Evaluation of Some Salicylaldehyde-derived Baylis-Hillman Adducts and Coumarin Derivatives as Potential Antisickling Compounds

Open access


Some salicylaldehyde-derived Baylis-Hillman adducts and 3-(chloromethyl)coumarins have been synthesised and evaluated in vitro for their antisickling activities. The compounds were screened for inhibitory and reversal activity against mutated haemoglobin (HbSS) in red blood cells at four different concentrations (4 mg/mL, 2 mg/mL, 1 mg/mL and 0.5 mg/mL) as a measure of their antisickling potentials. Among the synthesized compounds, 6-chloro-3-(chloromethyl)coumarin 4d showed the highest inhibitory activity (83.75±1.90%), followed by 6-chlorocoumarin-3-methylsulfinic acid 5d (80.90 ±0.91%) and the least was tert-butyl-3-hydroxy- 3-(2-hydroxyphenyl)-2-methylenepropanoate 3a (33.33±1.86%). The results obtained from the reversal antisickling experiment showed that the percentage of sickle cells able to revert to the normal biconcave shape was dose dependent. Compound 5d had the highest reversal activity (66.49±1.39%) followed by 6-bromo-3- (chloromethyl)coumarin 4c (59.66±2.95) and 4d (55.50±1.95%) at 4 mg/mL. Compound 4c had higher reversal activity than the standard p-hydroxybenzoic acid at 2 mg/mL, 1 mg/mL and at 0.5 mg/mL. The 3-substituted coumarins 4a-d, and 5d had higher inhibitory antisickling activities than their Baylis-Hillman precursors 3a-d. Effect of 4a-d and 5d on the rate of polymerization of sickle cell heamoglobin was further studied spectrophotomerically using hemolysate of HbSS. The considerable inhibitory and reversal activities of these compounds make them good candidates for further antisickling studies.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Appendino G. Mercalli E. Fuzzati N. Arnoldi L. Stavri M. Gibbons S. Ballero M. and Maxia A. 2004. Antimycobacterial coumarins from the sardinian giant fennel (Ferula communis). J. Nat. Prod. 67(12) 2108-2110.

  • Archer N. Galacteros F. and Brugnara C. 2015. Clinical trials update in sickle cell anemia. Am. J. Hematol. 90(10) 934-950.

  • Ashley-Koch A. Yang Q. and Olney R.S. 2000. Sickle hemoglobin (Hb S) allele and sickle cell disease: A HuGE review. Am. J. Epidemiol. 151(9) 839-845.

  • Asif M. 2015. Pharmacological activities and phytochemistry of various plant containing coumarin derivatives. Curr. Sci. Perspect. 1(3) 77-90.

  • Bernaudin F. Socie G. Kuentz M. Chevret S. Duval M. Bertrand Y. Vannier J.-P. Yakouben K. Thuret I. Bordigoni P. Fischer A. Lutz P. Stephan J.-L. Dhedin N. Plouvier E. Margueritte G. Bories D. Verlhac S. Esperou H. Coic L. Vernant J.-P. and Gluckman E. 2007. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood110(7) 2749-2756.

  • Buchanan G.R. De Baun M.R. Quinn C.T. and Steinberg M.H. 2004. Sickle cell disease. Hematology2004 35-47.

  • Charache S. Terrin M.L. Moore R.D. Dover G.J. Barton F.B. Eckert S.V. McMahon R.P. and Bonds D.R. 1995. Effect of hydroxyurea on the frequency of painful crises in Sickle cell anemia. N. Engl. J. Med. 332 1317-1322.

  • Chikezie P.C. Chikezie C.M. and Amaragbulem P.I. 2010. Effect of antimalarial drugs on polymerization of sickle cell hemoglobin (HbS). Turk. J. Biochem. 35(1) 41-44.

  • Dadwal M. Mohan R. Panda D. Mobin S. M. and Namboothiri I.N.N. 2006. The Morita–Baylis–Hillman adducts of β-aryl nitroethylenes with other activated alkenes: synthesis and anticancer activity studies. Chem. Comm. 2006 338-340.

  • Egunyomi A. Moody J.O. and Eletu O.M. 2009. Antisickling activities of two ethnomedicinal plant recipes used for the management of sickle cell anaemia in Ibadan Nigeria. Afr. J. Biotech. 8(1) 20-25.

  • Haywood C.M. Beach C. Bediako S. Carroll C. P. Lattimer L. Jarrett D. and Lanzkron S. 2011. Examining the characteristics and beliefs of hydroxyurea users and nonusers among adults with sickle cell disease. Am. J. Hematol. 86(1) 85-87.

  • He J.-Y. Zhang W. He L.-C. and Cao Y.-X. 2007. Imperatorin induces vasodilatation possibly via inhibiting voltage dependent calcium channel and receptor-mediated Ca2+ influx and release. Eur. J. Pharmacol. 573 170-175.

  • Hoban M.D. Orkin S.H. and Bauer D.E. 2016. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood127(7) 839-848.

  • Hoult J.R. and Paya M. 1996. Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. Gen. Pharmacol. 27 713-722.

  • Imaga N.A. Chukwu C.E. Blankson A. and Gbenle G.O. 2013. Biochemical assessment of Ciklavit® a nutraceutical used in sickle cell anaemia management. Journal of Herbal Medicine3 137-148.

  • Iwu M.M. Igboko A.O. Onwubiko H. and Ndu U.E. 1988. Effect of cajaminose from Cajanus cajan on gelation and oxygen affinity of sickle cell haemoglobin. J. Ethnopharmacol. 23 99-104.

  • Kaye P.T. and Musa M.A. 2002. A Convenient and Improved Baylis-Hillman Synthesis of 3-Substituted 2H-1-benzopyran-2-ones. Synthesis18 2701-2706.

  • Kaye P.T. Musa M.A. and Nocanda X.W. 2003. Efficient and chemoselective access to 3-(chloromethyl)coumarins via direct cyclisation of unprotected Baylis–Hillman adducts. Synthesis4 531-534.

  • Kennedy R.O. and Thornes R.D. (Eds.). Coumarins: Biology Applications and Mode of Action. Wiley New York 1997.

  • Kidane A.G. Salacinski H. Tiwari A. Bruckdorfer K.R. and Seifalian A.M. 2004. Anticoagulant and antiplatelet agents: their clinical and device application(s) together with usages to engineer surfaces. Biomacromolecules5 798-813.

  • Kontogiorgis C.A. and Hadjipavlou L.D. 2004. Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage. Bioorg. Med. Chem. Lett. 14 611-614.

  • Kutlar A. Ataga K. and Reid M. 2012. A phase 1/2 trial of HQK-1001 an oral fetal globin inducer in sickle cell disease. American. J. Hematol. 87(11) 1017-1021.

  • Ma T. Liu L. Xue H. Li L. Han C. Wang L. Chen Z. and Liu G. 2008. Chemical library and structure-activity relationships of 11-demethyl-12-oxo calanolide A analogues as anti-HIV-1 agents. J. Med. Chem. 51 1432-1446.

  • Ma Y.- L. Rees D.C. Gibson J.S. and Ellory J.C. 2012. The conductance of red blood cells from sickle cell patients: ion selectivity and inhibitors. J. Physiol. 590(9) 2095-2105.

  • Makani J. Williams T. N. and Marsh K. 2013. Sickle cell disease in Africa: burden and research priorities. Ann. Trop. Med. Parasitol. 101(1) 3-14.

  • Mehanna A.S. 2001. Sickle cell anemia and antisickling agents then and now. Current Medicinal Chemistry8 79-88.

  • Narender P. Srinivas U. Gangadasu B. Biswas S. and Rao V.J. 2005. Anti-malarial activity of Baylis-Hillman adducts from substituted 2-chloronicotinaldehydes. Bioorg. Med. Chem. Lett. 15 5378-5381.

  • Nelson D.L. and Cox M.M. Lehninger Principles of Biochemistry. Fourth edition (2008) pp 75-189. W.H. Freeman New York.

  • Oder E. Safo M.K. Abdulmalik O. and Kato G.J. 2016. New Developments in Anti-Sickling Agents: Can Drugs Directly Prevent the Polymerization of Sickle Haemoglobin In Vivo? British Journal of Haematology175(1) 24-30.

  • Olomola T.O. Klein R. Mautsa N. Sayed Y. and Kaye P.T. 2013. Synthesis and evaluation of coumarin derivatives as potential dualaction HIV-1 protease and reverse transcriptase inhibitors. Bioorg. Med. Chem. 21 1964-1971.

  • Olomola T.O. Mosebi S. Klein R. Traut-Johnstone T. Coates J. Hewer R. and Kaye P.T. 2014. Novel furocoumarins as potential HIV-1 integrase inhibitors. Bioorg. Chem. 57 1-4.

  • Panepinto J.A. Walters M.C. Carreras J. Marsh J. Bredeson C.N. Gale R.P. Hale G.A. Horan J. Hows J.M. Klein J.P. Pasquini R. Roberts I. Sullivan K. Eapen M. and Ferster A. 2007. Matched-related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research. Brit. J. Haematol. 137 479-485.

  • Rashamuse T.J. Musa M.A. Klein R. and Kaye P.T. 2009. Regiocontrolled Michaelis–Arbuzov reactions of 3-(halomethyl)-coumarins. J. Chem. Res. 5 302-305.

  • Saraceno R. Teoli M. and Chimenti S. 2008. Hydroxyurea associated with concomitant occurrence of diffuse longitudinal melanonychia and multiple squamous cell carcinomas in an elderly subject. Clin. Ther. 30(7) 1324-1329.

  • Steinberg M.H. 1999. Management of sickle cell disease. N. Engl. J. Med. 340(13) 1021-1030.

  • Vasconcellos M.L.A.A. Silva T.M.S. Camara C.A. Martins R.M. Lacerda K.M. Lopes H.M. Pereira V.L.P. de Souza R.O.M.A. and Crespo L.T.C. 2006. Baylis–Hillman adducts with molluscicidal activity against Biomphalaria glabrata. Pest Managment Science62 288-292.

  • Yang Y.Z. Ranz A. Pan H.Z. Zhang Z.N. Lin X. B. and Meshnick S.R. 1992. Daphnetin: a novel antimalarial agent with in vitro and in vivo activity. Am. J. Trop. Med. Hyg. 46 15-20.

Journal information
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 259 136 11
PDF Downloads 193 95 10