Synthesis and Evaluation of Substituted 2-Chloro-N-Phenylacetamide Derivatives
1. Synthesis, Characterization, Molecular Docking and Biological evaluation
of substituted 2-chloro-N-Phenylacetamide derivatives
Chetan Singh Rathore, Sandeep Kumar, Satheesh Kumar, Sushil K. Singh
Department of Pharmaceutics IIT BHU Varanasi, Uttar Pradesh 221005, India.
ABSTRACT
No. B-72
ABSTRACT
The discovery of antimicrobial agents was not less a boon to mankind that helped the wounded soldier to
recover back quickly during Second World War. However, their unwarranted use and ability of microbes to
mutate rapidly lead to devilment of antimicrobial resistance. Substituted acetamide nucleus has shown vari-
ous biological abilities including antimicrobial, antitumor, antitubercular, anti-inflammatory, antiviral activ-
ities etc. The present work focuses on synthesis of substituted pyridine derivative of 2-chloro-N-
phenylacetamide and the evaluation of antimicrobial activity on various strains of bacteria viz. S. aureus,
E.coli, S. typhi and fungal strains i.e. C. albicans, A. niger, C. krusie. The substituted chloro derivative of N
-phenylacetamide shown significant and comparable antibacterial activity with Ciprofloxacin and antifungal
activity with Amphotericin B. 2-Chloro-N-phenylacetamide (Al) and 2-chloro-N-(4-methoxyphenyl)
acetamide (A2) showed zone of inhibition 32.43±0.20mm & 29.55±0.10mm aganist E. coli,
31.15±0.03mm, 29.00±0.03mm against S. typhi and 29.35±0.20mm & 29.70±0.15mm against C. krusei re-
spectively. Further, the biological evaluation was supplemented with docking against DNA gyrase (PDB
code 2XCS).
Keyword: antimicrobial, 2-chloro-N-Phenylacetamide.
.
INTRODUCTION
Multidrug resistance (MDR) to antibiotics is a problem that has long plagued public health. Substituted
acetamide nucles has shown various biological capabilities including antimicrobial, antitumor, anti-
tubercular, anti-inflammatory, antiviral activities.
Bravo et al (2008) synthesized a series of acetanilide with different substituents in Cα and in the aromatic
ring and those compounds showed antifungal activity with MIC of 250 µg/ml.
M. Shanmugapiya et al. (2012) prepared Mannich base by treating morpholine and salicyladehyde with
acetanilide. The compound showed good antimicrobial activity against both gram positive S. aureus, B.
subtilis, gram negative E.coli, P. aeruginosa and antifungal activity against C. albicans.
S.R. Pattan et al. in 2006 has synthesized 2-acetanilido-4-arylthiazole derivatives for their antimicrobial
activity.J.B. et al. synthesized Dioxanide furoate is considered as a safe and effective drug for the treat-
ment of asymptomatic or mildly symptomatic person who are passing crysts of Entamebahistolytica.
Aim of our work is to synthesis pyridine substituted 2-chloro-N-phenylacetamide derivative and their mi-
crobial evaluation on various strains of bacteria viz. S. aureus, E.coli, S. typhi and fungal strains Viz. C.
albicans, A. niger, C. krusie.
Presented at the 67th
Indian Pharmaceutical Congress, JSS University, Mysuru held during December 19-21, 2015.
EXPERIMENTAL METHOD
To a well stirred solution of aniline/p-anisidine in DCM, triethylamine was added drop wise at 0˚C. The
resulting mixture was stirred for 15 min. Chloroacetyl chloride was added drop wise and the reaction
mixture was stirred at room temperature for 20 min. Then 1M sodium hydroxide solution was added and
stirred for 3 hours. Later, extracted with DCM to obtained 2-Chloro-N-phenylacetamide (A1) and 2-
chloro-N-(4-methoxyphenyl)acetamide (A2) respectively.
Equimolar 2-Chloro-N-phenylacetamide and 2-chloro-N-(4-methoxyphenyl)acetamide with various sub-
stituted aminopyridines were dissolved in 20 ml DCM and refluxed overnight at room temperature. The
white precipitate formed was washed with brine solution and recrystallized with methanol.
The compounds were characterized and tested for antimicrobial activity against S. aureus, P. aeruigeno-
sa, E. coli and various strains of Candida and MIC was determined.
RESULTS AND DISCUSSION
The compound synthesize were characterized and evaluated for antimicrobial activity on various
strains of bacteria viz. S. aureus, E.coli, S. typhi and fungal strains i.e. C. albicans, A. niger, C. krusie.
The substituted chloro derivative of N-phenylacetamide shown significant and comparable antibacteri-
al activity with Ciprofloxacin and antifungal activity with Amphotericin B. 2-Chloro-N-
phenylacetamide (Al) and 2-chloro-N-(4-methoxyphenyl)acetamide (A2) showed zone of inhibition
32.43±0.20mm & 29.55±0.10mm aganist E. coli, 31.15±0.03mm, 29.00±0.03mm against S. typhi and
29.35±0.20mm & 29.70±0.15mm against C. krusei respectively. Further, the biological evaluation was
supplemented with docking score in the range of -7 to -8 kcal/mole against GlcN-P( PDB id-2PUT ).
Fig. 1–Zone of Inhibition of 2-chloro N-Phenylacetamide derivatives against various Bacterial and Fungal
Strains.
CONCLUSION
We assessed the antimicrobial activity of some novel 2-chloro-N-phenylacetamide derivatives and compared their activity to that of Ciprofloxacin and Amphotericin. 2-Chloro-N-phenylacetamide (Al) and 2-chloro-N-(4-
methoxyphenyl)acetamide (A2) showed good zone of inhibition. Thus further studies on 2-chloro-N-Phenylacetamide derivative and structure activity studies may produce better chemotherapeutic agents.
REFERENCE
Schmid M.B.; “Seeing is believing: the impact of structural genomics on antimicrobial drug discovery”; Nat. Rev. Microbiol.; 2(9); 739-746; 2004.
Singh R.B., Das N., Jana S., Das A.; “Synthesis and in vitro antibacterial screening of some new 2, 4, 6-trisubstituted-1, 3, 5-triazine derivatives”; Lett. Drug. Des. Discov.; 9(3); 316-321; 2012.
Bravoa H.R., Villarroela E. , Copajaa S. , Argandon V.H.; “Chemical Basis for the Phytotoxicity of N-Aryl Hydroxamic Acids and Acetanilide Analogues”; Z. Naturforsch; 63 ; 389-94; 2008.
REACTION SCHEME
Fig 1—Docking Image of 2-Chloro-N-phenylacetamide (A1)
with GlcN-P synthase ( PDB id-2PUT).
NH2
R
+ Cl
O
Cl
Et3N(R),CH2Cl2(S)
R
HN
Cl
3hr,0-RT
R=H,OCH3
HN
R
O
Cl
i
ii
iii
HN
R
HN
R
HN
R
O
H
N
O
HN
O
H
N
N
N
N
R=H,OCH3
i=2-aminopyridine
ii=3-aminopyridine
iii=4-aminopyridine
0
5
10
15
20
25
30
35
40
Compounds
S. aureus E.coli E.coli C. albicans A.niger C. krusie
ZoneofInhibition(inmm)