Thiouronium Salt Derivatives Based on Vicinal Diamines as Potential Neuroprotectors

Most of the medicinal products that are currently approved and used in clinical practice for neurodegenerative diseases, in particular Alzheimer’s disease, have a compensatory mechanism of action that enhances neurotransmitter signalling. It is an urgent need to develop new medicinal products combining cognitive-enhancing, neuroprotective, and disease-specific effects resulting from a multi-target mechanism of action including, in particular, prevention of glutamate-induced neuronal calcium uptake and stabilisation of microtubules.

The aim of this study was to search for potentially neuroprotective and tauopathy-alleviating medicines amongst new thiouronium salt derivatives based on vicinal diamines.

Materials and methods. The study investigated the ability of thiouronium salts to block glutamate-induced ⁴⁵Ca²⁺ uptake by synaptosomes prepared from the brain of Wistar rats. The authors evaluated effects of these new compounds on polymerisation of a preparation of C57bl mouse brain tubulin and microtubule-associated proteins. The evaluation was carried out in the presence of guanosine triphosphate (GTP) and based on specific absorbance changes at 355 nm due to formation of microtubules. The authors analysed the structure of these microtubules, using negative staining followed by transmission electron microscopy. The IC₅₀ determination and the statistical analysis were performed using standard software (Excel and PRISM 6.02).

Results. The authors developed a screening algorithm for a number of new thiouronium salt derivatives based on vicinal diamines and studied biological activity of these derivatives by the effects on glutamate-induced calcium uptake by synaptosomes and on microtubule assembly processes. The authors identified compounds suppressing glutamate-induced calcium uptake by synaptosomes, i.e. compounds with neuroprotective potential. In addition, a number of new compounds were able to stimulate GTP-dependent microtubule assembly processes. The authors observed formation of microtubules with a normal structure in the presence of isopropyl-N’-[2-(benzoylamino)-1,2-diphenylethyl]-N-ethylimidothiocarbamate hydrobromide and considered the compound a promising scaffold for further optimisation.

Conclusions. Chemical modification of thiouronium salts is a promising direction for developing effective neuroprotectors and microtubule stabilisers. 

1. Binvignat O, Olloquequi J. Excitotoxicity as a target against neurodegenerative processes. Curr Pharm Des. 2020;26(12):1251–62. https://doi.org/10.2174/1381612826666200113162641

2. Bachurin SO, Bovina EV, Ustyugov AA. Current trends in the development of drugs for the treatment of Alzheimer’s disease and their clinical trials. Biomedical Chemistry: Research and Methods. 2018;1(3):e00015. https://doi.org/10.18097/BMCRM00015

3. Tan CC, Zhang XY, Tan L, Yu JT. Tauopathies: mechanisms and therapeutic strategies. J Alzheimers Dis. 2018;61(2):487–508. https://doi.org/10.3233/JAD-170187

4. Valeeva FG, Karimova TR, Pavlov RV, Bakhtiyarov DI, Sapunova AS, Ivshin KA, et al. Introduction of isothiuronium surfactant series: synthesis, structure-dependent aggregation overview and biological activity. J Mol Liq. 2021;324(15):114721–31. https://doi.org/10.1016/j.molliq.2020.114721

5. Jang D, Szabo C, Murrell GA. S-substituted isothioureas are potent inhibitors of nitric oxide biosynthesis in cartilage. Eur J Pharmacol. 1996;312(3):341–7. https://doi.org/10.1016/0014-2999(96)00369-X

6. Kazimierczuk Z, Chalimoniuk M, Laudy AE, Moo-Puc R, Cedillo-Rivera R, Starosciak BJ, Chrapusta SJ. Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives. Arch Pharm Res. 2010;33(6):821–30. https://doi.org/10.1007/s12272-010-0604-8

7. Galkina IV, Bakhtiyarov DI, Usupova LM, Gerasimov AV, Shulaeva MP, Pozdeev OK, et al. Antimic robial activity of novel isothiuronium salts with 7-chloro-4,6-dinitrobenzofuroxan-5-olate anion. Mendeleev Communications. 2021;31(3):365–7. https://doi.org/10.1016/j.mencom.2021.04.027

8. Ferreira M, Assunção LS, Silva AH, Filippin-Monteiro FB, Creczynski-Pasa TB, Sá MM. Allylic isothiouronium salts: the discovery of a novel class of thiourea analogues with antitumor activity. Eur J Med Chem. 2017;129:151–8. https://doi.org/10.1016/j.ejmech.2017.02.013

9. Sun J, Wang J, Ma L, Jiang T, Li X, Guo Q, Li X, Sui Z. Determination and pharmacokinetic study of isothiouronium-modified pyrimidine-substituted curcumin analog (1G), a novel antitumor agent, in rat plasma by liquid chromatography-tandem mass spectrometry. Artif Cells Nanomed Biotechnol. 2019;47(1):1505–12. https://doi.org/10.1080/21691401.2019.1602537

10. El-Henawy AA, Khowdiary MM, Badawi AB, Soliman HM. In vivo anti-leukemia, quantum chemical calculations and ADMET investigations of some quaternary and isothiouronium surfactants. Pharmaceuticals (Basel). 2013;6(5):634–49. https://doi.org/10.3390/ph6050634

11. Li ZH, Ma JL, Liu GZ, Zhang XH, Qin TT, Ren WH, et al. [1,2,3]Triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety as a novel scaffold for LSD1 inhibitors. Eur J Med Chem. 2020;187:111989. https://doi.org/10.1016/j.ejmech.2019.111989

12. Fechner GA, Jacobs JJ, Parsons PG. Inhibition of melanogenesis in human melanoma cells by novel analogues of the partial histamine (H2) agonist nordimaprit. Biochem Pharmacol. 1993;46(1):47–54. https://doi.org/10.1016/0006-2952(93)90346-x

13. Barnes JC, Brown JD, Clarke NP, Clapham J, Evans DJ, O’Shaughnessy CT. Pharmacological activity of VUF 9153, an isothiourea histamine H3 receptor antagonist. Eur J Pharmacol. 1993;250(1):147–52. https://doi.org/10.1016/0014-2999(93)90632-R

14. Iwamoto T, Watano T, Shigekawa M. A novel isothiourea derivative selectively inhibits the reverse mode of Na + /Ca 2+ exchange in cells expressing NCX1. J Biol Chem. 1996;271(37):22391–7. https://doi.org/10.1074/jbc.271.37.22391

15. Watano T, Kimura J, Morita T, Nakanishi H. A novel antagonist, No. 7943, of the Na + /Ca 2+ exchange current in guinea-pig cardiac ventricular cells. Br J Pharmacol. 1996;119(3):555–63. https://doi.org/10.1111/j.1476-5381.1996.tb15708.x

16. Proshin AN, Grigor’ev VV, Tikhonova IG, Palyulin VA, Bachurin SO. Tetrasubstituted thiuronium salts as multitarget compounds affecting brain NMDA and AMPA receptors. Russ Chem Bull. 2015;64(9):2189–94. https://doi.org/10.1007/s11172-015-1137-6

17. Proskurnina MV, Lozinskaya NA, Tkachenko SE, Zefirov NS. Reaction of aromatic aldehydes with ammonium acetate. Russian Journal of Organic Chemistry. 2002;38(8):1149–53. https://doi.org/10.1023/A:1020997325550

18. Hajós F. An improved method for the preparation of synaptosomal fractions in high purity. Brain Res. 1975;93(3):485–9. https://doi.org/10.1016/0006-8993(75)90186-9

19. Petrova LN, Bachurin SO. Specificity of glutamate receptors in P 2 synaptosomal fraction from rat brain cortex. Bull Exp Biol Med. 2006;142(1):43–6. https://doi.org/10.1007/s10517-006-0287-9

20. Bachurin SO, Makhaeva GF, Shevtsova EF, Aksinenko AY, Grigoriev VV, Shevtsov PN, et al. Conjugation of aminoadamantane and γ-carboline pharmacophores gives rise to unexpected properties of multifunctional ligands. Molecules. 2021;26(18):5527. https://doi.org/10.3390/molecules26185527

21. Shevtsov PN, Shevtsova EF, Burbaeva GSh, Bachurin SO. Effects of anti-Alzheimer drugs on phosphorylation and assembly of microtubules from brain microtubular proteins. Bull Exp Biol Med. 2014;156(6):768–72. https://doi.org/10.1007/s10517-014-2445-9