Molecular hybridization of bioactives: Synthesis and antitubercular evaluation of novel dibenzofuran embodied homoisoflavonoids via Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.bmcl.2012.10.056

A novel series of natural product like dibenzofuran embodied homoisoflavonoids [(E)-3-(dibenzo[b,d]furan-2-ylmethylene)chroman-4-ones] designed by molecular hybridization were synthesized in very good yields via a sequence of reactions involving base catalyzed Baylis-Hillmann (BH) reaction of 2-dibenzofuran carboxaldehyde and methyl acrylate; bromination of BH adduct; condensation of resulted allylic bromide with substituted phenols or 2-dibenzofuranol followed by cyclization. Among the all 11 new compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB), (E)-3-(dibenzo[b,d]furan-2-ylmethylene)-6- fluorochroman-4-one (7f) and (E)-3-(dibenzo[b,d] furan-2-ylmethylene)-6- fluorochroman-4-one (7g) were found to be active with MIC 12.5 μg/mL.

Full text of DOI:10.1016/j.bmcl.2012.10.056

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7426–7430
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Molecular hybridization of bioactives: Synthesis and antitubercular
evaluation of novel dibenzofuran embodied homoisoflavonoids via
Baylis–Hillman reaction
Thirumal Yempala a, Darmarajan Sriram b, Perumal Yogeeswari b, Srinivas Kantevari a,
⇑
a Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, INDIA.
b Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad-500078 INDIA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2012
Revised 22 September 2012
Accepted 11 October 2012
Available online 22 October 2012
A novel series of natural product like dibenzofuran embodied homoisoflavonoids [(E)-3-(dibenzo[b,d]-
furan-2-ylmethylene)chroman-4-ones] designed by molecular hybridization were synthesized in very
good yields via a sequence of reactions involving base catalyzed Baylis–Hillmann (BH) reaction of
2-dibenzofuran carboxaldehyde and methyl acrylate; bromination of BH adduct; condensation of
resulted allylic bromide with substituted phenols or 2-dibenzofuranol followed by cyclization. Among
the all 11 new compounds screened for in vitro antimycobacterial activity against Mycobacterium
tuberculosis H37Rv (MTB), (E)-3-(dibenzo[b,d]furan-2-ylmethylene)-6-fluorochroman-4-one (7f) and
(E)-3-(dibenzo[b,d] furan-2-ylmethylene)-6-fluorochroman-4-one (7g) were found to be active with
Keywords:
Dibenzofuran
Homoisoflavonoids
Baylis–Hillmann (BH) reaction
Antimycobacterial activity
Molecular hybridization
MIC 12.5 lg/mL.
Ó 2012 Elsevier Ltd. All rights reserved.
Tuberculosis (TB) is an ancient chronic infectious disease
caused mainly by Mycobacterium tuberculosis (MTB).1 It has be-
come more prevalent disease claiming over two million lives
worldwide each year and dwells hidden in as many as two billion
people. Additionally, the evolution of its new virulent forms like
multi drug resistant (MDR–TB) and extremely drug resistant
(XDR-TB) has become a major threat to human kind.2 The resur-
gence of TB is more alarming in HIV infected people due to the
development of pathogenic synergy.2,3 The worsening situation
has prompted the world health organization (WHO) to declare
tuberculosis a global public health crisis.3 All the above facts also
stressed an urgent need for development of fast acting new antitu-
bercular drugs with diverse and unique structural features.4
Molecular hybridization5 is a fairly new concept in drug design
and development based on the combination of pharmacophoric
moieties of different bioactive natural or synthetic substances to
produce a new hybrid compound with improved affinity and effi-
cacy, when compared to the parent drugs. Additionally, this strat-
egy can result in compounds presenting different and/or dual
modes of action, modified selectivity profile and reduced undesired
side effects.6 Homoisoflavonoids7 (Fig. 1) constitute a class of natu-
ral products prevalently isolated from the bulbs, rhizomes, or roots
of several genera of Hyacinthaceae and Caesal pinioideae. Several
natural and synthetic homoisoflavonoids were found to possess
various biological properties such as antifungal, antiviral, antitu-
bercular antimutagenic, antiproliferative, antioxidant, antiallergic
and antihistaminic, anti-inflammatory, and protein tyrosine kinase
(PTK) inhibitor activities.8 On the other hand, dibenzofuran is a
basic framework in several natural products with pronounced
biological properties.9 Simple dibenzofurans are also occurring in
higher plants, where they often act as antifungal phytoalexins.9
Synthetic heterocycles derived from dibenzofuran manifests a
number of important and therapeutically useful biological activities
such as antibacterial, antidepressant, and antituberculasis10 (Fig. 1).
We therefore envisaged that designing newer heterocycles
through molecular hybridization of bioactive dibenzofuran deriva-
tives with natural homoisoflavonoids in one molecular frame
(Fig. 2) could result pharmacologically relevant natural product like
newer analogues as potential candidates for biological evaluation.
Continuing our work11 on synthesis of dibenzofuran derived antitu-
bercular agents, we herein report an efficient synthesis and antitu-
bercular evaluation of natural product like dibenzofuran conjugated
homoisoflavonoids [(E)-3-(dibenzo[b,d]furan-2-yl methylene)chro-
man-4-ones] in very good yields via Baylis–Hillmann (BH) reaction.
Screening all new compounds 7a–k for in vitro activity against
Mycobacterium tuberculosis H37Rv (MTB) resulted (E)-3-(diben-
zo[b,d]furan-2-ylmethylene)-6-fluorochroman-4-one (7f) and (E)-
3-(dibenzo[b,d]furan-2-ylmethylene)-6-fluorochroman -4-one (7g)
as active antitubercular agents with MIC of 12.5 lg/mL.
Dibenzo[b,d]furan-2-carbaldehyde (1), being versatile substrate
in the synthesis of heterocyclic compounds, is chosen as starting
⇑
Corresponding author.
E-mail address: kantevari@yahoo.com (S. Kantevari).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.056

T. Yempala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7426–7430
7427
Table 1
O
OH
O
Optimization of Baylis-Hillmann reaction conditionsa
(A)
H3CO
OH
O
HO
OCH3
H3CO
O
HO
O
OH
O
CHO
+
Bonducellin
Base
Autumnalin
O
O
OCH3
OH
O
O
O
2
1
H3CO
N
HO
O
OCH3
O
Entry
Base
Solvent
Time (days)
Yieldb of 2 (%)
Eucomin
Chromone Alkaloid
O
1
2
3
4
5
6
7
8
9
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
Methanol
THF
THF: Water (1:1)
Neat
Neat
Neat
Neat
Neat
Neat
Neat
6
6
6
4
6
15
12
12
32
49
70
72
22
25
20
O
OH
(B)
OH
O
H
HO
O
N
N
O
P
7
HO
H
N
O
12
12
12
12
OH
N
OCH3
Usnic acid
N
CGS-34043
K2CO3
N(Et)3
10
O
H3CO
OH
OR
a
All the reactions were performed with 1 (1.0 mmol), Base (1.0 mmol), methyl
O
acrylate (8.0 mmol) and the progress of reaction was monitored by TLC.
b
Isolated yield.
OH
O
O
R=H;
Lucidafuran
O
Benzofurobenzopyran
R=CH : Eriobofuran
Ruscodibenzofuran
OH
OH
3
OH
OH
OH
OH
OH
OCH3
Figure 1. Representative bioactive analogues of (A) natural homo isoflavonoids (B)
natural and synthetic dibenzofuran.
Br
4g
OH
F
OCH3
CH3
4c
material. It was prepared from dibenzofuran following the modi-
fied literature protocol developed in our laboratory.11 Having
dibenzo[b,d]furan-2-carboxaldehyde (1) in hand, efforts were
focused on Baylis–Hillmann (BH) reaction12 of 1 with methyl acry-
late and base. Several reaction conditions examined to achieve the
best yield of Baylis–Hillmann adduct 2 are shown in Table 1. The
reaction was proceeded effectively, when 1 was reacted with 8
equivalents of methyl acrylate at room temperature in the pres-
ence of DABCO for 7 days to give Baylis–Hillmann adduct 2 in
70% yield (Table 1, entry 6). The use of solvents such as methanol,
THF or combination of THF and water in the Baylis–Hillmann (BH)
reaction did not give good yield even after 6 days of reaction
(Table 1, entries 1–3). Change of base to DBU or K2CO3 or N(Et)3
are also not fruitful. Also prolonging the BH reaction to 12 days
did not show any significant improvement in product yield
(Table 1, entry 7). The BH adduct 2 was fully characterized by 1H
and 13C NMR, IR and mass (EI-MS) spectral data.13
4a
4b
4d
4e
4f
OH
OH
OH
N
H
O
4k
4h
4j
4i
Figure 3. Phenols 4a–k used in the present study.
resulted aklenyl acids 6a–k in 82–90% overall yield from 3 to 6a–
k. The compounds 6a–k was characterized by 1H NMR, IR and mass
spectral data.16 To obtain desired products with enhanced lipo-
philic nature, aklenyl acids 6a–k was cyclized with TFAA in dichlo-
romethane to give hybrid homoisoflavonoids 7a–k (Fig. 4) in very
good yields. All the new compounds 7a–k was fully characterized
by 1H and 13C NMR, IR and mass (EI-MS & HR-MS) spectral data17
(see Supplementary data).
The antimycobacterial activity of the synthesized dibenzofuran
embodied homoisoflavonoids 7a–k has been screened against M.
tuberculosis H37Rv (MTB) by agar dilution method for the determi-
nation of minimum inhibitory concentration (MIC) in triplicates.18
The MIC is defined as the minimum concentration of compound re-
quired to completely inhibit the bacterial growth. The MIC values
of 7a–k along with the standard drugs for comparison are fur-
nished in Table 2. Eleven new compounds screened have showed
in vitro activity against MTB with MIC ranging from 12.5–
Further, Allylic bromide analogue 314, prepared in excellent
yield through bromination of Methyl 2-(dibenzo[b,d]furan-2-
yl(hydroxy)methyl)acrylate (2) with HBr/H2SO4 in dichloro meth-
ane at 0 °C, was reacted with series of phenols 4a–k (Fig. 3) to give
alkylated esters 5a–k (Scheme 1).15 Base hydrolysis of 5a–k
O
O
R
O
25.0
l
g/mL. Two compounds 7f and 7g inhibited MTB with MIC
g/mL.When compared to pyrazinamide (MIC 50.8 g/mL),
all the 11 compounds were found to be more potent, though all
Natural product
R
of 12.5
l
l
O
O
the compounds were less potent than other anti-TB drugs isoniazid
(0.1 lg/mL) and ethambutol (MIC 3.13 lg/mL). Structure–activity
O
Hybrid analogues
correlations of the new compounds 7a–k with respect to their anti-
tubercular activity reveal that natural homoisoflavonoids were
tuned for first time to act as antitubercular agents by conjugating
with dibenzofuran unit. Also fluoro/bromo substituent on phenyl
ring of homoisoflavonoid architecture (Table 1) profoundly
O
Antitubercular agent
Figure 2. Design strategy for new dibenzofuran-chromanone hybrids.

7428
T. Yempala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7426–7430
O
O
OH
O
(ii)
(i)
OCH3
OCH3
OCH3
OR
O
O
Br
4a-k
O
2
3
5a-k
O
(iii)
(iv)
OH
OR
7a-k
O
6a-k
Scheme 1. Synthesis of dibenzofuran conjugated homoisoflavonoids 7a–k. Reaction conditions: (i) HBr/H2SO4, DCM, 12 h (ii) 4a–k, K2CO3, Acetone, 6–7 h (iii) aq KOH,
Acetone, 12 h (iv) TFAA, DCM, reflux, 8 h.
O
O
O
OCH3
CH3
O
O
O
O
O
O
7c
O
O
O
O
O
O
7b
7a
F
O
7e
7f
7d
O
O
O
H3CO
O
O
O
Br
O
O
O
O
O
O
7i
7g
7j
7h
O
O
NH
O
O
O
O
7k
Figure 4. Structures of dibenzofuran embodied homoisoflavonoids 7a–k.
Table 2
Physical data and antitubercular evaluation of 7a–k. against M. tuberculosis H37RV
Entry
Phenols 4
Intermediate compounds
homoisoflavonoids
Mp (°C)
LogP/CLogPb
MIC (lg/mL)
5
6
Yielda 3 to 6 (%)
7
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
—
—
—
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
—
—
—
6a
6b
6c
6d
6e
6f
6g
6h
6i
90
86
83
88
82
85.5
90
90
86
83
88
—
7a
7b
7c
7d
7e
7f
7g
7h
82
80
76
73
70
71
89
85
80
68
75
—
115
88
96
3.69/5.69
3.56/5.72
4.17/6.19
3.56/5.72
5.39/7.52
3.84/5.88
4.51/6.60
4.68/6.86
4.68/6.86
4.35/7.63
4.38/7.20
0.1
25.0
25.0
25.0
25.0
25.0
12.5
12.5
25.0
25.0
25.0
25.0
98
116
119
67
119
126
85
96
—
—
—
7i
7j
7k
6j
6k
Isoniazid
Ethambutol
Pyrazinamide
—
—
—
—
3.13
50.0
a
Isolated yields.
Calculated using chemdraw ultra 11.0.
b
decreased their MIC values 25
l
g/mL to 12.5
l
g/mL. logP/ClogP
7a–k with respect to their antitubercular activity reveal that intro-
duction of electron with drawing groups such as fluoro/ bromo de-
creases log P (Clog p) values with increased antitubercular activity
(Table 2, entries 6 and 7)
In conclusion we have synthesized a novel series of dibenzofu-
ran embodied homoisoflavonoids 7a–k designed by molecular
values of studied compounds 7a–k were calculated using Chem
Bio Draw Ultra 11.0. The described logP (Clogp) values are the
mean of lipophilic contributions of individual atoms, fragments
and the pairs of interacting fragments in the chemical structure.
Structural correlations of the newly synthesized compounds

T. Yempala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7426–7430
7429
11. (a) Patpi, S. R.; Pulipati, L.; Yogeeswari, P.; Sriram, D.; Jain, N.; Sridhar, B.;
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Sriram, D.; Sridhar, B. Bioorg. Med. Chem. Lett. 2011, 21, 4316; (d) Kantevari, S.;
Patpi, S. R.; Sridhar, B.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2011,
21, 1214; (e) Kantevari, S.; Patpi, S. R.; Addla, D.; Putapatri, S. R.; Sridhar, B.;
Yogeeswari, P.; Sriram, D. ACS Comb. Sci. 2011, 13, 427.
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13. Methyl 2-(dibenzo[b,d]furan-2-yl(hydroxy)methyl)acrylate 2 dibenzo[b,d]furan-
2-carbaldehyde 1 (1.0 g, 5 mmol) and DABCO (0.571 g, 5 mmol) was added
methyl acrylate (2.75 mL, 40 mmol) at room temperature and continue
stirring. After 7 days (tlc) the reaction mixture was diluted with ethyl
acetate (20 mL), washed successively with 2 N HCl (2 Â 5 mL), water
(2 Â 5 mL) and saturated NaHCO3 solution (5 mL) and dried over anhyd.
Na2SO4. The solvent was evaporated under vacuum and crude residue thus
obtained was chromatographed over silica gel (hexane: ethyl acetate; 8:1) to
give methyl 2-(dibenzo[b,d]furan-2-yl(hydroxy) methyl)acrylate 2 as pale red
thick syrup. 1H NMR (300 MHz, CDCl3) d: 7.94–7.82 (m, 2H), 7.58–7.44 (m, 2H),
7.43–7.35 (m, 2H), 7.28 (t, J = 7.5 Hz, 1H), 6.31 (s, 1H), 5.86–5.82 (m, 1H), 5.65
(s, 1H), 3.70 (s, 3H), 3.10 (br, s, 1H). 13C NMR (75 MHz, CDCl3) d: 166.7, 156.5,
142.1, 140.9, 135.8, 127.2, 126.0, 125.8, 122.7, 121.2, 120.7, 118.8, 111.6, 111.4,
109.2, 73.1, 51.9. IR (KBr, CmÀ1) 3450(br), 2951, 1718, 1629, 1478, 1446, 1196,
1149, 1040, 816, 750. ESI-MS found (M+Na)+ =305 for C17H14O4.
hybridization. The sequence of reactions employed are (i) base
catalyzed Baylis–Hillmann (BH) reaction of 2-dibenzofuran
carboxaldehyde and methyl acrylate (ii) bromination of BH adduct
(iii) condensation of resulted allylic bromide with substituted phe-
nols or 2-dibenzofuranol followed by cyclization. All the products
obtained in very good yields were characterized by spectra data.
Screening all these new derivatives against M. tuberculosis H37Rv
(MTB) resulted homoisoflavonoids 7f and 7g as most potent
antitubercular agents with MIC 12.5 lg/mL. Structure–activity
correlations of the new compounds 7a–k with respect to their
antitubercular activity reveal that natural homoisoflavonoids were
tuned for first time to act as potent antitubercular agents by
conjugating with dibenzofuran unit. The results observed here is
useful to generate novel natural product like potent antimycobac-
terial homoisoflavonoids.
Acknowledgments
Authors (S.K. and T.Y.) are thankful to Dr. J. S. Yadav, Director
and Dr. V.J. Rao, Head, CPC Division (Organic Chemistry Division-
II), CSIR-IICT, Hyderabad for their continuous support, encourage-
ment and financial assistance from MLP & Net Work projects. T.Y.
(SRF) is thankful to CSIR for fellowship.
14. (Z)-methyl 2-(bromomethyl)-3-(dibenzo[b,d]furan-2-yl)acrylate 3: Methyl 2-
(dibenzo[b,d]furan-2-yl(hydroxy)methyl)acrylate 2 (2.05 g, 8.8 mmol) in dry
dichloromethane (30 mL) at 0 °C was added slowly aq. HBr (1.43 mL, 26 mmol)
and conc. H2SO4 (2.59 mL, 48.7 mmol) and stirred at room temperature for
12 h. The reaction mixture was diluted with dichloromethane (20 mL), poured
in water (20 mL). The organic layer was separated, washed with water
(2 Â 10 mL), dried over anhyd. Na2SO4 and evaporated to dryness. The crude
residue thus obtained chromatographed over silica gel column eluted with
hexane: ethyl acetate (9:1) to give required (Z)-methyl 2-(bromomethyl)-3-
(dibenzo[b,d]furan-2-yl) acrylate 3 (2.5 g, 83%) as brown colored solid. mp
108–112 °C. 1H NMR (300 MHz, CDCl3) d: 8.26(s,1H), 8.02–7.92(m, 2H), 7.70–
7.53(m, 3H), 7.47(t, J = 8.309 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H), 4.46(s, 1H), 3.90(s,
3H). 13C NMR (75 MHz, CDCl3) d: 166.6, 156.6, 156.5, 143.1, 129.2, 128.9, 127.8,
Supplementary data
Supplementary data (copies of 1H, 13C NMR and mass spectra of
all the new compounds 2, 3 & 7a–k and 1H NMR of 6a–k) associ-
ated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2012.10.056.
127.5, 124.9, 124.7, 123.1, 122.1, 120.8, 112.1, 111.8, 52.4, 27.2. IR (KBr, CmÀ1
2923, 1699, 1582, 1433, 1313, 1196, 1075, 839, 756. EI-MS found M+ =344 for
17H13BrO3.
)
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Ortuso, F.; Alcaro, S. J. Med. Chem. 2011, 54, 2155; (b) Lin, L.-G.; Xie, H.; Li, H.-L.;
Tong, L.-J.; Tang, C.-P.; Ke, C.-Q.; Liu, Q.-F.; Lin, L.-P.; Geng, M.-Y.; Jiang, H.;
Zhao, W.-M.; Ding, J.; Ye, Y. J. Med. Chem. 2008, 51, 4419; (c) Li, V.-F.; Zai-qun
liu; Xu-yang luo J. Agric. Food Chem. 2010, 58, 4126.
9. (a) Kokubun, T.; Harborne, J. B.; Eagles, J.; Waterman, P. G. Phytochemistry 1995,
1033, 39; (b) Manniche, S.; Sprogøe, K.; Dalsgaard, P. W.; Christophersen, C.;
Larsen, T. O. J. Nat. Prod. 2004, 67, 2111; (c) Chen, J.-J.; Luo, Y.-T.; Liao, C.-H.;
Chen, I.-S.; Liaw, C.-C. Chem. Biodivers. 2009, 6, 774; (d) Rezanka, T.; Hanus, L.
O.; Kujan, P.; Dembitsky, V. M. Eur. J. Org. Chem. 2005, 2708; (e) Stefano, S.;
Claudio, F. Synlett 2003, 2005.
10. (a) Prado, S.; Ledeit, H.; Michel, S.; Koch, M.; Darbord, J. C.; Cole, S. T.; Tillequin,
F.; Brodin, P. Bioorg. Med. Chem. Lett. 2006, 14, 5423; (b) Khouri, T. I.; Gaslonde,
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Kordulakova, J.; Jackson, M.; Brosch, R.; Janin, Y. L.; Daffé, M.; Tillequin, F.;
Michel, S. Eur. J. Med. Chem. 2010, 45, 5833; (c) Prado, S.; Janin, Y. L.; Saint-
Joanis, B.; Brodin, P.; Michel, S.; Koch, M.; Cole, S. T.; Tillequin, F.; Bost, P. E.
Bioorg. Med. Chem. Lett. 2007, 15, 2177.
(E)-3-(dibenzo[b,d]furan-2-yl)-2-(phenoxymethyl)acrylicacid (6a) white solid. 1
H
NMR (300 MHz, DMSO-d6) d: 8.17(s, H), 8.14 (d, J = 1.5 Hz, 1H), 7.63–7.54(m,
4H), 7 .45(t, J = 7.3 Hz, 1H), 7.37–7.31(m, 3H), 7.27(t, J = 7.3 Hz, 1H), 7.06–
6.99(m, 2H), 4.87(s, 2H). (E)-3-(dibenzo[b,d]furan-2-yl)-2-((4-methoxyph
enoxy)methyl) acrylic acid (6b) white solid. 1H NMR(300 MHz, DMSO-d6) d:
8.14(d, J = 8.1, 2H), 7.62–7.49(m, 4H), 7.42(t, J = 7.7 Hz, 1H), 7.27(t, J = 7.7, 1H),
6.96(d, J = 9.0 Hz, 2H), 6.84(d, J = 9.0 Hz, 2H), 4.80(s, 2H), 3.79(s, 3H). (E)-3-
(dibenzo[b,d]furan-2-yl)-2-(p-tolyloxy methyl)acrylic acid (6c) light yellow solid.
1H NMR (300 MHz, DMSO-d6) d: 8.13(d, J = 7.9, 2H), 7.64–7.50(m, 4H), 7.43(t,
J = 7.5 Hz, 1H), 7.25(t, J = 7.5, 1H), 7.12(d, J = 8.4 Hz, 2H), 6.91(d, J = 8.4 Hz, 2H),
4.82(s,
2H),
2.34(s,3H).
(E)-3-(dibenzo[b,d]furan-2-yl)-2-((2-methoxy
phenoxy)methyl) acrylic acid (6d) yellow solid. 1H NMR (300 MHz ,DMSO-d6)
d: 8.26(s, 1H), 8.15(s, 1H), 7.67(d, J = 8.0 Hz, 2H), 7.57 (t, J = 9.5 Hz, 2H), 7.46 (t,
J = 7.3 Hz, 1H), 7.30(t, J = 7.3 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.01–6.94(m, 2H),
6.92–6.85(m, 1H), 4.85(s, 2H), 3.84(s, 3H). (E)-2-((4-tert-butylphenoxy)methyl)-
3-(dibenzo[b,d]furan-2-yl)acrylic acid(6e) white solid. 1H NMR (300 MHz,
DMSO-d6) d: 8.14(s, 1H), 8.07(s, 1H), 7.79(d, J = 12.8 Hz, 1H), 7.62–7.50(m,
2H), 7.48–7.38(m ,2H), 7.34(d, J = 8.6 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 6.95 (d,
J = 8.6 Hz, 2H), 4.83(s, 2H), 1.35(s, 9H).(E)-3-(dibenzo[b,d]furan-2-yl)-2-((4-
fluorophenoxy)methyl) acrylic acid (6f) pale yellow solid. 1H NMR (300 MHz,
DMSO-d6) d: 8.17(s, 1H), 8.11(s, 1H), 7.66–7.50(m, 4H), 7.43(t, J = 7.7 Hz, 1H),
7.29(t, J = 7.3 Hz, 1H), 7.06–6.94(m, 4H), 4.83(s, 2H). (E)-2-((4-

7430
T. Yempala et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7426–7430
bromophenoxy)methyl)-3-(dibenzo[b,d]furan-2-yl) acrylic acid (6g) White solid .
1678, 1615, 1475, 1418, 1292, 1250, 1193, 1122, 1014, 829, 755. EI-MS found
M+ =382 for C26H22O3 and HRMS calculated for [M+H]+ is 383.1647, found
383.1652. (E)-3-(dibenzo[b,d]furan-2-ylmethylene)-6-fluoro chroman-4-one (7f)
yellow solid; mp 124 °C. 1H NMR (300 MHz, CDCl3) d: 8.04(m, 1H), 7.97(dd,
J = 0.5,7.3 Hz, 1H), 7.89(d, J = 1.5 Hz, 1H), 7.73–7.58(m, 3H), 7.56–7.46(m, 1H),
7.45–7.32(m, 2H), 7.26–7.15(m, 2H) 7.03–6.92(m, 1H), 5.44(d, J = 1.7, 2H). 13C
NMR (75 MHz, CDCl3) d: 182.3, 156.7, 156.0, 154.1, 138.3, 129.7, 129.3, 127.9,
123.4, 123.2, 123.1, 122.7, 122.4, 120.8, 119.5, 119.4, 114.0, 113.0, 112.7, 112.1,
111.9, 67.8. IR (KBr, CmÀ1) 2924, 2854, 1738, 1662, 1579, 1492, 1291, 1194,
1126, 1032, 816, 741. EI-MS found M+ =344 for C22H13FO3 and HRMS calculated
for [M+H]+ is 345.0926, found 345.0912. (E)-3-(dibenzo[b,d]furan-2-yl
methylene)-6-bromochroman-4-one(7g) pale yellow solid; mp 60 °C. 1H NMR
(300 MHz, CDCl3) d: 8.07–8.03(m, 1H), 7.98(s, 1H), 7.68–7.62(m, 2H), 7.61–
7.52(m, 3H), 7.51–7.42(m, 2H), 7.38(t, J = 7.3 Hz, 1H), 6.91(d, J = 8.6 Hz, 1H),
5.48(d, J = 1.3 Hz, 2H). IR (KBr, CmÀ1) 2924, 2853, 1740, 1670, 1599, 1467,
1282, 1197, 1125, 1020, 818, 742. EI-MS found M+ =404 for C22H13BrO3. (E)-2-
(dibenzo [b,d]furan-2-ylmethylene)-2,3-dihydro-1H-benzo[f]chromen-1-one (7h)
white solid; mp 114 °C. 1H NMR (300 MHz, CDCl3) d: 9.45 (d, J = 8.4 Hz, 1H),
8.04(s, 1H), 7.98–7.85(m, 3H), 7.76–7.55(m, 4H), 7.53–7.29(m, 4H), 7.07(d,
J = 8.8 Hz, 1H), 5.46(d, J = 1.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) d: 182.3, 162.9,
156.6, 156.3, 138.8, 137.3, 136.8, 131.8, 131.3, 130.0, 129.4, 129.1, 128.4, 127.7,
127.2, 126.4, 124.9, 123.5, 123.1, 122.1, 120.7, 118.6, 114.2, 111.9, 111.8, 67.4.
IR (KBr, Cm-1) 2922, 1653, 1594, 1432, 1238, 1195, 1141, 815, 744. EI-MS found
M+ =376 for C26H16O3 and HRMS calculated for [M+H]+ is 377.1177, found
1H NMR(300 MHz, DMSO-d6) d : 8.19(s, 1H), 8.11(s, 1H), 7.67–7.54(m, 4H),
7.50–7.39(m, 3H), 7.31(t, J = 7.3 Hz, 1H), 6.98(d, J = 8.8 Hz, 2H), 4.83(s, 2H). (E)-
3-(dibenzo[b,d]furan-2-yl)-2-((naphthalen-2-yloxy)methyl)
acrylic
acid(6h)
white solid. 1H NMR (300 MHz, DMSO-d6) d: 8.19(s, 1H), 8.16(s, 1H), 7.82(t,
J = 8.8 Hz, 2H), 7.74–7.27(m, 10H), 7.15(t, J = 7.9 Hz, 1H), 4.85(s, 2H). (E)-3-
(dibenzo[b,d]furan-2-yl)-2-((naphthalen-1-yloxy)methyl) acrylic acid(6i) white
solid. 1H NMR (300 MHz, DMSO-d6) d: 8.34 (d, J = 8.1 Hz, 1H), 8.25(s, 1H),
8.17(s, 1H), 7.86(d, J = 7.9 Hz, 1H) 7.62(d, J = 8.4 Hz, 1H), 7.56–7.32(m, 8H),
7.13-7.02(m, 1H), 6.97(d, J = 7.3 Hz, 1H), 5.03(s, 2H). (E)-3-(dibenzo[b,d]furan-2-
yl)-2-((dibenzo[b,d]furan-2-yloxy)methyl) acrylic acid (B) White solid. 1H NMR
(300 MHz, DMSO-d6) d: 8.23(s, 1H), 8.20(s, 1H), 8.00–7.80(m, 2H), 7.68–
7.58(m, 3H), 7.57–7.50(m, 3H), 7.47–7.36(m, 2H), 7.28(t, J = 7.3 Hz, 1H), 7.23–
7.14(m, 2H),4.98(s, 2H). (E)-2-((9H-carbazol-3-yloxy)methyl)-3-(dibenzo
[b,d]furan-2-yl)acrylic acid (6k) White solid. 1H NMR (300 MHz, DMSO-d6) d:
10.72(br s, 1H), 8.24–8.14(m, 2H), 7.99–7.89(m, 2H), 7.63(d, J = 8.8 Hz, 1H),
7.59–7.43(m, 3H), 7.42–7.31(m, 2H), 7.26(t, J = 7.7 Hz, 1H), 7.15–7.03(m, 3H),
6.91(dd, J = 1.1, 8.4 Hz, 1H), 4.96(s, 2H).
17. General procedure for the synthesis of dibenzofuran embodied homoisoflavonoids
7a–k: to a solution of 6a–k (1 mmol) in anhydrous dichloro methane (4 mL)
was added trifluoroacetic anhydride (TFAA, 1.2 mmol). After refluxing for 8 h,
the reaction mixture was concentrated and chromatographed over silica gel
column eluted with hexane: ethylacetate (7:1) to give required
homoisoflavonoids (7a–k) as white solids. (E)-3-(dibenzo[b,d]furan-2-
ylmethylene) chroman-4-one (7a) white solid; mp 140 °C. 1H NMR (300 MHz,
CDCl3) d: 8.05–7.93(m, 3H), 7.88(t, J = 1.5 Hz, 1H), 7.65–7.55(m, 2H), 7.53–
7.43(m, 2H), 7.42–7.28(m, 2H), 7.06(t, J = 8.3 Hz, 1H), 6.94(d, J = 8.3 Hz, 1H),
5.43(d, J = 2.2, 2H). 13C NMR (75 MHz, CDCl3) d: 182.3, 161.0, 156.6, 156.5,
137.8, 135.9, 130.0, 129.3, 127.9, 127.8, 125.1, 124.8, 123.4, 123.1, 122.3, 121.9,
120.8, 117.8, 112.9, 112.0, 111.8, 67.6. IR (KBr, CmÀ1) 2923, 2853, 1670, 1604,
1469, 1320, 1197, 1020, 840, 743 .EI-MS found M+ =326 for C22H14O3. (E)-3-
(dibenzo[b,d]furan-2-ylmethylene)-6-methoxy chroman-4-one (7b) pale yellow
solid; mp130 °C. 1H NMR (300 MHz, CDCl3) d: 8.03–7.92(m, 2H), 7.88(d,
J = 1.5 Hz, 1H), 7.65–7.55(m, 2H), 7.48 (dt, J = 1.1, 7.7, 1H), 7.43–7.32(m, 3H),
7.06 (dd, J = 3.1, 9.0 Hz, 1H), 6.88(d, J = 8.8 Hz, 1H), 5.38 (d, J = 1.1, 2H), 3.85(s,
3H). 13C NMR (75 MHz, CDCl3) d: 182.0, 156.6, 156.4, 154.4, 137.5, 130.4, 130.2,
129.3, 127.8, 127.3, 125.0, 123.9, 123.4, 123.15, 122.3, 121.9, 120.7, 119.1,
112.0, 111.8, 108.1, 67.6, 55.8. IR (KBr, CmÀ1) 2923, 1670, 1603, 1490, 1429,
1287, 1198, 1136, 1037, 815, 743. EI-MS found M+ =356 for C23H16O4 and
HRMS calculated for [M+H]+ is 357.1126, found 357.1144. (E)-3-
(dibenzo[b,d]furan-2-ylmethylene)-6-methylchroman-4-one (7c) brown solid;
mp 146 °C. 1H NMR (300 MHz, CDCl3) d: 8.02–7.93(m, 2H), 7.88(d, J = 1.5 Hz,
1H), 7.80(d, J = 2.2 Hz, 1H), 7.64–7.55(m, 2H), 7.53–7.31(m, 3H), 7.30–7.24(m,
1H), 6.84(d, J = 8.3 Hz, 1H), 5.39 (d, J = 1.5 Hz, 2H), 2.37(s, 3H). 13C NMR
(75 MHz, CDCl3) d: 182.2, 159.0, 156.6, 156.4, 137.4, 136.8, 131.3, 130.3, 129.3,
127.8, 127.4, 125.0, 124.8, 123.4, 123.1, 122.3, 121.6, 120.7, 117.6, 111.9, 111.8,
67.6, 29.6. IR (KBr, CmÀ1) 2923, 1659, 1590, 1483, 1421, 1292, 1188, 1023, 823,
749. EI-MS found M+ =340 for C23H16O3. (E)-3-(dibenzo[b,d]furan-2-
ylmethylene)-8-methoxychroman-4-one (7d) black solid; mp125 °C. 1H
NMR (300 MHz, CDCl3) d : 8.03–7.86(m, 2H), 7.69–7.27(m, 5H), 7.10–6.84(m,
3H), 5.48(d, J = 2.2 Hz, 2H), 3.87(s, 3H). 13C NMR (75 MHz, CDCl3) d: 182.0,
156.5, 156.4, 150.9, 137.7, 129.6, 129.5, 129.3, 127.8, 127.4, 123.1, 122.9, 122.4,
377.1181
.
(E)-3-(dibenzo [b,d]furan-2-ylmethylene)-2H-benzo[h]chromen-
4(3H)-one (7i) yellow solid; mp 180 °C. 1H NMR (300 MHz, CDCl3) d: 8.23 (d,
J = 8.309 Hz, 1H), 8.08–7.90(m, 4H), 7.78(d, J = 8.3 Hz, 1H), 7.76–7.42(m, 7H),
7.37(t, J = 7.5 Hz, 1H), 5.69(d, J = 2.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) d: 182.5,
162.2, 156.7, 156.4, 140.0, 139.6, 137.4, 137.1, 136.9, 130.6, 129.6, 129.3, 127.8,
127.3, 126.2, 125.0, 124.8, 123.4, 123.1, 122.5, 122.3, 121.5, 120.8, 112.0, 111.9,
68.3. IR (KBr, CmÀ1) 2923, 2854, 1742, 1663, 1594, 1453, 1283, 1195, 1100,
813, 740. EI-MS found M+ =376 for C26H16O3. (E)-2-(di benzo[b,d]furan-2-
ylmethylene)-2,3-dihydro-1H-benzofuro [3,2-f]chromen-1-one (7j) White solid;
mp 194 °C. 1H NMR (300 MHz, CDCl3) d: 9.14 (d, J = 7.5 Hz, 1H), 8.11(s, 1H),
7.99–7.90 (m, 2H), 7.71–7.30(m, 9H), 7.06(d, J = 9.0 Hz, 1H), 5.44(d, J = 1.5 Hz,
2H). 13C NMR (75 MHz, CDCl3) d: 183.2, 168.7, 165.2, 158.8, 157.8, 156.7, 156.5,
147.3, 139.9, 137.5, 130.4, 129.3, 128.4, 127.8, 127.2, 123.5, 123.1, 122.6, 122.3,
120.8, 119.0, 117.1, 117.0, 112.0, 111.9, 111.7, 111.2, 67.8. IR (KBr CmÀ1) 2923,
2853, 1669, 1591, 1434, 1307, 1274, 1193, 1081, 1019, 816, 743. EI-MS found
M+ =416 for C28H16O4. (E)-2-(dibenzo[b,d]furan-2-ylmethylene)-2,3-dihydro
pyrano [2,3-c]carbazol-1(7H)-one (6l) yellow solid; mp 178 °C. 1H NMR
(300 MHz, CDCl3) d: 11.82-11.80(br, 1H), 8. 27–8.11(m, 3H), 8.03–7.95(m,
2H), 7.79–7.48(m, 5H), 7.42(t, J = 7.1 Hz, 1H), 7.33(t, J = 7.3 Hz, 1H), 7.18(t,
J = 7.3 Hz, 1H), 6.76(d, J = 8.3 Hz, 1H), 5.59 (d, J = 0.9 Hz, 2H). 13C NMR (75 MHz,
CDCl3) d: 181.3, 168.6, 155.8, 155.6, 144.7, 142.9, 140.1, 138.4, 137.8, 135.2,
133.5, 130.2, 129.7, 128.9, 128.3, 127.7, 124.4, 123.0, 122.7, 121.6, 119.5, 118.9,
117.4, 112.2, 111.7, 111.4, 107.7, 67.5. IR (KBr, CmÀ1) 2923, 2854, 1742, 1653,
1596, 1457, 1319, 1192, 1117, 1011, 818, 750. EI-MS found M+ =415 for
C
28H17NO3.
18. Antitubercular evaluation assay: tenfold serial dilutions of each test compounds
7a–k and drugs were prepared and incorporated into Middlebrook 7H11 agar
medium with OADC Growth Supplement. Inoculum of M. tuberculosis H37Rv
ATCC 27294 was prepared from fresh Middlebrook 7H11 agar slants with
OADC (oleic acid, albumin, dextrose and catalase; Difco) Growth Supplement
adjusted to 1 mg/mL (wet weight) in Tween 80 (0.05%) saline diluted to 10À2 to
122.2, 121.3, 120.7, 119.0, 116.5, 111.9, 111.8, 111.6, 68.1, 56.1. IR (KBr, CmÀ1
)
2922, 2852, 1706, 1669, 1486, 1258, 1196, 1021, 839, 747. EI-MS found M+
=356 for C23H16O4 and HRMS calculated for [M+H]+ is 357.1126, found
357.1134. (E)-6-tert-butyl-3-(di benzo[b,d]furan-2-ylmethylene)chroman-4-one
(7e) White solid; mp 132 °C. 1H NMR (300 MHz, CDCl3) d: 8.01–7.92(m, 2H),
7.88(d, J = 1.5 Hz, 1H), 7.64–7.28(m, 7H), 6.87 (d, J = 8.3 Hz, 1H), 5.40(d,
J = 2.2 Hz, 2H), 1.37(s, 9H). 13C NMR (75 MHz, CDCl3) d: 182.4, 158.9, 156.6,
156.4, 144.8, 137.3, 133.5, 130.4, 129.3, 127.8, 124.8, 123.8, 123.5, 123.1, 122.3,
121.2, 120.8, 117.4, 111.9, 111.8, 67.5, 34.3, 31.2. IR (KBr, CmÀ1) 2957, 2925,
give a concentration of ꢀ107 cfu/mL. A 5
lL amount of bacterial suspension
was spotted into 7H11 agar tubes containing 10-fold serial dilutions of drugs
per mL. The tubes were incubated at 37 C, and final readings were recorded
after 28 days. This method is similar to that recommended by the National
Committee for Clinical Laboratory Standards for the determination of MIC in
triplicate.