Synthesis and in vitro antitubercular activity of 4-aryl/ alkylsulfonylmethylcoumarins as inhibitors of Mycobacterium tuberculosis

Article abstract of DOI:10.1016/j.bmcl.2012.05.054

A series of 4-aryl/alkylsulfonylmethylcoumarins have been synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB). Four of the compounds showed MIC in the range of 0.78-3.13 μg/mL proving their potential activity.

Full text of DOI:10.1016/j.bmcl.2012.05.054

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4807–4809
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and in vitro antitubercular activity of 4-aryl/alkylsulfonylmethylcou-
marins as inhibitors of Mycobacterium tuberculosis
Malaichamy Jeyachandran a, Penugonda Ramesh b, , Dharmarajan Sriram c, Palaniappan Senthilkumar c,
⇑
Perumal Yogeeswari c
a Post Graduate and Research Department of Chemistry, Sri Paramakalyani College, Alwarkurichi, Tirunelveli 627 412, Tamil Nadu, India
b Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
c Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad
500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 4-aryl/alkylsulfonylmethylcoumarins have been synthesized and screened for in vitro antitu-
Received 24 November 2011
Revised 29 April 2012
Accepted 14 May 2012
Available online 23 May 2012
bercular activity against Mycobacterium tuberculosis H37Rv (MTB). Four of the compounds showed MIC in
the range of 0.78–3.13 lg/mL proving their potential activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
4-Aryl/alkylsulfonylmethylcoumarins
Antitubercular activity
Mycobacterium tuberculosis
Tuberculosis (TB) remains the leading cause of mortality due to
a bacterial pathogen, Mycobacterium tuberculosis. Approximately
one-third of the world’s population has been infected with the
causative organism M. tuberculosis (MTB), eight million become
sick with TB every year, and globally it accounts for almost three
million deaths annually.1 One-fifth of all deaths of adults in devel-
oping countries are due to TB, which is a reemerging problem par-
ticularly in many industrialized countries. It is estimated that
between 2005 and 2020, one billion people will be newly infected,
over 125 million people will get sick and 30 million will die of
tuberculosis if control is not further strengthened.2–4 In addition,
the evolution of its new virulent forms like multidrug resistant
(MDR-TB) and extremely drug resistant (XDR-TB) has become a
major threat to human kind.2 Among HIV infected people, the
resurgence of TB is alarming due to the development of pathogenic
synergy.3,4 The worsening situation has prompted the World
Health Organization (WHO) to declare tuberculosis a global public
health crisis.4 Thus, there is an urgent need for the development of
potent new antituberculosis agents, having a unique mechanism of
action different from that of the currently used antitubercular
drugs, effective against both drug-susceptible and drug resistant
strains of M. tuberculosis with low toxicity profiles and shortened
therapy duration.5
Coumarins constitute an important class of benzopyrones that
are found in nature and act as a structural subunit of more complex
natural products. These molecules generally exhibit broad spec-
trum of biological activity6 such as antibacterial7 vasorelaxant,8
anticancer,9 cytotoxic,10 anti-inflammatory11 and inhibitory of
HIV-1 protease.12 Coumarin substituted sulfones possesses antitu-
bercular,13–15 anti-HCV,16 HIV-1A protease inhibitors,17 antibacte-
rial and antifungal activities.18 In pursuit of this goal, our
research efforts herein have been directed toward the synthesis
of coumarin substituted sulfones that are effective as antitubercu-
losis agents.
Allylic bromination of methoxycoumarins (1a–c) with NBS in
the presence of benzoyl peroxide in carbon tetrachloride as a
solvent, gave 4-bromomethylcoumarins (2a–c). Compounds 2a–c,
on further reaction with appropriate thiols afforded the corre-
sponding sulfides (3a–c to 8a–c); which on oxidation with aq
KMnO4 (3%) in acetone afforded corresponding sulfones (9a–c to
14a–c) in high yield (Tables 1 and 2 Scheme 1). The final products
as well as the intermediates have been characterized by spectro-
scopic data (IR, NMR) and elemental analysis. Compounds 3a–c
to 8a–c and 9a–c to 14a–c contained sulfur; the presence of
sulfone moiety in 9a–c to 14a–c is established by IR bands19 in
the region 1300–1360 cmÀ1 (unsymmetrical S@O stretching) and
1120–1140 cmÀ1 (symmetrical S@O stretching). In the 1H NMR
spectrum of 9c (a representative example), a proton singlet at d
2.58 (2H, s) is due to C-4 methylene group (–CH2SO2–) and the
⇑
Corresponding author. Tel.: +91 452 2459035.
E-mail address: npc_ramesh@yahoo.co.in (P. Ramesh).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.054

4808
M. Jeyachandran et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4807–4809
Table 1
Table 3
Yield and mp of compounds 3a–c to 8a–c
MIC values of compounds 9a–c to 14a–c
Entry Compound
R
Yield (%)
b
Mp (°C)
Compounds
MIC (
lg/mL)
a
c
a
b
c
a
b
c
1
2
3
4
5
6
3
4
5
6
7
8
Phenyl
87 95 90 186 221 202
83 96 86 174 194 183
85 89 92 191 213 197
90 94 91 173 197 182
9
10
11
12
13
14
6.25
12.5
12.5
7.5
6.25
3.13a
1.56a
0.78a
6.25
12.5
12.5
12.5
6.25
6.25
6.25
12.5
p-Methylphenyl
p-Chlorophenyl
2-Benzoxazolyl
2-Benzimidazolyl 87 95 90 186 207 198
Cyclohexyl 89 93 93 171 223 211
1.61a
6.25
6.25
1.56
Pyrazinamide
Ethambutol
a
High potent antitubercular compounds.
Table 2
Yield and mp of compounds 9a–c to 14a–c
most potent compound in vitro with MIC of 0.78
MTB and two times more potent than Ethambutol.
l
g/mL, against
Entry Compound
R
Yield (%)
b
Mp (°C)
a
c
a
b
c
In conclusion, we have synthesized 4-aryl/alkylsulfonylmethyl
coumarins from 4-aryl/alkylthiolmethyl coumarins23,24 and were
screed for antitubercular activity. In vitro antitubercular activity
of the title compounds against MTB H37Rv strain has been
evaluated. Four of the compounds showed MIC in the range of
1
2
3
4
5
6
9
10
11
12
13
14
Phenyl
62 67 66 171 209 193
60 64 65 160 189 178
63 68 63 182 195 183
61 65 65 162 184 171
p-Methylphenyl
p-Chlorophenyl
2-Benzoxazolyl
2-Benzimidazolyl 59 63 62 177 191 173
Cyclohexyl 61 61 60 159 215 201
0.78–3.13 lg/mL, proving their potential activity.
Acknowledgments
The authors thank School of Chemistry for providing FT-NMR
(under DST-IRHPA program) and one of the authors (M.J.) is grate-
ful to Madurai Kamaraj University for USR fellowship.
three proton singlet at d 3.82 is assigned to methoxyl group at C-7.
The one proton singlet at is ascribed to d 6.12 the C-3 methine
group and the aromatic protons resonate as a multiplet at d
6.92–7.63.
Compounds 9a–c to 14a–c was screened for their in vitro anti-
tubercular activity against M. tuberculosis H37Rv (MTB), by agar
dilution method for the determination of MIC in duplicate.20–22
The minimum inhibitory concentration (MIC) is defined as the
minimum concentration of compound required to completely inhi-
bit the bacterial growth. The MICs of the synthesized compounds
are reported in Table 3. In the first phase of screening against
MTB, all the compounds showed excellent in vitro activity against
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
05.054.
References and notes
1. Ginsburg, A. S.; Grosset, J. H.; Bishai, W. R. Lancet Infect. Dis. 2003, 3, 432.
2. (a) Russell, D. G.; Barry, C. E.; Flynn, J. L. Science 2010, 328, 852; (b) Russell, D. G.
Nat. Rev. Microbiol. 2007, 5, 39; (c) Kaufmann, S. H. E.; McMichael, A. J. Nat. Med.
2005, 11, 578; (d) Manabe, Y. C.; Bishai, W. R. Nat. Med. 2000, 6, 1327.
MTB with MIC ranging from 0.78 to 12.50
10b, 11b, 12b and 13a inhibited MTB with MIC range of
0.78–3.13 g/mL, in which compound 12b was found to be the
lg/mL. Four compounds
l
Scheme 1. Synthesis of 4-aryl/alkylsulfonylmethyl coumarins 9a–c to 14a–c.

M. Jeyachandran et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4807–4809
4809
3. (a) Nikalie, A. G.; Mudassar, P. Asian. J. Biol. Sci. 2011, 4, 101; (b) Sacchettini, J.
C.; Rubin, E. J.; Freundlich, J. S. Nat. Rev. Microbiol. 2008, 6, 41.
20. Kumar, P. S.; Dinakaran, M.; Banerjee, D.; Devakaram, R. V.; Yogeeswari, P.;
China, A.; Nagaraja, V.; Sriram, D. Bioorg. Med. Chem. 2008, 16, 2558.
21. Dinakaran, M.; Kumar, P. S.; Yogeeswari, P.; China, A.; Nagaraja, V.; Sriram, D.
Bioorg. Med. Chem. 2008, 16, 3408.
22. Dinakaran, M.; Kumar, P. S.; Yogeeswari, P.; China, A.; Nagaraja, V.; Sriram, D.
Int. J. Antimicrob. Chemother. 2008, 31, 337.
4. Global tuberculosis control:
a short update to the 2009 report. http://
www.who.int/tb/publications/global_report/2009/update/en/index.html.
5. Duncan, K. Tuberculosis 2003, 83, 201.
6. Jie, W.; Yun, L.; Zhen, Y. J. Org. Chem. 2001, 66, 3642.
7. Kayser, O.; Kolodziej, H. Planta Med. 1997, 63, 508.
8. Vilar, S.; Quezada, E.; Santana, L.; Uriarte, E.; Yanez, M.; Fraiz, N.; Alcaide, C.;
Cano, E.; Orallo, F. Bioorg. Med. Chem. Lett. 2006, 16, 257.
9. Wang, C. J.; Hsieh, Y. J.; Chu, C. Y.; Lin, Y. L.; Tseng, T. H. Cancer Lett. 2002, 183,
163.
10. Kostova, I. Curr. Med. Chem. Anti Cancer Agents 2005, 5, 29.
11. Bhalla, M.; Nathani, P. K.; Kumar, A.; Bhalla, T. N.; Shanker, K. Indian. J. Chem.,
Sect. B 1992, 31, 183.
23. Typical procedure for the preparation of 4-(aryl/alkylthiomethyl)-2H-chromen-2-
one (3a–c to 8a–c): To
a
solution of 7-methoxy/7,8-dimethoxy-4-
bromopmethylcoumarin (2a–c) (0.10 mol) in dry DMF (10.0 mL), appropriate
thiols (0.10 mol) as sodium salts in DMF (5.0 mL) were added and the mixture
was refluxed for 1 h. The reaction mixture was poured into cold water and the
separated solid was filtered, washed with water, dried and recrystallised from
aqueous ethanol. Characteristics are given for a representative compound 3c;
IR (KBr): 1715 (C@O str.), 1612 cmÀ1 1H NMR (300 MHz, CDCl3) d 2.40 (s, 2H,
;
12. Kirkiacharian, S.; Thuy, D. T.; Sicsic, S.; Bakhchinian, R.; Kurkjian, R.; Tonnaire,
T. Il Farmaco 2002, 57(9), 703.
4-CH2), 3.88 (s, 3H, OCH3), 6.14 (s, 1H, H-3), 6.85–7.51 (m, 8H, Ar–H); Anal.
Calcd for C17H14O3S: C, 68.44; H, 4.73. Found: C, 68.49; H, 4.71.
13. Jaysukhlal, R. M.; Arvind, S. G.; Paresh, J. S.; Shyam, S. S. Chem. Ind. (London)
1979, 10, 351.
14. Jaysukhlal, R. M.; Paresh, J. S. Chem. Ind. (London) 1980, 19, 791.
15. Jaysukhlal, R. M.; Nirmal, M. K.; Arvind, S. G. Chem. Ind. (London) 1982, 23,
955.
16. Jie, W.; Zhen, Y.; Reza. F.; Qiang, Z. U.S. Pat. Appl. Publ., 752654, 538, 2004.
17. Serge, K.; Thanh, T. D.; Sames, S.; Robert, B.; Raffi, K.; Thierry, T. Il Farmaco
2002, 57, 703.
18. Nofal, Z. M.; Mandour, A. H.; Nassar, M. I. Egypt. J. Chem. 1990, 33, 509.
19. Jeyachandran, M.; Ramesh, P. Organic Chemistry International, 2011, Article ID
360810, doi: http://dx.doi.org/10.1155/2011/360810.
24. Typical procedure for the preparation of 4-(aryl/alkylsulfonylmethyl)-2H-
chromen-2-one (9a–c to 14a–c): To a solution of 4-(aryl/alkylthiomethyl)-2H-
chromen-2-one (3a–c to 8a–c) in acetone (30.0 mL), aq KMnO4 (3.0%, 20 mL)
was added and the reaction mixture was stirred at room temperature for 2 h.
The excess of KMnO4 was decolorised by passing SO2 gas and the liberated
solid was filtered, dried and recrystallised from aqueous ethanol. Compound
9c; IR (KBr): 1717, 1619, 1397 (S@O unsym. str.), 1129 (S@O unsym. str.) cmÀ1
;
1H NMR (300 MHz, CDCl3) d: 2.58 (s, 2H, 4-CH2), 3.82 (s, 3H, OCH3), 6.12 (s, 1H,
H-3), 6.92–7.63 (m, 8H, Ar–H); 13C NMR (75 MHz) d: 55.4, 62.8, 100.9, 110.8,
111.6, 112.6, 125.6, 127.6, 129.1, 132.5, 137.8, 153.6, 155.2, 160.1, 160.3; Anal.
Calcd for C17H14O5S: C, 61.81; H, 4.73. Found: C, 61.86; H, 4.71.