Crystal structures, in-silico study and anti-microbial potential of synthetic monocarbonyl curcuminoids

Article abstract of DOI:10.1016/j.molstruc.2017.05.061

In this work the screening of 20 unsymmetrical chalcone and curcuminoids analogues in regard of their antimicrobial properties was conducted. Electron donating groups in the aromatic rings in the chalcone and curcuminoid derivatives produced higher antimicrobial effect. Compounds 1, 9 and 15 exhibited good activity against Escherichia coli and Staphylococcus aureus. These compounds were further evaluated against nine micro-organisms of pathological interest. Pharmmaper was used for target fishing of compounds against important bacterial targets. Molecular Docking helped to verify the results of these compounds against the selected bacterial target D-alanyl-D-alanine carboxypeptidase (PDB ID: 1PW1). The crystal structure of ligand and docked conformers in the active site of 1PW1 were analyzed. As a result structure-activity relationships are proposed. Structures of compounds 14 and 16 were obtained through single crystals X-ray diffraction studies. Compound 14 crystallizes in monoclinic space group P2₁/c with unit cell dimensions a = 13.1293(3) ?, b = 17.5364(4) ?, c = 15.1433(3) ?, β = 95.6440(10), V = 3469.70(13) ?³ and Z = 8. Compound 16 crystallizes in triclinic space group Pī with unit cell dimensions a = 6.8226(4) ?, b = 7.2256(4) ?, c = 18.1235(12) ?, β = 87.322(4), V = 850.57(9) ?³ and Z = 2.

Full text of DOI:10.1016/j.molstruc.2017.05.061

Accepted Manuscript
Crystal structures, DFT analysis, in-silico study and anti-microbial potential of
synthetic monocarbonyl curcuminoids
Ud Din Zia, N.F.G. Serrano, Kastriot Ademi, C.P. Sousa, Victor Marcelo Deflon,
Pedro Ivo da Silva Maia, Edson Rodrigues-Filho
PII:
S0022-2860(17)30674-9
10.1016/j.molstruc.2017.05.061
MOLSTR 23802
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 11 June 2016
Revised Date: 13 May 2017
Accepted Date: 14 May 2017
Please cite this article as: U.D. Zia, N.F.G. Serrano, K. Ademi, C.P. Sousa, V.M. Deflon, P.I.d.S.
Maia, E. Rodrigues-Filho, Crystal structures, DFT analysis, in-silico study and anti-microbial potential
of synthetic monocarbonyl curcuminoids, Journal of Molecular Structure (2017), doi: 10.1016/
j.molstruc.2017.05.061.
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Graphical Abstract

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Crystal structures, DFT analysis, in-silico study and anti-microbial potential of synthetic
monocarbonyl curcuminoids
Zia Ud Din1*, Serrano NFG2, Kastriot Ademi3 Sousa CP2 Victor Marcelo Deflon4 , Pedro Ivo
,
,
da Silva Maia4, Edson Rodrigues-Filho1
1LaBioMMi, Departamento de Química, Universidade Federal de São Carlos, CP 676,
13.565-905, São Carlos, SP, Brazil.
2UFSCar, Department of Morphology and Pathology, Laboratory of Microbiology
Microbiology and Biomolecules, Rodovia Washington Luis, Km 235, CEP 13.565-090, Sao
Carlos, SP, Brazil, (+5516) 33518760
3Department of Chemistry, Faculty of Natural Science, University of Prishtina “Hasan
Prishtina”, Mother Teresa Street 5, 10000 Prishtine, Republic of Kosova
4GQIEB, Instituto de Química de São Carlos, Universidade de São Paulo, 13566-590 São
Carlos, SP, Brazil.
Abstract:
In this work the screening of 20 unsymmetrical chalcone and curcuminoids analogues in
regard of their antimicrobial properties was conducted. Electron donating groups in the
aromatic rings in the chalcone and curcuminoid derivatives produced higher antimicrobial
effect. Compounds 1, 9 and 15 exhibited good activity against Escherichia coli and
Staphylococcus aureus. These compounds were further evaluated against nine micro-
organisms of pathological interest. Pharmmaper was used for target fishing of compounds
against important bacterial targets. Molecular Docking helped to verify the results of these
compounds against the selected bacterial target D-alanyl-D-alanine carboxypeptidase (PDB
ID: 1PW1). The crystal structure of ligand and docked conformers in the active site of 1PW1
were analyzed. As a result structure-activity relationships are proposed. Structures of
compounds 14 and 16 were obtained through single crystals X-ray diffraction studies.
Compound 14 crystallizes in monoclinic space group P21/c with unit cell dimensions a =
13.1293(3) Å, b = 17.5364(4) Å, c =15.1433(3) Å, β = 95.6440(10), V = 3469.70(13) Å3 and
Z = 8. Compound 16 crystallizes in triclinic space group Pī with unit cell dimensions a =
6.8226(4) Å, b= 7.2256(4) Å, c = 18.1235(12) Å, β = 87.322(4), V = 850.57(9) Å3 and Z = 2.
Keywords: Chalcone analogues, curcumin analogues, anti-microbial activity, docking
analysis.

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1. Introduction:
Antimicrobial resistance within a wide number of bacteria and fungi is a complex public
health threat to many countries and multiple sectors. This phenomenon affects ever-widening
range of infectious agents, most of which can cause a broad spectrum of diseases in humans
and animals. The proportion of Escherichia coli, Klebsiella pneumonia and Staphylococcus
aureus resistant to commonly used antibacterial drugs exceeds 50% in many clinical cases
[1]. Facing this scenario, there is an urgent need for new efficient antimicrobial agents.
Chalcone and their derivatives represent a versatile group of molecules due to its biological
properties. Chalcone (Figure 1) is a natural product which consists of two aromatic moieties
connected by a three carbon α,β-unsaturated carbonyl group. Chalcones are considered as the
precursor of flavonoids and isoflavonoids richly found in plants. The enone linkage presents
in the model structure plays a crucial role for the biological activity of chalcone derivatives.
Chalcones attracted the attention of scientific community because of their pharmacological
activities such as anti-angiogenic effects [2], anti-tumor [3], anti-viral [4], anti-inflammatory
[5,6], anti-fungal [7], anti-cancer [8], anti-nematodal [9], anti-plasmodial [10], anti-
tuberculosis [11], antiplatele [12], anti-HIV [13] and lipoxygenase inhibitors activities [14].
Several reviews have been published about the chemistry, synthesis and medicinal properties
of chalcones [15–17]. Due to the pharmacological potential of chalcone derivatives, which is
fully described in the specialized literature and their role in defense mechanisms in plants, we
carried investigation to screen the anti-microbial activity of our synthesized chalcone and
curcuminoids analogues [18]. It was observed that the presence of an electron-donating
moiety in the aromatic rings has a significant effect upon the biological activity. In addition
we concluded that the antimicrobial activity of selected chalcone derivatives is reduced when
electron-withdrawing groups are substituted in the aromatic rings. Our results are in
agreement with that reported in literature [19], which also explain the efficiency of the
electron donating group position on aromatic ring. Different researchers have tried to obtain
chalcones having electron donating substitution to evaluate their anti-microbial potential [20].
From a literature review it is clear that most efforts have been directed to the synthesis and
biological evaluation of chalcone derivatives with electron-donating groups in aromaric rings
but the research is far from exhausted [21,22]. Literature survey also suggest that curcumin
loses its activity by the replacement of methoxy substitution, that is why most of the
analogues were reported in the result of hydroxyl substitution in order to get potent
compounds. The underlying mechanisms of action, particularly with respect to the direct
cellular targets have not been rigorously characterized, which forces challenges to structure-

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guided rational development of therapeutic with acceptable target-selectivity profile [23].
Large number of natural product analogues were found to inhibit D-alanyl-D-alanine
carboxypeptidase [24], which is an enzyme involved in bacterial cell wall biosynthesis during
the transpeptidation that crosslink the peptide side chains of peptidoglycan. Chalconoids and
curcuminoids were found to target the above mentioned protein. Monocarbonyl compounds
were reported to have good antimicrobial activities compared to dicarbonyl curcuminoids due
to their instability. Molecular docking results showed that synthesized compounds have good
activity against target 1PW1, and compounds 1, 9 and 15 were found most active by
exhibiting binding energy of -7.9, -8.0 and -8.5 kcal/mol respectively.
Figure 1: Chalcone and curcumin structure and their analogues
2. Experimental Protocols
2.1. Synthesis of the chalcones
The chalcones were prepared by condensation reactions between four aldehydes with
butanone resulting in the four 4-aryl-3-methylbutenones (compounds 1-4). Each chalcone
derivative was used as starting material for the production of sixteen compounds through
further condensation reaction with the four aldehydes (compounds 5-20) [18]. The in vitro
anti-microbial activities of compounds 1-20 were evaluated preliminarily against a gram-
negative and gram-positive indicator strain. The promising compounds were further studied
for their anti-microbial activity against a collection of nine selected clinically relevant
pathogens.

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2.2. Bioassays
2.2.1. Bacterial strains: species, storage and growth conditions
The indicator strains used in the antimicrobial screening stage were the gram-negative
and gram-positive bacteria Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC
25923, respectively. For the second phase trials, we employed additional gram-negative
bacteria (Pseudomonas aeruginosa ATCC 14207, Shigella sonnei ATCC 29930), gram-
positive bacteria (Bacillus cereus ATCC 11778, Enterococcus faecalis ATCC 29212,
Staphylococcus saprophyticus ATCC 15305) and fungi (Candida albicans ATCC 10231,
Candida krusei ATCC 90878). All the strains were store at -80 ºC and sub-cultured on
Mueller-Hinton broth (MHB) (37°C, 18h). A microbial inoculum was prepared by adjusting
the turbidimetry of the medium to 0.5 McFarland standard value [23,24]. Bacteria and fungi
were obtained from the Culture Collection of Laboratory of Microbiology and Biomolecules
(Federal University of Sao Carlos, Brazil).
2.2.2. Minimum Inhibitory Concentration (MIC)
The broth-micro dilution technique was used for the antimicrobial activity evaluation of
the 20 compounds. This biological activity was tested in the indicator strains E. coli and S.
aureus [23,24]. The lyophilized compounds were solubilized in DMSO and then diluted in
MHB. The twofold concentrated solutions were transferred to a 24-well microtiter plate and
the double-dilutions were sequentially prepared in MHB. The DMSO reached maximal final
concentration of 5.0% per well, which did not inhibit microbial strains. The sealed plates were
incubated at 37°C for 18 h under gentle agitation of 120 rpm. The MIC value was considered
as the lowest concentration in which no microbial growth was observed by naked eye. For
confirmation of the MIC value, MTT dye colorimetric method was then applied. In the
selected wells, 20 µl (1 mg/mL) of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) reagent was added followed by 20 minutes of incubation at 37°C. The
solutions remained clear/yellowish for those with no microbial growth, while the emergence
of dark blue color indicated growth [27,28]. In the second phase, the compounds that showed
inhibitory effect on the indicator strains were further evaluated against the additional gram-
negative, gram-positive bacteria and fungi (previously described) through the same broth
micro dilution technique. Ciprofloxacin was used as a positive control.

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2.3. Molecular Docking
2.3.1. Selection of protein structure and considerations
The crystal structure of D-alanyl-D-alanine carboxylpeptidas was selected from the
Protein Data Bank (PDB ID: 1PW1, resolution 1.20 Å) [29]. DD-Peptidase structure was
prepared for docking by removal of native ligand (2-amino-2-deoxy-D-glucitol-6-phosphate)
and water molecules. Swiss PDB Viewer was used to check structure for missing segments
and minimization energy [30]. Pdbsum [31] was used to find residues involved in active site
are Gly61, Ser62, Phe120, Thr-123, Tyr159, Asn161, Leu214, Trp233 Arg285, His298,
Thr299, Gly300, Thr301, Gln303, Ser326 and Asn327.
2.3.2. Preparation of chalcone structures for docking
The ligands were drawn in ChemSketch v15.0.9 (Chemaxon) assigned with proper 2D
orientation and the structure of each compound was analyzed for connection error in bond
order. Energy of the molecules was minimized using Avogadro [32] with MMFF94 force
field.
2.3.3. Protein-Ligand Docking Studies
PharmMapper Server was used to obtain information regarding possible mechanisms
behind the activity of studied compounds [33]. PharmMapper Server is a freely accessed web-
server designed to identify potential target candidates for the given probe small molecules
(drugs, natural products, or other newly discovered compounds with binding targets
unidentified). PharmMapper utilizes an integrated pharmacophore matching platform with
statistical method for potential target identification [34]. Compounds are scored according to
their fitness on the pharmacophore models. Moreover, the program encompasses z0 score
which is a score generated from the molecule’s fit score and a library score matrix calculated
beforehand. It combines the fit score and its corresponding vector in the score matrix together
and normalizes it to a vector with a mean of zero and a standard deviation of one. Compared
to the fit score z0-score not only applies the pharmacophore matching method but also
considers statistic factors lying behind. Generally, large positive z0-score indicates high
significance of the target to a query compound; as well large negative z0-score indicates that
the target may not be significant enough.

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Docking studies calculations were performed by Auto dock Vina v1.1.2 [35]. Protein
and chalcone derivatives structures were converted to pdbqt files by MGL Tools 1.5.6 RC1.
The grid size box was set at 22 x 26 x 22, and the grid center was set to 20.089, -11.808 and
38.599 for x, y and z respectively, which covered all amino acid residues in the considered
active pocket. The spacing between grid points was 1.000 Å. Kollman charges and polar
hydrogen atoms were added to protein structure. Gastiger charges were added and non-polar
hydrogen atoms were merged for ligands structure. After calculation docking results provide
different conformation of ligands in active site. Each of them is studied and best conformation
was chosen with the lowest binding energy (kcal/mol) between protein and ligand (chalcone
derivative). The interactions of complex protein-ligand conformations, were analyzed using
Auto dock Tools 4.2 [35], Discovery studio 4.1 [36].
2.4. X-ray crystallography
Compounds 14 and 16 were recrystallized from ethanol. The X-ray diffraction data were
collected using a BRUKER APEX II duo diffractometer with Mo-Kα radiation (λ = 71.073
pm). Structure solution and refinement were performed with SHELXS-97 [37]. All non-
hydrogen atoms were refined with anisotropic displacement parameters with SHELXL-2013.
The hydrogen atoms' positions were found in Fourier maps or calculated in their idealized
positions. More details on data collections and structure calculations are summarized in Table
1.
Table 1.Crystal data and structure refinement details of compounds 14 and 16.
Identification code
Empirical formula
Formula weight
Temperature (K)
Wavelength
Compound (14)
C21H23NO2
Compound (16)
C20H22N2O3
321.40
336.38
296(2)
296(2)
0.71073 Å
Monoclinic
P21/n
0.71073 Å
Triclinic
Crystal system
Space group
Pī
Unit cell dimensions
a
b
c
13.1293(3) Å
17.5364(4) Å
15.1433(3) Å
6.8226(4) Å
7.2256(4) Å
18.1235(12) Å

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α (deg)
90
88.371(4)
87.322(4)
72.394(3)
850.57(9)
2
β (deg)
95.6440(10)
γ (deg)
Volume (Å3)
90
3469.70(13)
8
Z
Density (calculated)
3
3
1.313 Mg/m
1.231 Mg/m
Absorption coefficient
-1
-1
0.078 mm
1376
0.089 mm
356
F(000)
Theta
range
for
data 1.78 to 25.04°
2.25 to 25.05
collection
Index ranges
-15<=h<=15, -16<=k<=20,
-8<=h<=8, -8<=k<=8,
-21<=l<=21
-17<=l<=18
Reflections collected
Independent reflections
Absorption correction
max/min transmission
20977
9772
6116 [R(int) = 0.0155]
Multi-scan
2965 [R(int) = 0.0260]
Multi-scan
0.9529 and 0.9228
0.9911 and 0.9746
2965 / 0 / 229
1.057
Data / restraints / parameters 6116 / 0 / 441
1.031
Final R indices [I>2sigma(I)] R1 = 0.0389, wR2 = 0.1004
2
Goodness-of-fit on F
R1 = 0.0480, wR2 = 0.1315
R1=0.0685, wR2 = 0.1469
R indices (all data)
R1 = 0.0447, wR2 = 0.1046
-3
Largest diff. peak and hole
-3
0.176 and -0.162 e.Å
0.161d -0.203 e.Å
3. Results and discussion
3.1. Chemistry
Compounds 1-20 were prepared by standard procedures [18]. Structure representations
of compounds 1-20 are presented in Figure 2a and 2b. Compounds 1-4 were produced by acid
catalyzed reaction (HCl gas) and act as intermediate for the synthesis of compounds 5-20.

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Base catalysis was carried for the preparation of compounds 5-20 by NaOH in ethanol.
Figure 2a: Synthesis of the intermediate compounds 1-4 and chalconoids 5-20.
Figure 2b: Chemical structure of compounds 5-20.

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3.2.Crystallographic Characterization
Ellipsoid representations of the molecular structures of the compounds 14 and 16 with
numbering scheme are presented in Figure 3, while crystal packing and selected bond
distances are reported in Fig. S1 and Table S3 in Electronic Supporting Information. Selected
bond distances are reported in Table 2. As can be observed, the bond lengths along the carbon
chain between the two aromatic rings are within values for alternate single and double bonds.
For example, the C(12)-C(13) bond presents a single bond character while the C(11)-C(12) is
a typical double bond. This alternation of single and double bonds make the structure more
flexible and less planar. As expected, only weak interactions are observed in the crystal
packing of the compounds. Detailed information about the structure determination is given in
Table 1. The complete information of both crystal structures is reported in Electronic
Supporting Information (see table S1 and S2).
Figure 3. Ortep view with thermal ellipsoids at the 50% probability level and atomic
numbering scheme compound 14 (left) and compound 16 (right).
3.3. Biological activity
The compounds (1-20) were preliminarily screened for their in vitro anti-microbial
activity against Escherichia coli and Staphylococcus aureus (Table 2). The active compounds
(1, 9 and 15) were further screened against 7 different bacteria's and 2 fungi to evaluate their
anti-biotic potential (see Table S4 in Electronic Supporting Information).
In preliminarily screening compound 15 was the only one able to inhibit the growth of
both microbial indicator strains: E. coli and S. aureus (MIC of 500 µg/mL and 250 µg/mL
respectively). Compound 1 (MIC 250 µg/mL) and 9 (MIC 62.5 µg/mL) were selectively good
inhibitors for gram-negative and gram-positive strains respectively. Compounds 9 (MIC 62.5
µg/mL) and 15 (MIC 250 µg/mL) (for S. aureus) showed lower MIC values when compared
with the positive control: ciprofloxacin. Taking into account the structure, compound 1 has no
substituents in the aromatic rings, compounds 9 has one p-methoxy substitution in aromatic

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ring A and 15 has two p-N,N-dimethyl substitution in both ring A and B. It is concluded that
among three active compounds two afforded electron-donating substituent’s showed good
inhibitory activity, even better than the positive control.
Table 2. Inhibitory activity (MIC, µg/mL) of compounds 1-20
S. Number
Escherichia coli
Staphylococcus aureus
ATCC 25922
ATCC 25923
1
2
3
4
5
6
7
8
250
> 1000
1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
9
> 1000
> 1000
> 1000
> 1000
> 1000
> 1000
500
62.5
10
11
12
13
14
15
16
17
> 1000
> 1000
> 1000
> 1000
> 1000
250
> 1000
> 1000
> 1000
> 1000
18
19
> 1000
> 1000
> 1000
> 1000
20
PC
> 1000
500
> 1000
500
PC (positive control): Ciprofloxacin
The biological activity of compounds against E. coli showed that electron donating
substitution (p-N,N-dimethyl) on both aromatic ring A and B in case of compounds 15
exhibited increase in antimicrobial activity. Compound 1 is monoaryl having no substitution
on aromatic ring A also shows good activity. The rest of compounds tested showed a decrease
in potency. Concerning the biological activity of compounds against S. aureus, it is
remarkable that electron donating substitution of aromatic ring A and B reflected an
improvement in antimicrobial action. Compound 9 having p-methoxy substitution on
aromatic ring A, and compound 15 having two p-N,N-dimethyl substitution on aromatic ring
A and B, show potency in activity.

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Biological activity results indicated that electron donating groups (p-methoxy on
compounds 5 while p-N,N-dimethyl on compound 15) significantly enhances the activity.
Some other factors which also influence the activity include length and size of side chains and
polar or non-polar hydrophilic groups are more favorable to improve the biological activity of
the chalcone compounds. The modifications discussed may facilitate the interaction of the
compounds with microbial cellular membrane. It is noteworthy that the weak antimicrobial
activity is linked with the polar nature of some compounds that did not allow the membrane
penetration.
According to the data presented (see Table S4 in Electronic Supporting Information),
compound 1 displayed its activity preferentially against gram-negative bacteria (and weak
antimicrobial action against fungi) if compared to the gram-positive ones. Compound 2
exhibited potent activity against gram negative bacteria Shigella sonnei, gram positive
bacteria Staphylococcus saprophyticus, and against two fungi Candida albicans and Candida
krusei. Compound 9 was found the most potent one against gram positive, negative bacteria
and fungi. Additionally, the compound 9 showed good bioactivity for Shigella sonnei,
Staphylococcus aureus, Staphylococcus saprophyticus, Candida albicans and Candida krusei.
The same antimicrobial behavior of compound 9 was demonstrated by compound 15.
3.5. Molecular Docking
The pharmmapper produced the top 300 ligand ranked based on the fit score. Working on the
highest antimicrobial targets, the key bacterial enzymes found were D-alanyl-D-alanine
carboxypeptidase (1PW1), glucousamine 6-Photsphate Synthase (1MOQ) and beta-lactamase
(1I2W). By reverse-docking of potent compounds (1, 9, and 15) for selected target, the
enzyme D-alanyl-D-alanine carboxylpeptidase (1PW1) was found the suitable target for our
ligands (Table 3).
Table 3. Pharmmaper and Autodock vina results for selected targets
PDB ID,S
Ligands
1MOQ
z-score
1PW1
1I2W
z-score
kcal/mol z-score kcal/mol
kcal/mol
-6.5
-0.21
-0.429
-0.214
-7.3
-7.5
-7.4
1.123
0.842
1.32
-7.9
-8.0
-8.5
0.195
0.312
1.438
1
9
15
-6.8
-6.5

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Molecular docking results confirmed that the most suitable target for our compounds is D-
alanyl-D-alanine carboxylpeptidase (PDB ID: 1PW1). Auto dock vina allows the flexible
docking of ligands into its site of action. It has ability to use all the rotatable bonds of the
ligands to give a number of conformations from which the best mode could be achieved. Our
ligands occupy the same space in the active site as that of native ligand in the crystal of
enzyme (see Figure S2 in Electronic Supporting Information). Ligands 1, 9 and 15 were most
active ligands with lowest binding energy -7.9, -8.0 and -8.5 kcal/mole (see Table S5 in
Electronic Supporting Information). Our ligands formed hydrogen bond contact with Thr-116,
Tyr-159,Asn-161 and Thr-299. While hydrophobic contacts were with Phe-120, Thr-123,
Tyr-159, Gln-278 and Arg-285. Based on interactions of ligands with protein`s residues, it is
clear that mechanism of action of ligands are based on both types of interactions; hydrogen
bonds and hydrophobic contacts (including π-π stacked, π-alkyl and π-σ). The inhibition
constant (Ki) was also calculated and show best value for compounds 1, 9 and 15 to be 3.80,
2.65 and 2.14 µM. The smaller the Ki, the greater the binding affinity and the smaller amount
of drug may be needed in order to inhibit the activity of enzyme. If Ki is much larger, then
that drug is not likely to inhibit the activity of that enzyme. The potent compound 9 is shown
in the active site of enzyme in Figure 4. Figure S3 in Electronic Supporting Information
shows protocol validation of docking through re-docked native ligand in same conditions.
Some of our compounds have shown docking scores much better than the docking score of
co-crystallized ligand which is docked in same condition as studied ligands (-7.5 kcal/mol)
and Ciprofloxacin used as comparing standard. In general a good correlation was observed
between in vitro and in silico results of analysis.
Figure 4. Best poses of ligands compound 9 interacting with active site residues of 1PW1.
The hydrogen bonds are represented as dashed-green and white lines.

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4. Conclusion:
This work has proved that synthetic curcumin and chalcone analogues can be used as anti-
microbial compounds. The bioassays and the computational calculations showed that electron
donating group on both rings A and B in this class of compounds is crucial for obtaining anti-
microbial activity. Among 20 studied compounds, compound 1 with no substitution,
compound 9 with one p-methoxy while compound 15 with two p-N,N-dimethyl moiety on
aromatic ring were found more active. Compound 1 was found active against Escherichia
coli, compound 9 against Staphylococus aureus while compound 15 were active against both
types of bacteria. In addition, electron-withdrawing substituents have no antimicrobial
activity. The present study provides a template to design new combinations of antibiotics and
non-antibiotics for the treatment of Staphylococus aureus and Escherichia coli infections.
Pharmmaper and molecular docking results provided significant interactive detail. Therefore
optimization must be performed in order to obtain more potent compounds.
Acknowledgments
The authors are great full to Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), ano
Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES) for financial Sport
and Third World Academy of Science (TWAS) for Ph.D. fellowship. The computational
resources of the centro nacional de processamento de alto desempenho em São Paulo are
highly appreciated.
Supplementary data
Some other necessary detail regarding biological activity and crystal structure are
given in Electronic Supporting Information.
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Research highlight
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We synthesized a series of close related monocarbonyl curcuminoids.
Crystal, DFT, in-silico study and anti-microbial potential were also studied.
The compounds were tested against gram-negative and gram-positive bacteria.
Compounds 1, 9 and 15 exhibited good activity against Escherichia coli and
Staphylococcus aureus.
•
Docking studies helped understanding these results.