Supplementary Information
Design, Synthesis, Pharmacological Evaluation and Molecular Docking Studies of Substituted
Oxadiazolyl-2-Oxoindolinylidene Propane Hydrazide Derivatives
Deweshri Kerzare,a,b Rupesh Chikhale,*,a,b,c Ratnadeep Bansode,c Nikhil Amnerkar,b Nazira Karodia,d
Anant Paradkarc and Pramod Khedekara
a
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University,
Amravati Road, 440 033 Nagpur-MS, India
b
Kamala Nehru College of Pharmacy, Butibori, 441 108 Nagpur-MS, India
c
Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre,
Kharghar, 410 210 Navi Mumbai-MS, India
c
Centre for Pharmaceutical Engineering Science, Faculty of Life Sciences, University of Bradford,
BD7 1DP Bradford, United Kingdom
d
School of Biology, Chemistry and Forensic Science, University of Wolverhampton, WV1 1LY
Wolverhampton, United Kingdom
General methods for synthesis of substituted ethyl benzoates (16-30)1
To a solution of substituted benzoic acid (1-15) (0.246 mol) in dry ethanol (2.5 mol), concentrated sulphuric
acid (0.5 mL) was added. The reaction mixture was refluxed for 8 h. Excess of ethanol was distilled off and the content
was allowed to cool. The residue was poured into separating funnel containing 60 mL of water. Carbon-tetrachloride
(5-10 mL) was added to obtain sharp separation of aqueous and ester layer. Ester layer was washed with sodium
hydrogen carbonate solution. The esters (16-30) were collected and recrystallised from ethanol, since the compounds
are very well known and characterised, we have done their preliminary investigations only to confirm the formation of
these compounds. Details of which is mentioned as below.
Ethyl benzoate (16)
Yield: 5.8 g (58%); b.p. 208-210 ºC; Rf 0.53 (chloroform).
Ethyl 4-hydroxybenzoate (17)
Yield: 7.3 g (73%); m.p. 114-116 ºC; Rf 0.57 (chloroform).
Ethyl 4-methylbenzoate (18)
Yield: 8.2 g (82%), b.p. 230-232 ºC; Rf 0.67 (chloroform).
Ethyl 3-nitrobenzoate (19)
Yield: 6.9 g (69%); m.p. 40-44 ºC; Rf 0.68 (chloroform).
Ethyl 2,3-dimethoxybenzoate (20)
Yield: 7.6 g (76%); m.p. 180-182 ºC; Rf 0.68 (chloroform).
Ethyl 4-chlorobenzoate (21)
Yield: 4.5 g (45%); b.p. 240-242 ºC; Rf 0.68 (chloroform).
Ethyl 4-nitrobenzoate (22)
Yield: 7.1 g (71%); m.p. 60-62 ºC; Rf 0.76 (chloroform).
Ethyl 4-acetylbenzoate (23)
Yield: 7.4 g (74%); m.p. 58-60 ºC; Rf 0.57 (chloroform).
Ethyl 4-fluorobenzoate (24)
Yield: 8.1 g (81%); b.p. 212-214 ºC; Rf 0.76 (chloroform).
Ethyl 2-chlorobenzoate (25)
Yield: 7.3 g (73%); b.p. 240-242 ºC; Rf 0.76 (chloroform).
Ethyl 2-nitrobenzoate (26)
Yield: 7.5 g (75%); b.p. 106-108 ºC; Rf 0.66 (chloroform).
Ethyl 3-chlorobenzoate (27)
Yield: 7.5 g (75%); b.p. 124-26 ºC; Rf 0.62 (chloroform).
Ethyl 2-fluorobenzoate (28)
Yield: 7.5 g (75%); b.p. 118-120 ºC; Rf 0.61 (chloroform).
Ethyl 4-bromobenzoate (29)
Yield: 7.5 g (75%); b.p. 134-136 ºC; Rf 0.54 (chloroform).
Ethyl 3-bromobenzoate (30)
Yield: 7.5 g (75%); b.p. 131-133 ºC; Rf 0.66 (chloroform), m.p. 26-30 ºC.
General methods for synthesis of substituted aryl acid hydrazides (31-45)2
The substituted ethyl benzoates (16-30) (0.01 mol) dissolved in dry ethanol (25 mL), hydrazine hydrate (99%,
0.01 mol) was added and the mixture was refluxed for 6 h. The reaction mixture was cooled and the solid obtained was
filtered and recrystallized from dilute ethanol. Since these compounds are very well known and characterised, we have
done their preliminary investigations only to confirm the formation of these compounds. Details of which is mentioned
as below.
Benzoic acid hydrazide (31)
Yield: 3.87 g (77%); m.p. 110-112 ºC; Rf 0.76 (chloroform).
4-hydroxybenzoic acid hydrazide (32)
Yield: 5.18 g (71%); m.p. 264-266 ºC; Rf 0.72 (chloroform).
4-Methylbenzoic acid hydrazide (33)
Yield: 5.67 g (70%); m.p. 114-116 ºC; Rf 0.68 (chloroform).
3-Nitrobenzoic acid hydrazide (34)
Yield: 4.69 g (69%); m.p. 158-160 ºC; Rf 0.54 (chloroform).
2,3-Dimethoxybenzoic acid hydrazide (35)
Yield: 5.55 g (74%); m.p. 76-78 ºC; Rf 0.65 (chloroform).
4-Chlorobenzoic acid hydrazide (36)
Yield: 3.12 g (71%); m.p. 162-164 ºC; Rf 0.65 (chloroform).
4-Nitrobenzoic acid hydrazide (37)
Yield: 5.25 g (70%); m.p. 218-220 ºC; Rf 0.63 (chloroform).
4-Acetylbenzoic acid hydrazide (38)
Yield: 5.69 g (73%); m.p. 206-208 ºC; Rf 0.77 (chloroform).
4-Fluorobenzoic acid hydrazide (39)
Yield: 6.8 g (85%); m.p. 164-166 ºC; Rf 0.69 (chloroform).
2-Chlorobenzoic acid hydrazide (40)
Yield: 6.2 g (82%); m.p. 120-122 ºC; Rf 0.69 (chloroform).
2-Nitrobenzoic acid hydrazide (41)
Yield: 4.8 g (65%); m.p. 122-124 ºC; Rf 0.69 (chloroform).
3-Chlorobenzoic acid hydrazide (42)
Yield: 5.8 g (75%); m.p. 154-156 ºC; Rf 0.69 (chloroform).
2-Fluorobenzoic acid hydrazide (43)
Yield: 6.4 g (83%); m.p. 77-79 ºC; Rf 0.69 (chloroform).
4-Bromobenzoic acid hydrazide (44)
Yield: 7.2 g (92%); m.p. 168-170 ºC; Rf 0.69 (chloroform).
3-Bromobenzoic acid hydrazide (45)
Yield: 6.3 g (81%); m.p. 158-160 ºC; Rf 0.69 (chloroform).
1
H NMR and 13C NMR spectra of selected compounds
N NH2
O
N
H
Figure S1. 1H NMR spectrum (400 MHz, DMSO) of 3-hydrazinylidene-1,3-dihydro-2H-indol-2-one (47).
N NH2
O
N
H
Figure S2. 13C NMR spectrum (100 MHz, DMSO-d6) of 3-hydrazinylidene-1,3-dihydro-2H-indol-2-one (47).
O
O OH
N NH
O
N
H
Figure S3. 1H NMR spectrum (400 MHz, DMSO) of 4-oxo-4-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazinyl]
butanoic acid (48).
O OH
N NH
O
N
H
13
Figure S4. C NMR spectrum (100 MHz, DMSO-d6) of 4-oxo-4-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-
hydrazinyl] butanoic acid (48).
O N N
N NH O
O
N
H
Figure S5. 1H NMR spectrum (400 MHz, DMSO) of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-N'-[2-oxo-1,2-dihydro-3H-
indol-3-ylidene]propane hydrazide (49).
O N N
N NH O
O
N
H
Figure S6. 13C NMR spectrum (100 MHz, DMSO-d6) of 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-N'-[2-oxo-1,2-dihydro-3H-
indol-3-ylidene]propane hydrazide (49).
O N N
N NH O
OH
O
N
H
Figure S7. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (50).
O N N
N NH O
OH
O
N
H
Figure S8. 13C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (50).
O N N
N NH O
CH3
O
N
H
Figure S9. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (51).
O N N
N NH O
CH3
O
N
H
Figure S10. 13C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (51).
O O
N N
N
O
N NH O
O
N
H
Figure S11. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (52).
O O
N N
N
O
N NH O
O
N
H
13
Figure S12. C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (52).
CH3
O N O
N
O
CH3
N NH O
O
N
H
Figure S13. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(2,3-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-
1,2-dihydro-3H-indol-3-ylidene]propane hydrazide (53).
CH3
O N O
N
O
CH3
N NH O
O
N
H
Figure S14. 13C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(2,3-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-
1,2-dihydro-3H-indol-3-ylidene]propane hydrazide (53).
O N N
N NH O
Cl
O
N
H
Figure S15. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (54).
O N N
N NH O
Cl
O
N
H
13
Figure S16. C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (54).
O N N
N NH O
O
N
O O
N
H
Figure S17. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (55).
O N N
N NH O
O
N
O O
N
H
13
Figure S18. C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (55).
O N N
N NH O
O
O CH3
N
H
Figure S19. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(4-acetylphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (56).
O N N
N NH O
O
O CH3
N
H
13
Figure S20. C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(4-acetylphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (56).
O N N
N NH O
F
O
N
H
Figure S21. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (57).
O N N
N NH O
F
O
N
H
13
Figure S22. C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (57).
O O
O N N
N
N NH O
O
N
H
Figure S23. 1H NMR spectrum (400 MHz, DMSO) of 3-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (59).
O O
O N N
N
N NH O
O
N
H
13
Figure S24. C NMR spectrum (100 MHz, DMSO-d6) of 3-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-
dihydro-3H-indol-3-ylidene]propane hydrazide (59).
References
1. Chikhale, R.; Thorat, S.; Pant, A.; Jadhav, A.; Thatimala, K. C.; Bansode, R.; Bhargavi, G.; Karodia, N.;
Rajasekharan, M. V.; Paradkar, A.; Khedekar, P.; Bioorg. Med. Chem. 2015, 23, 6689.
2. Furniss, B.; Hannaford, A. H.; Smith, P. W. G.; Tatchell, A. R.; Vogel’s Textbook of Practical Organic Chemistry,
5th ed.; Longman: Harlow, 1998.
