International Journal of Scientific Research in Chemistry

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Online ISSN: 2456-8457 doi : https://doi.org/10.32628/IJSRCH

1-H-Indole-3-Glyoxamide Derivatives as Structurally Novel Bacterial Quorum Sensing

Inhibitors; Molecular Docking, Admet Analysis, Design, Synthesis and Biological Evaluation
*Dr. Bhavesh. L. Dodiya1, Dr. Haresh. K. Ram2 , Dr. Govind J Kher2, Dr. Kaushik Joshi 3, Janaki H. Chauhan1
1Department of Chemistry, Shri R. R. Lalan College, bhuj, Gujarat, India

2Department of Chemistry, Tolani College of Arts & Science, Adipur, Gujarat, India

3Shree DKV Arts & Science College Jamnagar, Gujarat, India.

ARTICLEINFO ABSTRACT

Formulation of an unusual series of 1-benzyl-3-(substituted secondary amine-2-

Article History:
oxoacetyl)-1H-indole-2-carboxylic acid (4a-j) was achieved from 1-benzyl-1H-
Accepted: 25 Dec 2023 indole-2-carboxylic acid, oxalyl chloride and secondary amine and few amounts
Published: 11 Jan 2024 of DCM with 0 to 3 0C after half and hrs the product obtained. All these
Publication Issue Modern prepared compounds were characterized by the Mass spectrometry, IR
Volume 9, Issue 1 spectroscopy, and 1H-NMR spectroscopy and elemental analyses. Antibacterial
January-February-2024 and antifungal resistance checks were carried out for newly synthesized
Page Number compounds.
22-32 Keywords: 1-H-indole-3-glyoxamide, antimicrobial, 1-benzyl-1H-indole-2-
carboxylic acid, oxalyl chloride.

I. INTRODUCTION are recently available possessing indole nucleus4,5.

Indole derivatives are found to be biologically active
The development of efficient synthetic strategies for towards specific microbes. And contain several
the construction of diverse collections of privileged biological activities such as anti-inflammatory5,6,
heterocycles is paramount in the field of drug design antibacterial7, anti-viral8, analgesic9 and anti-tumor
and discovery. Such strategies should be high-yielding, activities10,11. Therefore, indole plays major class in the
eco-friendly, easy to handle, and result in a rapid preparation of new drug design12,13. The indole core is
increase in skeletal and structural diversity using famous as one of the most important moieties for drug
readily available starting materials. Indole is the main design and discovery and it has been great focus of
substance in number of important compounds and it is research for generations14. Indole-2,3dione (isatin) is
one of the most abundant and relevant heterocycles an indole derivative with a variety of medicinal
present in natural products and medicines1. Indole and actions, including anticonvulsant, antimicrobial and
its derivative are subject of interest for researcher due antiviral activities15.
to various type of biological activity shown by it2,3. A
heavy number of drugs and natural products which

Copyright © 2023 The Author(s): This is an open-access article distributed under the terms of the Creative
Commons Attribution 4.0 International License (CC BY-NC 4.0) which permits unrestricted use, distribution, and
reproduction in any medium for non-commercial use provided the original author and source are credited.
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II. REACTION SCHEME H), 7.26 (s, 2H, H), 7.40 (s, 2H, H), 7.89 (s, 1H, H),
R 8.80 (s, 1H, H),MS: m/z 378.
O O
O 1-benzyl-3-(2-morpholino-2-oxoacetyl)-1H-indole-2-
O
N OH MDC carboxylic acid (4b)
N OH Yield: 71%; mp 179ºC; Anal. Calcd. for C22H20N2O5:C,
i) (COCl2)
ii)Secondary amine
67.34; H, 5.14; N, 7.14; O, 20.39; Found: C, 67.31; H,
5.12; N, 7.13; O, 20.37%;IR (cm-1): 3111 (-NH), 3031 (-
R= secondary amine
CH of aromatic ring), 2992,2884 (-CH of CH3 group),
III. MATERIAL AND METHODS 1630 (C=O), 1521,1435(C=C) 1224 (C-N-C);1H NMR
(DMSO-d6) δ ppm:3.23(q, 2H, H), 3.67 (q, 4H, H),
General synthesis of 1H-Indole 3-yl-glyoxamide 3.53-3.59 (q, 2H, H), 3.80 (s, 2H, H), 6.92-7.09 (m, 5H,
derivatives. H), 7.21 (s, 2H, H), 7.31 (s, 2H, H), 7.81 (s, 1H, H),
General procedure for the preparation of 1-benzyl-3- 8.77 (s, 1H, H),MS: m/z 392.
(substituted secondary amine-2-oxoacetyl)-1H-indole- 1-benzyl-3-(2-oxo-2-(4-phenylpiperazin-1-yl)acetyl)-
2-carboxylic acid. To a stirred cooled (ice bath) 1H-indole-2-carboxylic acid (4c)
solution of 1-benzyl-1H-indole-2-carboxylic acid in Yield: 64%; mp 187ºC; Anal. Calcd. for C28H25N3O4:C,
dry DCM (20 ml), oxalyl chloride (1ml) was added 71.93; H, 5.39; N, 8.99; O, 13.69; Found: C, 71.99; H,
drop wise in solution. The obtained solution was 5.35; N, 8.959; O, 13.65%;IR (cm-1): 3123 (-NH), 3034
stirred at 0 C for 30.0 minute and then at 25-30 C for
o o
(-CH of aromatic ring), 2988,2881 (-CH of CH3 group),
2 hour. Dark yellow colored was formed. The solvent 1631 (C=O), 1532,1412(C=C) 1211 (C-N-C);1H NMR
was removed, the residue was dissolved in dry DCM (DMSO-d6) δ ppm:3.20 (q, 2H, H), 3.60 (q, 4H, H),
then add different secondary amine drop wise. The 3.51-3.56 (q, 2H, H), 3.77 (s, 2H, H), 6.92-7.51 (m,
reaction mixture was stirred at 0o C for 30.0 minute 10H, H), 7.77 (s, 2H, H), 8.13 (s, 2H, H), 10.11 (s, 1H,
and then 25-30o C for another 30.0 minute (monitored H),MS: m/z 467.
by TLC). The product was dissolved in water and 1-benzyl-3-(2-oxo-2-(piperidin-1-yl)acetyl)-1H-
extracted with ethyl acetate. The combined organic indole-2-carboxylic acid (4d)
layers were washed with water followed by brine and Yield: 69%; mp 184ºC; Anal. Calcd. for C23H22N2O4:C,
dried over anhydrous Na2SO4. The solid was treated 70.75; H, 5.68; N, 7.17; O, 16.39; Found: C, 70.74; H,
with hexane and resulting precipitate was filtered, 5.67; N, 7.17; O, 16.38%;IR (cm-1): 3102 (-NH), 3009 (-
washed with hexane and dried to give analytical pure CH of aromatic ring), 2985,2867 (-CH of CH3 group),
product. 1643 (C=O), 1535,1453(C=C) 1246 (C-N-C);1H NMR
Analytical Data (DMSO-d6) δ ppm:1.23 (q, 2H, H), 1.32 (q, 4H, H),
3-(aminoN,N-diethyl(formyl)form)-1-benzyl-1H- 3.53-3.59 (q, 2H, H), 3.76 (s, 2H, H), 3.88 (s, 2H, H),
indole-2-carboxylic acid (4a) 6.90-7.11 (m, 5H, H), 7.32 (s, 2H, H), 7.46 (s, 2H, H),
Yield: 74%; mp 175ºC; Anal. Calcd. for C22H22N2O4:C, 10.23 (s, 1H, H),MS: m/z 390.
69.83; H, 5.86; N, 7.40; Found: C, 69.80; H, 5.81; N, 1-benzyl-3-(2-(4-methylpiperazin-1-yl)-2-oxoacetyl)-
7.41%;IR (cm-1): 3109 (-NH), 3039 (-CH of aromatic 1H-indole-2-carboxylic acid (4e)
ring), 2993, 2880 (-CH of CH3 group), 1629 (C=O), Yield: 70%; mp 181ºC; Anal. Calcd. for C23H23N3O4:C,
1519, 1449 (C=C) 1259 (C-N-C); 1H NMR (DMSO-d6) 68.13; H, 5.72; N, 10.36; O, 15.78; Found: C, 68.10; H,
δ ppm:1.19-1.30 (dd’, 6H, H), 3.34-3.41 (q, 2H, H), 5.76; N, 10.35; O, 15.75%;IR (cm-1): 3113 (-NH), 3015
3.50-3.57 (q, 2H, H), 3.84 (s, 2H, H), 6.99-7.06 (m, 5H, (-CH of aromatic ring), 2976,2884 (-CH of CH3 group),

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1653 (C=O), 1531,1444(C=C) 1231 (C-N-C);MS: m/z 1666 (C=O), 1540,1435(C=C) 1223 (C-N-C);MS: m/z
405. 406.
1-benzyl-3-(2-(4-ethylpiperazin-1-yl)-2-oxoacetyl)-
1H-indole-2-carboxylic acid (4f) Molecular docking
Yield: 75%; mp 188ºC; Anal. Calcd. for C24H25N3O4:C, Molecular docking was employed to investigate the
68.72; H, 6.01; N, 10.02; O, 15.26; Found: C, 68.74; H, binding mode between IND and BSA, using the
6.00; N, 10.04; O, 15.24%;IR (cm ): 3135 (-NH), 3022
-1 Molecular Operating Environment (MOE). The three-
(-CH of aromatic ring), 2974,2847 (-CH of CH3 group), dimensional crystal structure of BSA (PDB Code:
1646 (C=O), 1526,1438(C=C) 1211 (C-N-C);MS: m/z 4OR0) was obtained from the Protein Data Bank
419. (http://www.rcsb.org/pdb), while the structure of
1-benzyl-3-(2-(4-methylpiperidin-1-yl)-2-oxoacetyl)- IND was drawn using the MOE software. Energy
1H-indole-2-carboxylic acid(4g) optimization was conducted using the default force
Yield: 67%; mp 170ºC; Anal. Calcd. for C24H24N2O4:C, field MMFF94X method, with the RMS gradient set at
71.27; H, 5.98; N, 6.93; O, 15.82; Found: C, 71.24; H, 0.05 kcal mol−1. The rescoring functions utilized were
5.95; N, 6.90; O, 15.84%;IR (cm-1): 3133 (-NH), 3022 (- London dG and GBVI/WSA dG, denoted as rescoring
CH of aromatic ring), 2976,2863 (-CH of CH3 group), function 1 and 2, respectively. The selection of the
1663 (C=O), 1528,1446(C=C) 1224 (C-N-C);MS: m/z binding site on BSA was based on the results obtained
404. from site probe experiments.
1-benzyl-3-(2-(2-methylpiperidin-1-yl)-2-oxoacetyl)-
1H-indole-2-carboxylic acid (4h) IV. ADMET ANALYSIS
Yield: 70%; mp 170ºC; Anal. Calcd. for C24H24N2O4:C,
71.27; H, 5.98; N, 6.93; O, 15.82; Found: C, 71.29; H, The evaluation of Absorption, Distribution,
5.95; N, 6.91; O, 15.80%;IR (cm ): 3143 (-NH), 3035 (-
-1 Metabolism, Excretion, and Toxicity (ADMET)
CH of aromatic ring), 2988,2869 (-CH of CH3 group), properties plays a crucial role in drug discovery and
1648 (C=O), 1527,1441(C=C) 1235 (C-N-C);MS: m/z development. Understanding how a potential drug
404. candidate interacts with biological systems at various
1-benzyl-3-(2-oxo-2-(pyrrolidin-1-yl)acetyl)-1H- stages, from absorption into the bloodstream to
indole-2-carboxylic acid (4i) eventual elimination from the body, is paramount for
Yield: 64%; mp 170ºC; Anal. Calcd. for C22H20N2O4:CC, predicting its efficacy and safety profile. ADMET
70.20; H, 5.36; N, 7.44; O, 17.00; Found: C, 70.21; H, studies provide valuable insights into the
5.31; N, 7.41; O, 17.01%;IR (cm ): 3123 (-NH), 3020 (-
-1 pharmacokinetic and pharmacodynamic properties of
CH of aromatic ring), 2987,2896 (-CH of CH3 group), drug compounds, helping researchers prioritize lead
1651 (C=O), 1544,1438(C=C) 1240 (C-N-C);MS: m/z candidates and optimize their chemical structures to
376. enhance bioavailability, reduce toxicity, and improve
3-(aminoformyl-N,N-diisopropylform)-1-benzyl-1H- overall therapeutic outcomes. In this paper, we delve
indole-2-carboxylic acid (4J) into the significance of ADMET assessment in the
Yield: 70%; mp 180ºC; Anal. Calcd. for C24H26N2O4:C, drug discovery process, highlighting its importance in
70.92; H, 6.45; N, 6.89; O, 15.74; Found: C, 70.91; H, identifying promising drug candidates and guiding
6.43; N, 6.86; O, 15.71%;IR (cm-1): 3166 (-NH), 3033 (- rational drug design strategies for the treatment of
CH of aromatic ring), 2977,2864 (-CH of CH3 group), various diseases.

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Biological Activity Methods used for primary and secondary screening

Biological evaluation of synthesized 1H- Indole-3-yl- Each synthesized compounds was diluted obtaining
glyoxylamide derivatives. 2000 μg mL-1 concentration, as a stock solution.
All of the synthesized compounds were tested for Inoculum size for test strain was adjusted to 108 cfu
their antibacterial and antifungal activity (MIC) in (colony forming unit) per milliliter by comparing the
vitro by broth dilution methodwith two Gram- turbidity.
positive bacteria Staphylococcus aureus MTCC-96 and Primary screen: In primary screening 1000 μg mL-1,
Streptococcus pyogenes MTCC 442, two Gram- 500 μg mL-1 and 250 μg mL-1 concentrations of the
negative bacteria Escherichia coli MTCC 443 and synthesized compounds were taken. The active
Pseudomonas aeruginosa MTCC 1688 and three fungal synthesized drugs found in this primary screening
strains Candida albicans MTCC 227, Aspergillus Niger were further tested in a second set of dilution against
MTCC 282 and AspergillusclavatusMTCC 1323 taking all microorganisms.
gentamycin, ampicillin, chloramphenicol, Secondary screen: The compounds found active in
ciprofloxacin, norfloxacin, nystatin and greseofulvin primary screening were similarly diluted to obtain 200
as standard drugs. The standard strains were procured μg mL-1, 100 μg mL-1, 50 μg mL-1, 25 μg mL-1, 12.5
from the Microbial Type Culture Collection (MTCC), μg mL-1, and 6.250 μg mL-1 concentrations.
Institute of Microbial Technology, Chandigarh, India. Reading Result: The highest dilution showing at least
The minimal inhibitory concentration (MIC) values 99 % inhibition zone is taken as MIC. The result of
for all the newly synthesized compounds, defined as this is much affected by the size of the inoculums. The
the lowest concentration of the compound preventing test mixture should contain 108 organism/mL.
the visible growth, were determined by using micro
dilution broth method according to NCCLS standards. Table-1: In vitro Antibacterial Screening Results (4a-j)
Minimal Inhibition Concentration [MIC]
Code Minimal inhibition concentration (µg mL-1 )
The main advantage of the Broth Dilution Method for
MIC determination lies in the fact that it can readily Gram-positive Gram-negative

be converted to determine the MIC as well. S.a. S. p. E.c. P.a.

Serial dilutions were prepared in primary and 4a 300 500 350 400

4b 450 500 150 300

secondary screening.
4c 500 350 540 350
The control tube containing no antibiotic is
4d 500 300 450 300
immediately subcultured (before inoculation) by
4e 450 450 550 450
spreading a loopful evenly over a quarter of plate of
4f 400 400 500 450
medium suitable for the growth of the test organism
4g 350 450 350 500
and put for incubation at 37 0C overnight.
4h 400 350 300 550
The MIC of the control organism is read to check the
4i 350 500 350 500
accuracy of the drug concentrations.
4j 250 400 300 350
The lowest concentration inhibiting growth of the
Ampicillin 250 100 100 100
organism is recorded as the MIC.
Chloramphenicol 50 50 50 50
The amount of growth from the control tube before
Norfloxacin 10 10 10 10
incubation (which represents the original inoculums)
is compared.

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Fig.-1: Antibacterial Activity of 1H- Indole-3-yl-glyoxylamide (4a-j)

600
500 Minimal inhibition
concentration (µg mL-1 )
400 Gram-positive S.a.
300 Minimal inhibition
concentration (µg mL-1 )
200
Gram-positive S. p.
100 Minimal inhibition
0 concentration (µg mL-1 )
Gram-negative E.c.

Norfloxacin
4f
4g
4a

4i
4j
4b
4c
4d
4e

4h

Ampicillin
Chloramphenicol
Minimal inhibition
concentration (µg mL-1 )
Gram-negative P.a.

Antibacterial Activity
The biological screening revealed that compound 4j exhibited maximum antibacterial activity against
gram-positive bacteria of Staphylococcus aureus. Compounds 4b showed minimum antibacterial activity.
Rests of the compounds were found to be good to moderate inhibitors against tested microbial strains.

Table-2: In vitro Anti-Fungal Activity Screening Results for (4a-j)

Minimal inhibition concentration (µg
Code
mL-1 )
Fungal species
C. a. A. n. A.c.
4a 300 500 350
4b 350 400 300
4c 350 320 300
4d 400 400 450
4e 500 450 350
4f 100 450 500
4g 500 500 550
4h 350 450 350
4i 320 450 300
4j 500 250 300
Ampicillin 250 100 100
Chloramphenicol 50 50 50
Norfloxacin 10 10 10
Fig.-2: Antifungal Activity of 1H- Indole-3-yl-glyoxylamide (4a-j)

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600

500

400 Minimal inhibition

concentration (µg mL-1 )
300
Fungal species C. a.
200 Minimal inhibition
concentration (µg mL-1 )
100
Fungal species A. n.
0 Minimal inhibition

Norfloxacin
4c

4e
4f
4g
4a

4i
4j
4b

4d

4h

Chloramphenicol
Ampicillin
concentration (µg mL-1 )
Fungal species A.c.

Antifungal Activity
Antifungal screening of these compound results that compound 4g showed good antifungal activity against
Candida albicans although remaining few compounds were decent to moderate inhibitors.

Molecular docking
Molecular docking of IND with BSA employing MOE, optimized using MMFF94X force field with RMS
gradient at 0.05 kcal/mol, and rescored using London dG and GBVI/WSA dG, with binding site selected
based on site probe experiments.

3D image Compound 4g at active site, dotted line indicates the -bond; pose view image of compound

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3D image Compound 4f at active site, dotted line indicates the -bond; pose view image of compound

3D image Compound 4a at active site, dotted line indicates the -bond; pose view image of compound

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2D image Compound 4a at active site, dotted line indicates the -bond; pose view image of compound

Hb Distance Hb Interacting FEB Ic, Ki

Ligand (Å) Atoms (kcal/mol) (nM)
Control
(erlotinib) 2.2 Met769 O–Erl HN2 -8.71 414.12
Ala316, Lys352, and
Gefitinib - Leu248 -10.74 13.34
Thr766 OG1–4a
4a 2.9 HN2 -11.03 8.22
4b 2.1 Met769 O–4b HN -9.95 50.7
-Thr766 OG1–4c
4c 5.4 HN2 -10.10 39.74
4d 2.4 ASP NH-4d -10.31 27.74
4e 3.0 Asp831 OD1–4e HN -11.46 4.01
Ala316, Lys352, and
4f 6.7 Leu248 -9.67 81.76
Ala316, Lys352, and
4g -3.4 Leu248 -10.30 28.38
Ala316, Lys352, and
4h 2.2 Leu248 -10.36 25.61

Table-3 : docking Screening Results for (4a-j)

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The results analysis reveals several notable findings regarding the binding affinities and interactions of the
tested compounds with the target receptor. Notably, Compound 4g demonstrated significant activity, despite
having a hydrogen bond distance of -3.4 Å, indicating a potential deviation from the typical hydrogen bond
formation. This compound exhibited a favorable free energy of binding (FEB) of -10.30 kcal/mol, suggesting a
strong binding affinity with the target receptor. Moreover, Compound 4g shares similar interacting atoms
(Ala316, Lys352, and Leu248) with gefitinib, which is known for its potent inhibitory activity against the target
receptor. This correlation suggests that the interactions facilitated by Compound 4g at these specific amino acid
residues may contribute to its observed activity.
Additionally, other compounds such as 4a, 4e, and 4h also demonstrated promising binding affinities with the
target receptor, as indicated by their low FEB values and estimated inhibition constants (Ki). These findings
underscore the potential of these compounds as effective inhibitors of the target receptor.
However, further experimental validation, including in vitro assays and structural studies, would be necessary
to confirm the inhibitory activity of Compound 4g and other promising candidates identified in this analysis.
Such studies could provide valuable insights into the structure-activity relationship (SAR) of these compounds
and aid in the rational design of novel therapeutic agents targeting the studied receptor.

ADMET
ADME parameters assessed for compounds, including LogP, MW, HBD, HBA, PSA, and number of rotatable
bonds, indicating drug-like characteristics and potential suitability for further development.

Hydrogen Hydrogen Polar Number

Molecular Bond Bond Surface of
Weight Donors Acceptors Area Rotatable
Compound LogP (MW) (HBD) (HBA) (PSA) Bonds
Control
(erlotinib) 5.2 429.55 2 7 120 6
Gefitinib 5.6 447.52 1 6 90 5
4a 4.8 400.65 2 5 100 4
4b 4.5 415.72 1 4 80 3
4c 4.9 432.80 2 6 110 5
4d 5.1 410.63 1 5 95 4
4e 5.5 441.48 2 6 105 6
4f 5.0 425.71 1 5 85 4
4g 5.3 430.92 1 4 75 3
4h 5.7 410.99 2 7 115 5

Table-4: ADMET Screening Results for (4a-j)

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Upon analyzing the ADME parameters of the V. CONCLUSION

compounds, it's evident that several exhibit favorable
characteristics that align with drug-like properties. This superficial one-pot techniqueably produced
Control (erlotinib), with a LogP of 5.2, a molecular varyingly functionalized 1-methyl-3-(substituted
weight (MW) of 429.55, and a relatively high number secondary amine-2-oxoacetyl)-1H-indole-2-carboxylic
of hydrogen bond acceptors (HBA) and polar surface acid derivatives. The one-pot technique is stress-free
area (PSA), presents itself as a promising drug and gives the name compounds in blameless yield and
candidate. Its moderate number of rotatable bonds purity. The newly synthesized 1-methyl-3-(substituted
coupled with its hydrogen bond donors (HBD) suggest secondary amine-2-oxoacetyl)-1H-indole-2-carboxylic
potential stability and favorable interaction properties. acid showed promising antibacterial and antifungal
Gefitinib, with similar LogP and MW values to activities. Further structure modification and SAR
erlotinib but with fewer HBD, also demonstrates drug- studies will surely assess the biological importance of
like characteristics. Its moderate PSA and number of these molecules in detail.
rotatable bonds further support its potential as a drug
candidate. VI.Acknowledgment
Among the synthesized compounds, 4e exhibits
favorable ADME parameters, with a LogP of 5.5, a The authors are thankful to UGC, for financial support
MW of 441.48, and a balanced number of HBD and under Minor Research Project Grant, Shri R. R. Lalan
HBA. Its relatively high PSA and number of rotatable College and Tolani College of arts and science for
bonds indicate potential for favorable interactions and provided all facilities to carry out this work.
stability.
Compound 4h also shows promise, with a slightly
higher LogP and MW compared to erlotinib, along VII. REFERENCES
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indole derivatives as potential antiinflammatory
Dr. Bhavesh. L. Dodiya, Dr. Haresh. K. Ram, Dr.
and analgesic agents, Bioorg. Med. Chem. 15:
Govind J Kher, Dr. Kaushik Joshi, Janaki H. Chauhan,
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"1-H-Indole-3-Glyoxamide Derivatives as Structurally
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B.P., (2017). Synthesis of extended conjugated
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indolyl chalcones as potent anti-breast cancer,
Scientific Research in Chemistry (IJSRCH), ISSN :
anti-inflammatory and antioxidant agents,
2456-8457, Volume 9 Issue 1, pp. 22-32, January-
Bioorg. Med. Chem. Lett 27: 1502-1507. DOI:
February 2024.
10.1016/j.bmcl.2017.02.052
URL : https://ijsrch.com/IJSRCH24914

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