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K. V. Sashidhara et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3926–3930
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Acknowledgments
Sashidhara, K. V.; Kumar, A.; Agarwal, S.; Kumar, M.; Kumar, B.; Sridhar, B. Adv.
Synth. Catal. 2012, 354, 1120; (c) Sashidhara, K. V.; Palnati, G. R.; Avula, S. R.;
Kumar, A. Synlett 2012, 611; (d) Sashidhara, K. V.; Kumar, A.; Rao, K. B.;
Kushwaha, V.; Saxena, K.; Murthy, P. K. Bioorg. Med. Chem. Lett 2012, 22, 1527;
(e) Sashidhara, K. V.; Kumar, A.; Rao, K. B. Tetrahedron Lett 2011, 52, 5659; (f)
Sashidhara, K. V.; Kumar, A.; Kumar, M.; Singh, S.; Jain, M.; Dikshit, M. Bioorg.
Med. Chem. Lett. 2011, 21, 7034; (g) Sashidhara, K. V.; Kumar, A.; Chatterjee, M.;
Rao, K. B.; Singh, S.; Verma, A. K.; Palit, G. Bioorg. Med. Chem. Lett. 2011, 21,
1937; (h) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sonkar, R.; Bhatia, G.;
Khanna, A. K. Bioorg. Med. Chem. Lett. 2010, 20, 4248; (i) Sashidhara, K. V.;
Rosaiah, J. N.; Kumar, A.; Bhatia, G.; Khanna, A. K. Bioorg. Med. Chem. Lett. 2010,
20, 3065; (j) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Srivastava, A.; Puri, A.
Bioorg. Med. Chem. Lett. 2010, 20, 6504; (k) Sashidhara, K. V.; Kumar, A.; Kumar,
M.; Sarkar, J.; Sinha, S. Bioorg. Med. Chem. Lett. 2010, 20, 7205; (l) Sashidhara, K.
V.; Rosaiah, J. N.; Kumar, M.; Gara, R. K.; Nayak, L. V.; Srivastava, K.; Bid, H. K.;
Konwar, R. Bioorg. Med. Chem. Lett. 2010, 20, 7127.
The authors are grateful to the Director, CDRI, Lucknow, India for
constant encouragement in drug development program, S.P. Singh
for technical support, SAIF for NMR, IR, and Mass spectral data.
A.K., R.P.D. and N.N.K. are thankful to CSIR, New Delhi, India for
financial support. This is CSIR-CDRI Communication Number 8246.
Supplementary data
Supplementary data associated with this article can be found, in
20. (a) Singh, C. Tetrahedron Lett. 1990, 31, 6901; (b) Singh, C.; Gupta, N.; Puri, S. K.
Tetrahedron Lett. 2005, 46, 205.
References and notes
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22. Representative procedure for the synthesis of compound 8a (methyl 8-methyl-2-
oxo-6-(6-(1-p-tolylvinyl)-1,2,4-trioxan-3-yl)-2H-chromene-3-carboxylate):
A
solution of allylic alcohol 7a (1 g, 6.18 mmol) and methylene blue (30 mg) in
acetonitrile (100 mL) was irradiated with a 500 W tungsten–halogen lamp at
À10 to 0 °C while oxygen was bubbled slowly into the reaction mixture for 4 h.
Methyl 6-formyl-8-methyl-2-oxo-2H-chromene-3-carboxylate 3a (2.28 g,
9.26 mmol) and concd HCl (0.2 mL) were added, and the reaction mixture
was left at 5 °C for 18 h. Usual workup followed by chromatography over silica
gel furnished trioxane 8a.
White solid, yield: 65%; mp 136–138 °C; IR (KBr): 3023, 1760, 1619, 1520,
1021 cmÀ1 1H NMR (CDCl3, 300 MHz): d 8.50 (s, 1H), 7.63 (s, 1H), 7.59 (s, 1H),
;
7.30 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 6.20 (s, 1H), 5.52 (s, 1H), 5.44 (d,
J = 10.1 Hz, 1H), 5.31 (s, 1H), 4.23 (dd, J = 11.68 Hz and 2.4 Hz, 1H), 3.94 (t,
J = 10.8 Hz, 1H), 3.94 (s, 3H), 2.45 (s, 3H), 2.35 (s, 3H); 13C NMR (CDCl3,
75 MHz): d 163.7, 156.5, 154.4, 149.2, 142.5, 138.4, 135.5, 134.1, 130.6, 129.4,
126.9, 126.4, 126.1, 118.2, 117.5, 116.6, 102.8, 80.8, 69.9, 53.0, 21.2, 15.5; ESI-
MS (m/z): 423 (M+H)+; Anal. Calcd for C24H22O7: C, 68.24; H, 5.25, found: C,
68.31; H, 5.30.
23. Evaluation of antimalarial activity: Chloroquine sensitive 3D7 strain of
Plasmodium falciparum was used to evaluate in vitro antimalarial activity of
compounds. The assay used was Malaria SYBR Green-I nucleic acid staining dye
based fluorescence (MSF) assay (Smilkstein et al., 2004). The compounds were
tested in 96 well plates in duplicate wells. The compounds were incubated for
72 h with 1% parasitized cell suspension containing 0.8–1% initial parasitaemia
at 37 °C in CO2 incubator in an atmosphere of 5% CO2 and air mixture. Finally
SYBR Green-I was added to each well and incubated for one hour at 37 °C. The
plates were examined at 485 20 nm of excitation and 530 20 nm of
emission (FLX800, BIO-TEK). Chloroquine was used as standard antimalarial.
To obtain 50% inhibitory concentration (IC50) of compounds Data were first
transferred into
a graphic programme (e.g., EXCEL) and expressed as
13. Kidane, A. G.; Salacinski, H. A.; Tiwari, K. R.; Bruckdorfer, A. M.
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Bioorg. Med. Chem. Lett. 2010, 20, 4248; (b) Sashidhara, K. V.; Rosaiah, J. N.;
Kumar, A.; Bhatia, G.; Khanna, A. K. Bioorg. Med. Chem. Lett. 2010, 20, 3065; (c)
Sashidhara, K. V.; Kumar, A.; Bhatia, G.; Khan, M. M.; Khanna, A. K.; Saxena, J. K.
Eur. J. Med. Chem. 1813, 2009, 44.
percentage of the untreated controls and then evaluated by Logit regression
analysis using pre-programmed Excel spreadsheet (Smilkstein, M.;
Sriwilaijaroen, N.; Kelly, J. X.; Wilairat, P.; Riscoe, M. Antimicrob. Agents
Chemother. 2004, 48, 1803.
24. 100% suppression of parasitemia means, number of parasites if at all present,
are below the detection limit. The parasites present below the detection limit
can multiply and eventually can be detected. In such cases though the drug is
providing near 100% suppression of the parasitemia but will not provide full
protection to the treated mice. Multi-drug-resistant Plasmodium yoelii
nigeriensis used in this study is resistant to chloroquine, mefloquine and
halofantrine.
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18. Sashidhara, K. V.; Kumar, M.; Modukuri, R. K.; Srivastava, R. K.; Soni, A.;
Srivastava, K.; Singh, S. V.; Saxena, J. K.; Gauniyal, H. M.; Puri, S. K. Bioorg. Med.
Chem. 2012, 20, 2971.