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25. General procedure for the synthesis of 3-Aracylphthalides (4a–4j): MSA (2 ml)
was added to a mixture of 2-carboxybenzaldehyde (5, 3.3 mmol) and aromatic
methyl ketones (6a–6j, 6.6 mmol) preheated in water bath at 60 °C. The
reaction was then warmed to 80 °C for the 15–30 min (Table 1). After
completion; reaction mixture was cooled, poured over crushed ice and
extracted with dichloromethane. Organic layer was washed successively
with saturated solution of sodium bicarbonate and water, dried over sodium
sulfate and concentrated to get crude product. Purification was done by
column chromatography with hexane-acetone (70:30) thereby providing the
corresponding 3-Aracylphthalide.
Figure 3. Comparison of IC50 in (
4a.
l
g mlÀ1) of most effective anti TB compounds with
isosterism concept26 for the betterment of biological activities.
Therefore, we have replaced pendant phenyl ring in 4a with isos-
teric furan (4i) and thiophene (4j).
All compounds (4a–4j) were subsequently screened for their
in vitro antitubercular activity against Mycobacterium tuberculosis
H37Ra following an established XTT Reduction Menadione Assay
4a: 3-Phenacylphthalide: IR (KBr); 1772, 1679 cmÀ1 1H NMR (CDCl3, 300 MHz)
,
(XRMA) protocol27 using Isoniazid (IC90; 0.125 g mlÀ1) as refer-
l
3.4 (dd, J = 17.3 Hz, 7.3 Hz, 1H), 3.78 (dd, J = 17.6 Hz, 5.57 Hz, 1H), 6.18 (m,
J = 6.7 Hz, 1H), 7.4–7.8 (m, 6H), 7.9 (m, 3H). 13C NMR (CDCl3, 75 MHz); 43.6,
77.9, 123.7–137.0, 170.6, 197.2 Anal. Calcd For C16H12O3: C, 76.22; H, 4.76.
Found: C, 76.08; H, 4.80.
ence standard. Table 1 depicts the IC50 values of 4a–4j that are in
the range of 0.81–3.00
l
g mlÀ1 implying their potential as promis-
4b: 3-(4-Methyl phenacyl)phthalide: IR (KBr); 1762, 1674 cmÀ1 1H NMR (CDCl3,
;
ing antitubercular agents.
300 MHz) 2.52 (s, 3H), 3.38 (dd, J = 17.6 Hz, 7.61 Hz, 1H), 3.78 (dd, J = 17.6 Hz,
5.6 Hz, 1H), 6.22 (m, J = 6.7 Hz, 1H), 7.26–7.36 (m, 2H), 7.5–7.78 (m, 3H), 7.9
(m, 3H). 13C NMR (CDCl3, 75 MHz); 22.2, 43.3, 78.1, 123.7–135.2, 145.1, 170.8,
196.8. Anal. Calcd For C17H14O3: C, 76.69; H, 5.2. Found: C, 76.8; H, 5.14.
Amongst these phthalides, 4c, 4d, 4i and 4j exhibited significant
inhibitory action as compared to remaining compounds. The en-
hanced activity of 4c and 4d might be due to presence of halogen
groups28 whereas better activity in case of 4i and 4j (Fig. 3) is in
accordance with the concept of isosterism. Further, presence of
other substituent (4b, 4e, 4f, 4g and 4i) does not contribute much
to the activity.
4c:3-(4-Bromophenacyl)phthalide: IR (KBr); 1752, 1681 cmÀ1 1H NMR (CDCl3,
;
300 MHz) 3.34 (dd, J = 17.6 Hz, 6.8 Hz, 1H), 3.73 (dd, J = 17.6 Hz, 6.0 Hz,1H),
6.14 (m, J = 6.3 Hz, 1H), 7.62 (m, 5H), 7.80 (m, 2H),.13C NMR (CDCl3, 75 MHz):
43.7, 77.1, 123.7–139.5149.0, 170.6, 195.2. Anal. Calcd for C16H11O3Br: C,
58.00; H, 3.32. Found: C, 58.26; H, 3.51.
4d: 3-(4-Chlorophenacyl)phthalide: IR (KBr); 1751, 1681 cmÀ1 1H NMR (CDCl3,
;
In conclusion, a simple one pot methodology envisaged in the
present work has successfully resulted in 3-Aracylphthalides
exhibiting significant antitubercular activity. Furthermore, four of
the synthesized compounds are found to be better candidates as
antitubercular leads in future.
300 MHz) 3.38 (dd, J = 17.6 Hz, 7.0 Hz, 1H), 3.76 (dd, J = 17.6 Hz, 5.86 Hz,1H),
6.16 (m, J = 6.5 Hz, 1H), 7.44–7.72 (m, 5H), 7.88–7.96 (m, 3H).13C NMR (CDCl3,
75 MHz); data 43.6, 77.9, 123.7–139.5, 170.6, 196.3. Anal. Calcd for C16H11O3Cl:
C, 67.01; H, 3.83. Found: C, 66.87; H, 3.98.
4e: 3-(4-Methoxyphenacyl)phthalide: IR (KBr); 1760, 1666 cmÀ1
;
1H NMR
(CDCl3, 300 MHz) 3.35 (dd, J = 17.6 Hz, 7.6 Hz, 1H), 3.75 (dd, J = 17.6 Hz,
5.6 Hz, 1H), 3.83 (s, 3H), 6.18 (m, J = 5.6 Hz, 1H), 6.95 (d, 2 H), 7.65 (m, 3H), 7.95
(m, 3H). 13C NMR (CDCl3, 75 MHz); 43.6, 55.9, 77.8, 114.3, 123.3–134.7, 164.4,
170.6, 194.8. Anal. Calcd for C17H14O4: C, 72.34; H, 4.96. Found: C, 72.14; H,
4.88.
Acknowledgments
4f: 3-(4-Nitrophenacyl)phthalide: IR (KBr); 1747, 1689 cmÀ1 1H NMR (CDCl3,
;
Authors are grateful to Dr. Rajeev C. Chikate for his extensive
help and guidance, Dr. S.G. Gupta, Principal, Abasaheb Garware
College, Director, National Chemical Laboratory, for providing the
necessary facilities, DST for infrastructure grant and University of
Pune for providing spectral analysis. R.A.L. is thankful to U.G.C.
for SRF.
300 MHz) 3.46 (dd, J = 17.6 Hz, 6.4 Hz, 1H), 3.78 (dd, J = 17.6 Hz, 6.5 Hz, 1H),
6.17 (m, J = 6.5 Hz, 1H), 7.55–7.72 (m, 3H), 8.10 (m, 3H) 8.40 (d, J = 8 Hz, 2H).
13C NMR (CDCl3, 75 MHz) 44.2, 77.6, 123.7–135.2, 141.5, 151.6, 170.6, 196.6.
Anal. Calcd for C16H11NO5: C, 64.65; H, 3.7. Found: C, 64.88; H, 3.88.
4g: 3-(4-Hydroxylphenacyl)phthalide: IR (KBr); 1755 cmÀ1, 1680 cmÀ1 1H NMR
;
(CDCl3, 300 MHz) 2.3 (s, 3H), 3.48 (dd, J = 17.6 Hz, 6.7 Hz, 1H), 3.82 (dd,
J = 17.6 Hz, 6.1 Hz,1H), 6.21 (m, J = 6.7 Hz, 1H), 7.45–7.80 (m, 5H),
8 (d,
J = 7.9 Hz, 2H), 12 (s, 1H). 13C NMR (CDCl3, 75 MHz) 45.1, 77.7, 118.3–
137.7159.1, 170.6, 201.9. Anal. Calcd for C17H14O4: C, 72.34; H, 4.96. Found: C,
72.48; H, 5.21.
Supplementary data
4h: 3-(2-Hydroxyphenacyl)phthalide: IR (KBr); 1766.5, 1637.5 cmÀ1 1H NMR
;
(CDCl3, 300 MHz) 3.42 (dd, J = 17.6 Hz, 6.6 Hz, 1H), 3.76 (dd, J = 17.6 Hz,
6.0 Hz,1H), 6.21 (t, J = 6.3 Hz, 1 Hz, 1H), 6.8 (m, J = 7.7 Hz, 1H), 6.9 (d, J = 8.0 Hz,
1H), 7.4–7.6 (m, 5H), 7.9 (d, J = 8.0 Hz, 1H), 11.98 (s, 1H). 13C NMR (CDCl3,
75 MHz); data 43.2, 76.5, 118.6, 118.8, 119.2, 122.5, 125.7, 128.99, 129.4,
129.6, 134.2, 137.0, 149.0, 162.30, 170.63, 201.92. Anal. Calcd for C16H12O4: C,
71.64; H, 4.47. Found: C, 71.41; H, 4.62.
Supplementary data (file provides general information, scanned
images of 1H, 13C spectra of 3-Aracylphthalides) associated with
this article can be found, in the online version, at http://
4i: 3-(2-Furanocyl)phthalide: IR (KBr); 1751, 1676 cmÀ1 1H NMR (CDCl3,
,
References and notes
300 MHz) 3.24 (dd, J = 17.0 Hz, 6.6 Hz, 1H), 3.57 (dd, J = 17.0 Hz, 6.5 Hz, 1H),
6.10 (m, J = 6.6 Hz, 1H), 6.56 (m, 1H), 7.26 (m, 1H), 7.5–7.7(m, 4H), 7.9 (m,1H).
13C NMR (CDCl3, 75 MHz) 43.3, 76.7, 112.5, 118.1, 122.3, 125.5, 129.2, 134.1,
146.9, 149.1, 151.9, 169.7, 184.3. Anal. Calcd for C14H10O4: C, 69.42; H, 4.13.
Found: C, 69.68; H, 4.43.
1. Bloom, B. R.; Murray, C. J. Science 1992, 257, 1055.
4j: 3-(2-Thiophenacyl)phthalide: IR (KBr); 1766.7, 1658.7 cmÀ1 1H NMR (CDCl3,
,
3. Garcia, J. R. Eur. J. Med. Chem. 2012, 49, 1–23.
300 MHz) 3.32 (dd, J = 17.0 Hz, 6.8 Hz, 1H), 3.64 (dd, J = 17.0 Hz, 6.0 Hz, 1H),
6.12 (m, J = 6.6 Hz, 1H), 7.14 (t, J = 4.4 Hz, 1H),7.5–7.8 (m, H), 7.90 (d, J = 7.4 Hz,
1H). 13C NMR (CDCl3, 75 MHz) 44.1, 76.9, 122.5, 125.6, 128.2, 129.3, 132.7,
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