Abstract

INTRODUCTION

Leishmaniasis and trypanosomiasis are among the most neglected diseases of animals and humans caused by kinetoplastid protozoa, such as genera Leishmania and Trypanosoma (^{Barrett, 2000}3. Barrett MP. Problems for the chemotherapy of human African trypanosomiasis. Curr Opin Infect Dis. 2000;13(6):647-651.; ^{Olliaro et al., 2002}21. 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... ). Sleeping sickness, commonly called human African trypanosomiasis (HAT), is a medical condition caused by protozoa of the genus Trypanosoma (Barrett et al., 2003; ^{Büscher et al., 2017}8. 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)31... ). Sleeping sickness is spread by the tsetse fly, and caused by two subspecies of Trypanosoma brucei brucei, T. b. gambiense and T. b. rhodesiense (Büscher et al., 2017). There are two stages of disease. Stage 1, commonly called hemolymphatic stage, involves the proliferation of the parasite in the blood and lymph. In Stage 2, referred to as the meningoencephalitic stage, the infection has crossed the blood brain barrier and reached the CNS (^{Bisser et al., 2006}5. 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... ; ^{Blum et al., 2006}6. 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.20... ). Cognitive dysfunction, sleep disturbance, coma and death are the signs and symptoms of late-stage HAT. Except for diagnosis and treatment in the early stage, drugs should be able to cross the blood-brain barrier to have a therapeutic effect. The non-availability of a vaccine for African trypanosomiasis (^{La Greca, Magez, 2011}16. 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... ) ensures that chemotherapy remains the only therapeutic option and requires a drive to discover and develop novel chemical entities into operational medicines for HAT and various other neglected diseases. Although the WHO suggests a decrease in HAT incidence over the last decade, it will still be necessary to develop novel and active agents to combat the disease (WHO Report. 2015).

Leishmaniasis is a disease caused by Leishmania, a genus of protozoan parasites. The reservoir hosts of the majority of Leishmania species are canids and rodents from which parasites are transferred to humans via phlebotomine sand flies; transmission from infected to non-infected humans also takes place via sand fly vectors but is a significant factor for only a few Leishmania species (^{Lipoldova, Demant, 2006}17. 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... ). Substantial rates of morbidity and mortality around the world are caused by leishmaniasis, and it affects many tropical and subtropical countries, including most Mediterranean nations, putting around 350 million humans at infection risk. The total occurrence of leishmaniasis is assessed to be 12 million cases around the globe, and the worldwide annual occurrence of all clinical forms of disease is 1.3 million (WHO Report, 2017). The latest refugee crisis and conflicts in North Africa and Middle East resulted in a very serious leishmaniasis outbreak (^{Du et al., 2016}10. 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.000... ). Global warming and this outbreak are the key reasons behind the increasing spread of leishmaniasis to Europe (^{Hotez, 2016}15. 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.000... ; ^{Naucke et al., 2008}20. 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-... ) and to North America (^{Gonzalez et al., 2010}13. 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.000... ). Yet, this disease also remains neglected and current treatment options are insufficient, undermining any efforts to contain its further spread. Although research is focussing on potential drug targets in Leishmania and Trypanosoma species, and the causes of drug resistance, an effective, safer and simple substitute therapy is immediately needed.

Based on our previous results (^{Alkhaldi et al., 2015}2. 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... ; ^{Changtam et al., 2010}9. 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... ; ^{Zha et al., 2016}26. 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.2016.04.01... ), we have endeavoured to discover new compounds with anti-protozoal activities and in doing so we have extended our earlier reported work (Zha et al., 2017) comprising 34 novel α,β-Unsaturated carbonyl-based compounds linked to ligustrazine (tetramethylpyrazine (TMP)). TMP is an important constituent of Chinese traditional medicinal plant chuanxiong (Ligusticum chuanxiong Hort). In this study, a series of novel α,β-Unsaturated carbonyl-based compounds coupled to one or two TMP moieties was evaluated for their activity against a number of Leishmania and Trypanosoma strains including the well-characterised multi-drug resistant Trypanosoma brucei clonal line B48. This clonal line B48 is extremely resistant to the two major classes of trypanocides, the diamidines and the melaminophenyl arsenicals, due to the loss of HAPT1 and TbAT1/P2 drug transporters (^{Bridges et al., 2007}7. 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... ).

MATERIAL AND METHODS

Material

Synthetic compounds were synthesized, characterized and reported by us previously (^{Zha et al., 2017}25. 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... ). Stock solutions in 100% DMSO for each compound were prepared and for the concentrations used in assay, the calculated amount of stock solution was taken and diluted with complete medium, ensuring that the final DMSO concentration did not exceed 1% in the final conditions.

Cell culture

Trypanosoma brucei bloodstream forms (BSF) in-vitro

In this research, two strains of the bloodstream forms of Trypanosoma brucei were utilised. The first was the wild-type strain of Trypanosoma brucei brucei (s427-WT) and the other was TbAT1-B48 that was acquired from the clone TbAT1-KO, itself derived from s427WT by deletion of the TbAT1 gene (^{Matovu et al., 2003}18. 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.), by exposure to pentamidine thus causing more resistance to pentamidine, diminazene and the melaminophenyl arsenicals. Consequently, these cells have neither TbAT1/P2 transporter nor the high affinity-pentamidine transporter genes (^{Bridges et al., 2007}7. 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... ; ^{Munday et al., 2014}19. 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... ). Both strains were cultured in HMI-9 medium (pH 7.4) supplemented with 10% heat-inactivated Fetal Calf Serum (FCS, BioSera) and 14 µL/L of 13.4 M β-mercaptoethanol (Sigma), as described by ^{Hirumi and Hirumi (Hirumi, Hirumi, 1989}14. 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.). The medium was sterilized by filtration (0.22 µm, Millipore) inside a flow cabinet. The T. b. brucei cultures were incubated at 37 ºC and 5% CO₂ and passaged in vented flasks three times a week.

Leishmania major and Leishmania mexicana promastigotes

Leishmania major strain Friedlin (LmjF) and strains of Leishmania mexicana (MNYC/BZ/62/M379) were propagated in essential medium (HOMEM) with a pH value of 7.4 and 10% FCS in plastic flasks, at a temperature of 25 ºC. The cultures were passed to fresh medium three times per week.

Alamar blue assay to determine the sensitivity to test compounds

Resazurin sodium salt (Alamar Blue) is commonly used as a cell metabolic function indicator. It is a non-fluorescent, blue dye that is mixed with cell cultures containing various drug concentrations, in order to determine the sensitivity of African trypanosomes or Leishmania cultures to the test compounds in vitro (^{Fumarola et al., 2004}12. 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... ; ^{Raz et al., 1997}22. 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.). In case there are no toxic effects caused by the drug, the color of the living cells changes from blue to red and fluorescent. Preparation of Alamar Blue involves the dissolution of 12.5 milligrams of Resazurin sodium salt (Sigma) in 100 mL of phosphate-buffered saline (PBS) of pH 7.4, which is then filter-sterilized and stored in the dark at 4 ºC.

Drug sensitivity using Alamar Blue assay in T. b. brucei BSF

For each test compound a solution of 200 µM in HMI-9 medium + 10% FCS is prepared using a 20 mM stock solution in DMSO; 200 μL of this is added to a first well of a 96-well plate. Of this, 100 μL is transferred to the next well, containing 100 μL of the same medium, achieving a 1:1 dilution, initiating a doubling dilution series across 2 rows of the plate; each experiment was positively controlled using pentamidine and the final well for each compound received 100 microliters of HMI-9 medium as negative, drug-free control. To each well, 100 μL of a suspension of 2×10⁵ cells/mL is added, amounting to 1×10⁵ cells/mL as the final cell density. The plate is then incubated for 48 hours at 37 ºC/5% CO ₂ after which 20 µL of the Alamar Blue solution is added, followed by another incubation of the plate for 24 hours. A fluorimeter (FluoStar Optima) is used to read the fluorescence of the plate at the wavelengths of 590 nm for emission and 530 nm for excitation and the data are analysed using the GraphPad Prism 5 software package, fitting the fluorescence to a sigmoid curve with variable slope to determine the EC₅₀value. A very similar protocol was followed using Leishmania promastigotes, as described (^{Al-Salabi et al., 2003}1. 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... ).

Cytotoxicity assay on Human Foreskin Fibroblast (HFF)

Toxicity of test compounds to mammalian cells was carried out using the resazurin assay previously described (^{Ebiloma et al., 2018}11. 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... ) with slight modifications. HFF human cells were grown in a culture medium containing 500 mL of Dulbecco’s Modified Eagle’s Medium (DMEM) (Sigma), 50 mL New-Born Calf Serum (NBCS) (Gibco), 5 mL Penicillin/Streptomycin (Gibco), and 5 mL of L-Glutamax (200 nM, Gibco). Mammalian cells were incubated at 37 ºC and 5% CO₂ and were passaged when they reached 80-85% of confluence in vented flasks. For the cytotoxicity assay cells were suspended at 3x10⁵ cell/mL and 100 μL was added to each well of a 96-well plate. The plate was incubated at 37 ºC and 5% CO₂ for 24 hours to allow cell adhesion. Serial test compounds dilution was performed in a different 96-well plate and 100 μL was transferred to each well containing cells. Pentamidine was used as positive control. The plates were incubated at 37 ºC and 5% CO₂ for an additional 30 hours before 10 μL of resazurin solution (125 mg/mL in PBS) was added to each well, followed by a final incubation at 37 ºC and 5% CO₂ for 24 hours. The plates were read using a FLUOstar Optima (BMG Labtech, Durham, NC, USA) at wavelength of 540 nm for the excitation, 590 nm for the emission. EC₅₀ values were calculated by non-linear regression using an equation for a sigmoidal dose-response curve with variable slope using Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA).

RESULTS AND DISCUSSION

In the present study, we demonstrated the effect of synthetic compounds (Table I) on the growth of promastigotes of L. major, L. mexicana and different strains of Trypanosoma brucei brucei in vitro. The antitrypanosomal and leishmanicidal activities of compounds are summarized in Table II.

Antitrypanosomal activity of synthetic compounds

All 34 synthetic α,β-Unsaturated carbonyl-based compounds and their oxime derivatives were assessed for in vitro trypanocidal properties on two different types of Ttrypanosoma brucei brucei including wild type (WT) and the highly resistant Trypanosoma brucei clonal line B48 (Table II). Twelve compounds inhibited both strains, with almost identical EC₅₀ values. The highest inhibitory activity was exhibited by oxime derivative 8o (EC₅₀ = 6.9 µM) for clonal line B48 and second most strong inhibitor was cyclohexanone derivative 5f with EC₅₀ = 8.0 µM.

All compounds bear a central cyclohexanone linker that was substituted with seven different types of functional groups. On both sides of central linker aldehydes were attached through an unsaturated bond. These compounds can be divided in two main groups on the basis of their chemical backbones for detailed explanation of their biological activities. The first group contains α,β-Unsaturated carbonyl-based cyclohexanone compounds (5a-g) and (6a-u). While the other group contains oximes (7b,e,f) and (8f,o,r) that were synthesized from α,β-Unsaturated carbonyl-based compounds. This first group of cyclohexanone derivatives can also be further subdivided in two classes as compounds 5a-g contain a tetramethylpyrazine (TMP) moiety on both sides of the central cyclohexanone linker while 6a-u contain TMP on only one side of the linker and a different type of substituted aldehyde on the other side (see scheme 1).

Scheme 1
Synthesis scheme of α, β-Unsaturated carbonyl based compounds, oxime and oxime ether analogs. Reagents and conditions: (i-a) 30% H₂O₂, acetic acid, 70 ºC, 8 h.; (i-b) acetic anhydride, reflux, 2 h; (i-c) 20% NaOH; (ii) IBX, DMSO, room temperature, 0.5 h; (iii) NaOH, EtOH, Room temperature (iv) NH₂OH.HCl, pyridine, ethanol, anhyd., reflux (^{Zha et al., 2017}25. 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... ).

In comparison of trypanocidal properties (Table II) of tested compounds it was observed that the first class of cyclohexanone derivatives (5a-g), containing a tetramethylpyrazine (TMP) moiety on both sides of central cyclohexanone linker, were more active than respective oximes (7b,e,f). As (5b, d, e and f) showed inhibition of Ttrypanosoma brucei brucei including wild type (WT) and the highly resistant Trypanosoma brucei clonal line B48 with EC₅₀ ranging from 11.2 to 61.0 µM but respective oximes (7b,e,f) displayed EC₅₀ above 100 µM and should be considered inactive against T. brucei. On the other hand, one oxime 8o was found to be a strong inhibitor for both strains although its carbonyl precursor 6o was completely inactive. It was also interesting observation that oximes were found active while they have TMP moiety on only one side of central cyclohexanone linker. These variations showed that central linkers and substitutions on the both sides of aromatic rings played a vital role in the biological properties of these compounds and different combinations of cyclohexanone substitutions and functional groups on aldehyde rings exhibited different patterns of trypanocidal properties. Compound 8o was the most active against Trypanosoma brucei but its carba-isoster, compound 8f was around 7 times less potent, so clearly the basic nitrogen seems important for activity. Curiously though, compounds 6m, 6n and 6o, all bearing the same R1 group as 8o, were not active at all, suggesting that the oxime is even more important than the basic Nitrogen. And, to make everything more interesting and complex, compound 8r, was inactive, despite having a basic nitrogen and the oxime group. The result with 8r made clear that there is a size limit for the alkyl group bonded to the basic nitrogen. All this seem to change in the symmetric series of compounds 5a-g, where 5f was the most active, bearing the bulkier substituent at the basic nitrogen.

All compounds showed similar effects on Trypanosoma brucei wild type and B48, which is a multi-drug resistant line with in vitro resistance to pentamidine, proving that there is no cross-resistance between this TMP/cyclohexanone/cyclohexoxime scaffold and the most important classes of trypanocides currently in clinical use. Indeed, in our previous study we reported on an extensive series of curcumin-related α,β-Unsaturated carbonyl-based compounds with various chemical modifications to the corresponding demethylated, methylated and higher alkylated analogs (^{Changtam et al., 2010}9. 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... ) and the result with the B48 line was unexpected, as this line displayed hypersensitivity to some of the most promising curcuminoids (Changtam et al., 2010).

Antileishmanial activity of synthetic compounds

The same 34 synthetic α,β-Unsaturated carbonyl-based compounds and their oxime derivatives were tested on promastigotes of L. major and L. mexicana (Table II). Only three new compounds (5f, 6i and 6s) showed any inhibition, with EC₅₀ values in the range 46.6 to 75.6 µM for L. major. The same three compounds, in addition to compound 6g, exhibited some inhibition of L. mexicana. However, the activity was generally below that displayed for Ttrypanosoma brucei brucei. In fact, we found only weak correlation between the trypanocidal and antileishmanial activity of these compounds, with 8o diaplaying no activity at all against either species of Leishmania, and 6s having no effect against T. brucei at 100 µM. The fact that 5f was active against both Trypanosoma and Leishmania indicates that maybe it has a molecular target that is common to both parasites, or at least is the same kind of receptor or enzyme. Therefore at least some of the compounds appear to act on a highly species-specific target, explaining the absence of activity against human cell lines (see below).

Effect of synthetic ligustrazine-based compounds on a human cell line

To assess whether the antiprotozoal activity depicted for tested compounds should be attributed to general toxicity, rather than specific antiprotozoal activity, some of the most active analogs (5d, 6f and 8o) were also tested for their effect on human foreskin fibroblast (HFF) cells. The toxicity to HFF cells was very low and the selected test compounds exhibited high EC₅₀ values. The highest concentration tested on HFF (human cells) was 300 µM. Cyclohexanone derivatives 5d and 6f showed the value > 300 µM and oxime derivative 8o showed the EC₅₀ value 280.6 ± 8.05 µM that was also very high. Phenylarsine oxide (PAO or PhAsO), an organometallic compound, was used as control and it was found to be strongly toxic with EC₅₀ =1.17±0.12 µM.

CONCLUSION

In this study some synthetic cyclohexanone and oxime derivatives have been identified with potential applications against trypanosomiasis and leishmaniasis, based on their sturdy antiparasitic activity and low toxicity. The results obtained herein revealed that some compounds including 5f and 8o can be effective against trypanosomiasis as they showed effects on both tested strains and they can serve as starting points for structure-based lead optimization and development against T. brucei.

REFERENCES

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