness score: 0.68
Molecular formula: C18 H20 O5
Molecular weight: 316.13
Number of HBA: 5
COC1=CC(O)C(C=
C1)C(=O)\C=C\C2=
C(OC)C(=CC=C2)O Number of HBD: 1
MolLogP : 1.84
C
10
3j
MolLogS : -2.85 (in Log(moles/L)) 441.97 (in
mg/L)
MolPSA : 51.66 A2
MolVol : 356.82 A3
Drug-likeness score: -0.76
Number of stereo centers: 2
Molecular formula: C17 H16 F3 N2 O2 S
Molecular weight: 369.09
Number of HBA: 5
2x9
Cc:1:n:c(C):c(:[cH]: Number of HBD: 2
MolLogP : 4.07
c:1Cc(:o):o)Cc:2:n:c
:3:c(F):c(F):[cH]:c(F
):c:3:s:2
MolLogS : -4.46 (in Log(moles/L)) 12.79 (in
mg/L)
MolPSA : 49.22 A2
MolVol : 312.63 A3
Drug-likeness score: 0.65
Number of stereo centers: 0