Synthetic ligustrazine based cyclohexanone and oxime analogs as Anti-Trypanosoma and Anti-Leishmanial agents

Abdulsalam A. M. Alkhaldi; Abdulsalam A. M. Alkhaldi; Harry P. de Koning; Syed Nasir  Abbas Bukhari

doi:10.1590/s2175-97902020000418997

Authors

Abdulsalam A. M. Alkhaldi Biology department, College of Science, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia
Abdulsalam A. M. Alkhaldi Biology department, College of Science, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia
Harry P. de Koning Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK
Syed Nasir Abbas Bukhari Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia https://orcid.org/0000-0001-8125-7972

DOI:

https://doi.org/10.1590/s2175-97902020000418997

Keywords:

Protozoan parasites. Sleeping sickness. α,β-Unsaturated carbonyl-based compounds; toxicity. Organic synthesis.

Abstract

In the present study a series of 34 synthetic ligustrazine-containing α, β-Unsaturated carbonyl-based compounds and oximes, recognized as anticancer compounds were assessed against protozoa of the Trypanosoma and Leishmania species. Ligustrazine, chemically known as tetramethylpyrazine (TMP), was selected as the core moiety for the synthesis of α, β-Unsaturated carbonyl-based compounds and these compounds were selected as precursors for the synthesis of new oximes. Some derivates, including 5f and 6i, showed multiple activities against all tested strains. In particular compounds 5f and 8o are the most potent and they are, therefore, potential candidates for trypanosomiasis and leishmaniasis.

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References

Al-Salabi MI, Wallace LJM, de Koning HP. A Leishmania major nucleobase transporter responsible for allopurinol uptake is a functional homolog of the Trypanosoma brucei H2 transporter. Mol Pharmacology. 2003;63(4):814-820. DOI: 10.1124/mol.63.4.814.

» https://doi.org/10.1124/mol.63.4.814

Alkhaldi AA, Creek DJ, Ibrahim H, Kim DH, Quashie NB, Burgess KE, Changtam C, Barrett MP, Suksamrarn A, de Koning HP. Potent trypanocidal curcumin analogs bearing a monoenone linker motif act on trypanosoma brucei by forming an adduct with trypanothione. Mol Pharmacol. 2015;87(3):451-64. DOI: 10.1124/mol.114.096016.

» https://doi.org/10.1124/mol.114.096016

Barrett MP. Problems for the chemotherapy of human African trypanosomiasis. Curr Opin Infect Dis. 2000;13(6):647-651.

Barrett MP, Burchmore RJ, Stich A, Lazzari JO, Frasch AC, Cazzulo JJ, Krishna S. The trypanosomiases. Lancet. 2003;362(9394):1469-80. DOI: 10.1016/s0140-6736(03)14694-6.

» https://doi.org/10.1016/s0140-6736(03)14694-6

Bisser S, Ouwe-Missi-Oukem-Boyer ON, Toure FS, Taoufiq Z, Bouteille B, Buguet A, Mazier D. Harbouring in the brain: A focus on immune evasion mechanisms and their deleterious effects in malaria and human African trypanosomiasis. Int J Parasitol. 2006;36(5):529-40. DOI: 10.1016/j.ijpara.2006.02.001.

» https://doi.org/10.1016/j.ijpara.2006.02.001

Blum J, Schmid C, Burri C. Clinical aspects of 2541 patients with second stage human African trypanosomiasis. Acta Trop. 2006;97(1):55-64. DOI: 10.1016/j.actatropica.2005.08.001.

» https://doi.org/10.1016/j.actatropica.2005.08.001

Bridges DJ, Gould MK, Nerima B, Maser P, Burchmore RJ, de Koning HP. Loss of the high-affinity pentamidine transporter is responsible for high levels of cross-resistance between arsenical and diamidine drugs in African trypanosomes. Mol Pharmacol. 2007;71(4):1098-108. DOI: 10.1124/mol.106.031351.

» https://doi.org/10.1124/mol.106.031351

Büscher P, Cecchi G, Jamonneau V, Priotto G. Human African trypanosomiasis. The Lancet. 2017;390(10110):2397-2409. DOI: 10.1016/S0140-6736(17)31510-6.

» https://doi.org/10.1016/S0140-6736(17)31510-6

Changtam C, de Koning HP, Ibrahim H, Sajid MS, Gould MK, Suksamrarn A. Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species. Eur J Med Chem. 2010;45(3):941-56. DOI: 10.1016/j.ejmech.2009.11.035.

» https://doi.org/10.1016/j.ejmech.2009.11.035

Du R, Hotez PJ, Al-Salem WS, Acosta-Serrano A. Old World Cutaneous Leishmaniasis and refugee crises in the Middle East and North Africa. PLoS Neglected Tropical Diseases. 2016;10:e0004545. DOI: 10.1371/journal.pntd.0004545.

» https://doi.org/10.1371/journal.pntd.0004545

Ebiloma GU, Ayuga TD, Balogun EO, Gil LA, Donachie A, Kaiser M, Herraiz T, Inaoka DK, Shiba T, Harada S, Kita K, de Koning HP, Dardonville C. Inhibition of trypanosome alternative oxidase without its N-terminal mitochondrial targeting signal (DeltaMTS-TAO) by cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde derivatives active against T. brucei and T. congolense. Eur J Med Chem. 2018;150:385-402. DOI: 10.1016/j.ejmech.2018.02.075.

» https://doi.org/10.1016/j.ejmech.2018.02.075

Fumarola L, Spinelli R, Brandonisio O. In vitro assays for evaluation of drug activity against Leishmania spp. Res Microbiol. 2004;155(4):224-30. DOI: 10.1016/j.resmic.2004.01.001.

» https://doi.org/10.1016/j.resmic.2004.01.001

Gonzalez C, Wang O, Strutz SE, Gonzalez-Salazar C, Sanchez-Cordero V, Sarkar S. Climate change and risk of leishmaniasis in north america: predictions from ecological niche models of vector and reservoir species. PLoS Negl Trop Dis. 2010;4(1):e585. DOI: 10.1371/journal.pntd.0000585.

» https://doi.org/10.1371/journal.pntd.0000585

Hirumi H, Hirumi K. Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. J Parasitol. 1989;75(6):985-9.

Hotez PJ. Southern Europe's Coming Plagues: Vector-Borne Neglected Tropical Diseases. PLoS Neglected Tropical Diseases. 2016;10(6):e0004243. DOI: 10.1371/journal.pntd.0004243.

» https://doi.org/10.1371/journal.pntd.0004243

La Greca F, Magez S. Vaccination against trypanosomiasis: can it be done or is the trypanosome truly the ultimate immune destroyer and escape artist? Hum Vaccin. 2011;7(11):1225-33. DOI: 10.4161/hv.7.11.18203.

» https://doi.org/10.4161/hv.7.11.18203

Lipoldova M, Demant P. Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis. Nat Rev Genet. 2006;7(4):294-305. DOI: 10.1038/nrg1832.

» https://doi.org/10.1038/nrg1832

Matovu E, Stewart ML, Geiser F, Brun R, Maser P, Wallace LJ, Burchmore RJ, Enyaru JC, Barrett MP, Kaminsky R, Seebeck T, de Koning HP. Mechanisms of arsenical and diamidine uptake and resistance in Trypanosoma brucei. Eukaryot Cell. 2003;2(5):1003-8.

Munday JC, Eze AA, Baker N, Glover L, Clucas C, Aguinaga Andres D, Natto MJ, Teka IA, McDonald J, Lee RS, Graf FE, Ludin P, Burchmore RJ, Turner CM, Tait A, MacLeod A, Maser P, Barrett MP, Horn D, De Koning HP. Trypanosoma brucei aquaglyceroporin 2 is a high-affinity transporter for pentamidine and melaminophenyl arsenic drugs and the main genetic determinant of resistance to these drugs. J Antimicrob Chemother. 2014;69(3):651-63. DOI: 10.1093/jac/dkt442.

» https://doi.org/10.1093/jac/dkt442

Naucke TJ, Menn B, Massberg D, Lorentz S. Sandflies and leishmaniasis in Germany. Parasitol Res. 2008;103(Suppl 1):S65-8. DOI: 10.1007/s00436-008-1052-y.

» https://doi.org/10.1007/s00436-008-1052-y

Olliaro P, Lazdins J, Guhl F. Developments in the treatment of leishmaniasis and trypanosomiasis. Expert Opinion on Emerging Drugs. 2002;7(1):61-67. DOI: 10.1517/14728214.7.1.61.

» https://doi.org/10.1517/14728214.7.1.61

Raz B, Iten M, Grether-Buhler Y, Kaminsky R, Brun R. The Alamar Blue assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro. Acta Trop. 1997;68(2):139-47.

WHO Report. Leishmaniasis. 2017. Fact sheet Nº375: Updated April 2017.

WHO Report. Investing to Overcome the Global Impact of Neglected Tropical Diseases,. Geneva, Switzerland. 2015; http://apps.who.int/iris/bit stream/10665/152781/1/9789241564861_eng.pdf?ua=1 (accessed 26 February 2015).

» http://apps.who.int/iris/bit stream/10665/152781/1/9789241564861_eng.pdf?ua=1

Zha GF, Qin HL, Youssif BGM, Amjad MW, Raja MAG, Abdelazeem AH, Bukhari SNA. Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance. Eur J Med Chem. 2017;135:34-48. DOI: 10.1016/j.ejmech.2017.04.025.

» https://doi.org/10.1016/j.ejmech.2017.04.025

Zha GF, Zhang CP, Qin HL, Jantan I, Sher M, Amjad MW, Hussain MA, Hussain Z, Bukhari SN. Biological evaluation of synthetic alpha,beta-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-beta aggregation. Bioorg Med Chem. 2016;24(10):2352-9. DOI: 10.1016/j.bmc.2016.04.015.

» https://doi.org/10.1016/j.bmc.2016.04.015