A novel medium size lactam ring analoges as antibacterial agents: Synthesis, biological evaluation and molecular docking studiES

Article abstract of DOI:10.17179/excli2017-193

A novel series of medium size (S)-3-alkyl-3,4,6,7-tetrahydro-1H-benzo[e][1,4]diazonine-2,5-dione (6a-f) analogues were synthesized from (E)-3-(2-nitrophenyl)acrylicacid (2) reacting with various amino acid esters using Di-isopropyl Carbodiimide as a coupling agent. The final cyclization is carried out by using reagent 1-Ethyl-3(3- dimethylaminopropyl) Carbodiimide Hydrochloride. The synthesized compounds have been supported by Mass, ¹H-NMR and ¹³C-NMR. Further antibacterial studies were conducted, where some molecules are noticed with potent activity, especially molecule 6d shown highest activity which was also supported by molecular docking studies. All final molecules were docked with enzyme peptide deformylase to determine the probable binding conformation.

Full text of DOI:10.17179/excli2017-193

EXCLI Journal 2017;16:1090-1098 – ISSN 1611-2156
Received: February 03, 2017, accepted: July 04, 2017, published: August 14, 2017
Original article:
A NOVEL MEDIUM SIZE LACTAM RING ANALOGES AS
ANTIBACTERIAL AGENTS: SYNTHESIS, BIOLOGICAL
EVALUATION AND MOLECULAR DOCKING STUDIES
Putcha A. N. V. Harita*1, Putcha Seshi Kumar2, Shiva Krishna Reddy Guduru3,
Parameshwar Ravula1, J N Narendra Sharath Chandra4
1
Department of Medicinal Chemistry, Guru Nanak Institutions Technical Campus, School
of Pharmacy, Jawaharlal Nehru Technological University, Hyderabad-501301, India
Shantha Biotechnics private limited. A Sanofi company, Medchal, India-501401
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli,
2
3
Hyderabad, India-500 046
Department of Pharmaceutical Chemistry, Bharat Institute of Technology,
4
Mangalpally, Telanagana, India-501510
* Corresponding author: Department of Medicinal Chemistry, Guru Nanak Institutions
Technical Campus - School of Pharmacy, Hyderabad, Telangana, India-501506.
E-mail: harita1122@gmail.com
http://dx.doi.org/10.17179/excli2017-193
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/).
ABSTRACT
A novel series of medium size (S)-3-alkyl-3,4,6,7-tetrahydro-1H-benzo[e][1,4]diazonine-2,5-dione (6a-f) ana-
logues were synthesized from (E)-3-(2-nitrophenyl)acrylicacid (2) reacting with various amino acid esters using
Di-isopropyl Carbodiimide as a coupling agent. The final cyclization is carried out by using reagent 1-Ethyl-3(3-
dimethylaminopropyl) Carbodiimide Hydrochloride. The synthesized compounds have been supported by Mass,
1H-NMR and 13C-NMR. Further antibacterial studies were conducted, where some molecules are noticed with
potent activity, especially molecule 6d shown highest activity which was also supported by molecular docking
studies. All final molecules were docked with enzyme peptide deformylase to determine the probable binding
conformation.
Keywords: medium size ring, synthesis, coupling reaction, lactam, bacillus subtilis, anti-bacterial, docking
INTRODUCTION
against such bacteria, their clinical value is in-
adequate to treat an exceeding group of life
threatening systemic infections because of
their comparatively high risk of toxicity
(Sanders and Sanders, 1979), emergence of
drug resistant strains (Ventola, 2015; Neu,
1992), pharmacokinetic differences, and in-
sufficiencies in their activity (Bush, 2004;
Levison and Levison, 2009). Our research
community is trying to synthesize molecules
Over the years, antibacterial agents are
playing a vital role to treat infectious diseases
(Woon and Fisher, 2016). Apart from the in-
creasing new diseases, emerging resistance in
bacteria against available antibacterial agents
is a world-wide problem (Lin et al., 2015;
Brickner et al., 1996; Neu, 1985). Even
though the design, development and expan-
sion of a number of new antibacterial agents
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which are having better pharmacokinetic
properties and are sufficient in their activity.
Literature results show, the 9-membered
medium size ring molecules and macrocycles
are bioactive and have promising therapeutic
potential value (Driggers et al., 2008). Espe-
cially macrocycles provide pre-organized ring
structure to molecules and are ideal for bind-
ing protein surface (Reayi and Arya, 2005; Yu
and Sun, 2013; Marsault and Peterson, 2011;
Kopp et al., 2012). Meseguer and co-workers
(1999, 2000), synthesized libraries of indolac-
tam analogs, where the 9-membered ring
structure is present in a natural product Indo-
entry
R=
R
O
sec-Bu
1
2
NH
NH
Bn
i-Pr
i-Bu
3
4
O
6
5
6
Me
H
Figure 2: Retrosynthesis of 9-membered ring
molecule
(S)-3-alkyl-3,4,6,7-tetrahydro-1H-benzo
lactam V (F1.1), the core structure of tumor- [e] [1,4]diazonine-2,5-dione analogues (6a-f)
protecting teleocidins. Marcantoni and co- are synthesized from intermediate (E)-3-(2-
workers (2000) synthesized a 9-membered nitrophenyl)acrylic acid (2) reacting with var-
medium size macrocyclic ring component of ious amino acid ester. The intermediate (E)-3-
Griseoviridin (F1.2) which is a broad spec- (2-nitrophenyl)acrylic acid (2) is in-turn syn-
trum antibiotic with in vitro inhibitory activity thesized from o-Nitrobenzaldehyde. The final
toward various pathogenic fungi and bacteria step cyclization is carried out using reagent 1-
(Figure 1).
ethyl-3(3-dimethylaminopropyl)
carbodi-
imide hydrochloride and acetonitrile as sol-
vent. Further, the synthesized compounds
were screened for antibacterial activity.
MATERIALS AND METHODS
Chemistry
All solvents and reagents were used, as re-
ceived from the suppliers and some of them
were distilled before use. All the reactions
were monitored by thin layer chromatography
(TLC) on pre-coated silica gel 60F254
(Merck, 1.05554) and the spots were visual-
ized with UV light at 254 nm or alternatively
by staining with ninhydrine or potassium per-
manganate or ceric ammonium molybdate.
Flash column chromatography was per-
formed using silica gel (Merck, 60A, 230-400
Mesh). All reactions were performed in oven
dried glassware. Dimethylformamide, di-
chloromethane, methanol and tetrahydrofuran
were dried immediately prior to use according
to standard procedures: Dimethylformamide,
dichloromethane was distilled under N2 from
CaH2, methanol was distilled under N2 over
Mg and tetrahydrofuran was distilled under
N2 over Na. All solvents were removed by
evaporation under reduced pressure. 1H-NMR
Figure 1: 9-membered ring containing molecules
in nature
A series of medium size ring [(S)-3-alkyl-
3,4,6,7-tetrahydro-1H-benzo[e][1,4]diazoni-
ne-2,5-dione] molecules (6a-f) was synthe-
sized on benzene ring and screened for anti-
bacterial activity. The key reactions that are
involved for constructing this (medium size)
ring are reduction of nitro group and amino
ester coupling reactions (Figure 2).
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Received: February 03, 2017, accepted: July 04, 2017, published: August 14, 2017
and 13C-NMR spectra were recorded on Var- solution was quenched with sodium bicar-
ian 400 MHz CDCl3 using TMS as internal bonate solution and further extracted with
standard. Electron impact (EI) and chemical ethyl acetate. The obtained organic layer was
ionization mass spectra were recorded on an washed with brine solution, and then dried
Agilent-6430 mass spectrometer instrument.
over anhydrous sodium sulphate. The solution
was filtered and concentrated to leave a crude
oil. The obtained liquid was purified by col-
umn chromatography to give the pure com-
pound.
General procedure for synthesis of (E)-ethyl
3-(2-nitrophenyl)acrylate (1)
To a solution of sodium hydride in dry tet-
rahydrofuran and triethyl phosphonoacetate
was added at 0 °C, and stirred under nitrogen General procedure for synthesis of
atmosphere for 30 min. A solution of 2-nitro- compounds (4a-f)
benzaldehyde in tetrahydrofuran was then
To a suspension of compound (3a-f) in ab-
added drop wise to the reaction mixture and solute ethanol, 10 % Pd/C was added and
allowed to stir for 4 h at 0 °C. After comple- stirred the reaction mixture for 12 h under hy-
tion of the reaction (monitored through TLC), drogen atmosphere at room temperature. Af-
the reaction mixture was quenched by adding ter completion of the reaction (monitored
saturated ammonium chloride solution and it through TLC), the reaction mixture was
was extracted with ethyl acetate. The col- passed through celite and concentrated. The
lected organic layers were washed with brine crude compound was subjected to column
solution, and then dried over anhydrous so- chromatography to give white colour oily
dium sulphate. The solution was filtered and compound.
concentrated, which was then purified by col-
General procedure for synthesis of
umn chromatography to give a yellow liquid
compounds (5a-f)
compound.
To the suspension of ester (4a-f) in Tetra-
General procedure for synthesis of (E)-3-(2-
nitrophenyl)acrylic acid (2)
hydrofuran and water, Lithium hydroxide
Monohydrate was added. For 12 h the reac-
To the solution of ester in methanol and tion mixture was stirred at room temperature.
water, lithium hydroxide monohydrate was The reaction was monitored through TLC.
added. The reaction mixture was stirred at Later after completion of reaction, the solu-
50 °C for 12 h. After completion of reaction tion was filtered and extracted with ethyl ace-
(monitored through TLC), methanol was re- tate. The obtained liquid was dried over so-
moved under reduced pressure. The obtained dium sulfate, filtered and concentrated.
aqueous solution was added with HCl till the
General procedure for synthesis of
pH is in between 5-6 and then extracted with
compounds (6a-f)
ethyl acetate. The combined organic phase
To the suspension of acid (5a-f) in ace-
were dried over sodium sulfate, filtered and
tonitrile, 1-ethyl-3(3-dimethylaminopropyl)
concentrated to obtained light yellow colour
carbodiimide hydrochloride were added at
room temperature and allow to stir under ni-
solid compound.
General procedure for synthesis of
compounds (3a-f)
trogen atmosphere for 12 h. After finishing of
reaction (which was monitored through TLC),
To a suspension of compound (2) in dry the solution was quenched with sodium bicar-
dimethylformamide, amino ester, diisopropyl bonate solution. It was then concentrated and
carbodiimide, 1-hydroxy-1H-benzotriazole extracted with ethyl acetate. The collected or-
and N, N-diisopropylethylamine were added ganic layer was washed with brine solution
at 0 °C and allowed to stirred for 12 h under and it was dried over anhydrous sodium sul-
nitrogen atmosphere. After completion of the phate. The solution was then filtered and con-
reaction (which was monitored through TLC), centrated to give a crude oil, later purified by
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column chromatography to give pure com- 5H), 2.17 (m, 1H), 1.70 (m, 1H), 1.53-1.43
pound.
(m, 1H), 1.10 (d, J = 6.90 Hz, 1H), 1.04 (t, J
= 7.43 Hz, 2H), 0.95 (t, J = 7.39 Hz, 1H), 0.81
(d, J = 6.81 Hz, 2H); C-NMR (400 MHz,
CDCl3) δppm : 180.1, 161.1, 133.8, 128.2,
127.7, 126.1, 125.2, 117.5, 71.9, 37.2, 26.6,
25.9, 24.5, 13.9, 11.9; LRMS : (ES+) m/z =
243.3 (Fragmented ion).
(S)-3-isobutyl-3,4,6,7-tetrahydro-1H-
13
benzo[e][1,4]diazonine-2,5-dione (6a)
Molecular Formula : C15H20N2O2;Rf: 0.2
at 0.2: 9.8 ethyl acetate/DCM; Yield : 26 %;
1H-NMR (400 MHz, CDCl3) δppm : 8.24 (d,
J = 8.01 Hz, 1H), 7.38-7.09 (m, 4H), 4.20 (m,
1H), 3.02-2.95 (m, 2H), 2.88 (m, 2H), 2.05 (S)-3-methyl-3,4,6,7-tetrahydro-1H-
(m, 1H), 1.82 (m, 1H), 1.54 (m, 1H), 1.02 (m, benzo[e][1,4]diazonine-2,5-dione (6e)
J = 17.83, 6.64 Hz, 6H); 13C-NMR (100
Molecular Formula : C12H14N2O2; Rf: 0.2
MHz, CDCl3) δppm : 180.6, 160.6, 133.7, at 3 : 7 ethyl acetate/hexanes; Yield : 40 %;
128.3, 127.8, 126.2, 125.2, 117.5, 67.2, 40.7, 1H-NMR (400 MHz, CDCl3) δppm : 8.23 (d,
29.7, 25.9, 25.2, 23.2, 21.7; LRMS : (ES+) J = 8.13 Hz, 1H), 7.39-7.30 (m, 2H), 7.20 (d,
m/z = 242.8 (Fragmented ion).
J = 7.31 Hz, 1H), 7.15 (t, J = 7.46 Hz, 1H),
4.17 (m, 1H) , 2.95 (m, J = 7.47 Hz, 2H),
2.90-2.85 (m, 2H),1.34(d, 3H); 13C-NMR
(100 MHz, CDCl3) δppm : 178.5,161.2,
134.7, 128.3, 127.8, 125.2, 123.8, 115.5, 72.6,
30.7, 25.1, 18.8; LRMS : (ES+) m/z = 200.5
(Fragmented ion).
(S)-3-benzyl-3,4,6,7-tetrahydro-1H-
benzo[e][1,4]diazonine-2,5-dione (6b)
Molecular Formula : C18H18N2O2; Rf: 0.2
at 3 : 7 of ethyl acetate/hexanes; Yield : 10 %;
1H-NMR (400 MHz,CDCl3) δppm : 8.16 (d, J
= 8.15 Hz, 1H),7.32-7.07 (m, 9H), 4.50-4.44
(s, 1H),3.36 (m, 1H), 3.13 (m, 1H), 2.77 3,4,6,7-tetrahydro-1H-benzo[e][1,4]diazo-
(m,4H); 13C-NMR (100 MHz,CDCl3) δppm : nine-2,5-dione (6f)
179.2, 161.2, 136.0, 133.4, 129.5, 128.2,
Molecular Formula : C11H12N2O2; Rf:
128.1, 127.7, 126.7, 126.2, 125.3, 117.5, 69.2, 0.35 at 3 : 7 ethyl acetate/hexanes; Yield :
1
37.2, 29.7, 25.7, 25.7; LRMS : (ES+) m/z = 54 %; H-NMR (400 MHz, CDCl3) δppm :
276.7 (Fragmented ion).
8.20 (d, J = 8.12 Hz, 1H), 7.38-7.31 (m, 2H),
7.25 (d, J = 7.31 Hz, 1H), 7.14 (t, J = 7.55
Hz, 1H), 4.15 (d, 2H) , 2.93 (m, J = 7.47 Hz,
2H), 2.91-2.85 (m, 2H); 13C-NMR (100 MHz,
CDCl3) δppm : 180.5,165.2, 136.8, 129.1,
127.8, 124.7, 122.8, 112.5, 74.6, 38.7, 25.7;
LRMS : (ES+) m/z = 185.7 (Fragmented ion).
(S)-3-isopropyl-3,4,6,7-tetrahydro-1H-
benzo[e][1,4]diazonine-2,5-dione (6c)
Molecular Formula : C14H18N2O2; Rf: 0.3
at 3 : 7 ethyl acetate/hexanes; Yield : 46 %;
1H-NMR (400 MHz, CDCl3) δppm : 8.25 (d,
J = 8.13 Hz, 1H), 7.37-7.28 (m, 2H), 7.24 (d,
J = 7.31 Hz, 1H), 7.16 (t, J = 7.46 Hz, 1H),
4.10 (m, 1H) , 2.98 (m, J = 7.47 Hz, 2H),
2.95-2.87 (m, 2H), 2.45-2.37 (m, 1H), 0.90
(m, 6H); 13C-NMR (100 MHz, CDCl3) δppm
: 179.5,161.2, 133.7, 128.3, 127.8, 126.2,
125.2, 117.5, 73.6, 29.7, 26.1, 19.3, 16.8,
14.1; LRMS : (ES+) m/z = 228.7 (Fragmented
ion).
Antibacterial activity
The title compounds were subjected for
antibacterial activity, where Zone of inhibi-
tion (Pandey et al., 2010; Kirby and Bauer,
1996) and Minimum inhibitory concentration
(Sarker et al., 2007; Gibbons et al., 2002; Pra-
chayasittikul et al., 2010) test were conducted
against test organism Bacillus subtilis which
is a gram positive bacteria, by using Cup Plate
Method and Microtitre Plate Method respec-
tively.
(S)-3-sec-butyl-3,4,6,7-tetrahydro-1H-
benzo[e][1,4]diazonine-2,5-dione (6d)
Molecular Formula : C15H20N2O2; Rf : 0.5
at 3 : 7 ethyl acetate/hexanes; Yield :
10 %;1H-NMR (400 MHz, CDCl3) δppm :
8.26 (m, 1H), 7.29 (m, 3H), 7.15 (t, J = 7.47
Hz, 1H), 4.26-4.13 (d, 1H), 3.02-2.87 (m,
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Determination of Zone of Inhibition - Cup
Plate Method
dehydration. Each plate has a set of positive,
negative and standard solution. The prepared
Cultures were sub-cultured on Nutrient plates were placed in an incubator at temper-
Agar (NA) and Sabouraud Dextrose Agar ature 37 ºC for 18-24 h. The change in colour
(SDA) plates and further stored in slants as was then observed visually. The colour
stock cultures. For the experiment, stock cul- changes from purple to pink or colourless is
tures were prepared by inoculating each cul- taken as positive. The lowest concentration at
ture from slants to flask in sterile Nutrient which change in colour occurred was consid-
Broth (NB) and incubated at 37 ºC for 24 h ered as MIC value.
(Bacteria). The stock cultures were adjusted
to 0.3 OD (Bacteria) at 650 nm by using spec- Molecular docking
trophotometer and used for assay. Sterile NA
Docking studies were carried on windows
plates where prepared at 0.1 ml of inoculums 2002 with MOE 2008.10 version according to
from standardized culture of test organism reported method (Ravula et al., 2016a, b).
and were spread evenly. A sterile borer was From the protein data bank (PDB code:
used to prepare wells with diameter 10 mm 1G27), peptide deformylase enzyme was
and 100 µl (in order to get the concentration taken and visualized the receptor by using se-
of 1000, 500, 250 µg/well) of the test mate- quence option and deleted further co-factors.
rial, standard antibiotic. A standard antibiotic, The ligand structures were written by using a
i.e., ciprofloxacin was tested against bacteria builder module and the partial charges were
and was added in each well separately. At adjusted and subsequently according to the
4 ºC the plates were kept for 1 h to carry out standard geometry, 3D protonation and hy-
the diffusion of test solution into the medium, drogen addition was performed. At cut off 12
so that the plates were incubated at a temper- using force field MMFF94x at 0.01KJ mole
ature best for the growth of test organism for gradient the ligand’s energy minimized. By
a period of time enough for the growth of at using the option simulation docking was per-
least 10 to 15 generations. The zone of inhibi- formed and was followed by using sequence
tion of microbial growth around the well was option dock on selected active site amino ac-
measured in mm.
ids were performed and eventually docked us-
ing setting options such as alpha triangle, re-
Determination of Minimum Inhibitory Con- ceptor and solvent, affinity dG, selected resi-
centration (MIC) - Microtitre Plate Method
dues, force field refinement and best 30 pose.
A sterile 96 well plate, prepared under After achieving docking results, best pose
aseptic conditions, was labelled. Into the first was retained out of the 30 best posed results
row of the plate a quantity of 100 µL of test for each chemical structure. The resultant best
material in DMSO (generally a stock concen- pose scores wereused for further examinina-
tration of 0.2 mg/ml for purified material and tion of docking and interaction.
2 mg/mL for crude extracts) was pipetted.
50 µL of sterile broth was added to all other
wells. Sterile dilutions were performed using
multichannel pipette. Discard the tips after
use, so that each well had 50 µL of the test
compound in consecutively descending con-
centrations. Resazurin indicator solution was
added to each well of 10 µL. A 30 µL of ster-
ile broth was added using a pipette. Lastly,
microbial suspension of 10 µL was added to
each well. By using cling film each plate was
wrapped loosely to protect the culture from
RESULTS AND DISCUSSION
Synthesis started from the commercially
available o-Nitrobenzaldehyde, it is subjected
to Horner-Wittig reaction followed by ester
hydrolysis obtained (E)-3-(2-nitrophenyl)-
acrylic acid (2). This was coupled with vari-
ous amino acid esters with the help of 1-hy-
droxy-1H-benzotriazole and di-isopropyl car-
bodiimide coupling reagents obtained (3a-f)
in a good yield. This coupled product sub-
jected to hydrogenation on Pd/C which results
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in one step nitro group and double bond re- Biological evaluation
duction. The resulted ester (4a-f) again hydro- The newly synthesized compounds 6a-f
lysed with Lithium hydroxide condition ob- were evaluated for their antibacterial activity
tained acid intermediate (5a-f). Finally ring (zone of inhibition and Minimum Inhibitory
closed with help of 1-Ethyl-3(3-dimethyla- Concentration) against Bacillus subtilis, a
minopropyl) carbodiimide hydrochloride gram positive organism. The screening data
coupling reagent obtained a medium size ring have been shown in Table 1, indicated that the
(6a-f) on benzene (Figure 3). The final syn- compound 6d showed significant antibacte-
thesized molecules were purified by column rial activity. Remaining compounds were
chromatography and were analyzed by physi- found to possess moderate activity. Ciprof-
cal and analytical methods.
loxacin was used as standard, for both the test,
its Minimum Inhibitory Concentration value
is >7.8 µg/ml, whereas the title molecules are
observed with value is 125 µg/ml shown in
Figure 4 and 5.
Figure 3: Synthesis of (S)-3-alkyl -3,4,6,7-tetrahydro-1H-benzo[e] [1,4]diazonine-2, 5-dione analogues
(6a-f)
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G
H
Figure 4: Zone of inhibition assay against B. subtilis by cup plate method
Figure 5: Minimum Inhibitory Concentration activity of test samples against B. subtilis at different con-
centrations
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Table 1: Zone of inhibition and MIC value of final cyclized molecules
Zone of inhibition in
mm (B.subtilis)
S. No
1
Sample Code
6a
Sample Name
MIC value
1000
500
250
µg/ml
µg/ml
µg/ml
RR1292
15.6
13.3
10.0
125 µg/ml
2
3
6b
6c
RR1293
RR1294
15.0
10.0
14.0
12.0
13.0
12.0
125 µg/ml
125 µg/ml
4
5
6d
6e
6f
RR1295
RR1296
RR1297
18.6
13.0
12.0
17.6
14.0
11.0
15.6
12.0
13.0
125 µg/ml
125 µg/ml
6
7
125 µg/ml
>7.8 µg/ml
Standard
Std (1 mg/ml) 61.6
(Ciprofloxacin)
Molecular docking
Molecular docking study was carried for
further study of action of final compounds
with peptide deformylase enzyme and eluci-
dated the observed biological results. Com-
paring of all final molecules, the docking re-
sults of compound 6d showed better interac-
tions of one hydrogen bond interaction i.e.,
oxygen of C=O and Arg 97; d=2.47Aº. Ben-
zene ring showed stacking interaction with
Arg 97. Moreover molecule was surrounded
by Glu 42, Cys90, Gly89 and Glu 87. This
overall supports the results obtained for anti-
bacterial activity (Figure 6).
Figure 6(B): Three-dimentional structural model
of compound 6d (purple) into peptide deformylase
enzyme.
CONCLUSION
The novel analogues of lactam containing
medium size ring molecules were synthesized
and screened for antibacterial activity. Of all
final compounds, compound 6d showed good
bacterial inhibition and other compounds
showed moderate inhibition. This was sup-
ported by molecular docking studies. With
further molecular modification and QSAR of
Figure 6(A): Two-dimentional representation of
the interaction mode of 6d with peptide deformyl-
ase enzyme.
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Neu HC. Relation of structural properties of beta-lac-
tam antibiotics to antibacterial activity. Am J Med.
1985;79(2A):2-13.
these compounds, several other promising bi-
oactive molecules can be developed in future.
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