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Exploring the latest breakthroughs in rhodesain inhibitors for African trypanosomiasis

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Abstract

Human African Trypanosomiasis is a serious public health concern, and new chemical therapeutic agents need to be developed to combat this disease. Rhodesain (RhD) inhibitors have shown promising results in medicinal chemistry, specifically against Trypanosoma brucei. These inhibitors target the cysteine protease RhD, which is essential for the survival of T. brucei. However, as the pharmaceutical industry lacks interest in these inhibitors, the development of drugs based on them is challenging. In this review, we showed the impact of RhD inhibitors on medicinal chemistry in the past 10 years (2013–2022), particularly against T. brucei, showing interesting RhD-based inhibitors, including peptidomimetic inhibitors such as Michael acceptors, cyanide groups, 3-bromoisoxazole, benzodiazepine, among others, as well as non-peptidyl inhibitors. Peptidomimetic inhibitors (5–7, 9–15, and 17) exhibited the highest potency with respect to dissociation constant (Ki) values for rhodesain, demonstrating promising activity against T. brucei targeting rhodesain. Thus, we explored recent advancements and perspectives in the context of RhD for potential treatments in sleeping sickness, highlighting its relevance in drug discovery applications.

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References

  1. World Health Organization. Neglected tropical diseases. www.who.int/health-topics/neglected-tropical-diseases#tab=tab_2 (Accessed Mar 16, 2023).

  2. Büscher P, Cecchi G, Jamonneau V, Priotto G. Human African Trypanosomiasis. Lancet. 2017;390:2397–409.

    Article  PubMed  Google Scholar 

  3. Gao JM, Qian ZY, Hide G, Lai DH, Lun ZR, Wu ZD. Human African Trypanosomiasis: the current situation in endemic regions and the risks for non-endemic regions from imported cases. Parasitology. 2020;147:922–31.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Simarro PP, Cecchi G, Paone M, Franco JR, Diarra A, Ruiz JA, et al. The Atlas of Human African Trypanosomiasis: a contribution to global mapping of neglected tropical diseases. Int J Health Geogr 2010;9:57.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kennedy PGE. Update on Human African Trypanosomiasis (Sleeping Sickness). J Neurol 2019;266:2334–7.

    Article  CAS  PubMed  Google Scholar 

  6. Fairlamb AH, Bowman IBR. Trypanosoma brucei: suramin and other trypanocidal compounds’ effects on sn-glycerol-3-phosphate oxidase. Exp Parasitol 1977;43:353–61.

    Article  CAS  PubMed  Google Scholar 

  7. Fairlamb AH, Bowman IB. Uptake of the trypanocidal drug suramin by bloodstream forms of Trypanosoma brucei and its effect on respiration and growth rate in vivo. Mol Biochem Parasitol 1980;1:315–33.

    Article  CAS  PubMed  Google Scholar 

  8. Willson M, Callens M, Kuntz DA, Perié J, Opperdoes FR. Synthesis and activity of inhibitors highly specific for the glycolytic enzymes from Trypanosoma brucei. Mol Biochem Parasitol 1993;59:201–10.

    Article  CAS  PubMed  Google Scholar 

  9. Morty RE, Troeberg L, Pike RN, Jones R, Nickel P, Lonsdale-Eccles JD, et al. A trypanosome oligopeptidase as a target for the trypanocidal agents pentamidine, diminazene and suramin. FEBS Lett. 1998;433:251–6.

    Article  CAS  PubMed  Google Scholar 

  10. Zimmermann S, Hall L, Riley S, Sørensen J, Amaro RE, Schnaufer A. A novel high-throughput activity assay for the Trypanosoma brucei editosome enzyme REL1 and other RNA ligases. Nucleic Acids Res. 2016;44:e24.

    Article  PubMed  Google Scholar 

  11. Albisetti A, Hälg S, Zoltner M, Mäser P, Wiedemar N. Suramin action in African trypanosomes involves a RuvB-like DNA helicase. Int J Parasitol Drugs Drug Resist. 2023;23:44–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shapiro TA, Englund PT. Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs. Proc Natl Acad Sci USA. 1990;87:950–4.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Baker N, Koning HP, Mäser P, Horn D. Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story. Trends Parasitol. 2013;29:110–8.

    Article  CAS  PubMed  Google Scholar 

  14. Fairlamb AH, Henderson GB, Cerami A. Trypanothione is the primary target for arsenical drugs against African trypanosomes. Proc Natl Acad Sci USA. 1989;86:2607–11.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vincent IM, Creek D, Watson DG, Kamleh MA, Woods DJ, Wong PE, et al. A molecular mechanism for eflornithine resistance in African trypanosomes. PLoS Pathog. 2010;6:e1001204.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Fairlamb AH, Henderson GB, Bacchi CJ, Cerami A. In vivo effects of difluoromethylornithine on trypanothione and polyamine levels in bloodstream forms of Trypanosoma brucei. Mol Biochem Parasitol. 1987;24:185–91.

    Article  CAS  PubMed  Google Scholar 

  17. Poulin R, Lu L, Ackermann B, Bey P, Pegg AE. Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites. J Biol Chem. 1992;267:150–8.

    Article  CAS  PubMed  Google Scholar 

  18. Keating J, Yukich JO, Sutherland CS, Woods G, Tediosi F. Human African Trypanosomiasis prevention, treatment and control costs: a systematic review. Acta Trop. 2015;150:4–13.

    Article  PubMed  Google Scholar 

  19. US National Library of medicine. Clinical trials home page. Bethesda (MD); National Library of Medicine. clinicaltrials.gov/ (Accessed Mar 13, 2023).

  20. Mesu VKBK, Kalonji WM, Bardonneau C, Mordt OV, Blesson S, Simon F, et al. Oral fexinidazole for late-stage African trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial. Lancet. 2018;391:144–54.

    Article  CAS  PubMed  Google Scholar 

  21. MEROPS, the peptidase database. www.ebi.ac.uk/merops/ (Accessed Mar 14, 2023).

  22. Rawlings ND, Barrett AJ, Thomas PD, Huang X, Bateman A, Finn RD. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res. 2018;46:D624–D632.

    Article  CAS  PubMed  Google Scholar 

  23. Steverding D, Caffrey CR. Should the enzyme name ‘Rhodesain’ be discontinued? Mol Biochem Parasitol. 2021;245:111395.

    Article  CAS  PubMed  Google Scholar 

  24. Ettari R, Previti S, Tamborini L, Cullia G, Grasso S, Zappalà M. The inhibition of cysteine proteases Rhodesain and TbCatB: a valuable approach to treat human African Trypanosomiasis. Mini Rev Med Chem. 2016;16:1374–91.

    Article  CAS  PubMed  Google Scholar 

  25. Lonsdale-Eccles JD, Grab DJ. Trypanosome hydrolases and the blood-brain barrier. Trends Parasitol. 2002;18:17–19.

    Article  CAS  PubMed  Google Scholar 

  26. Nikolskaia OV, Lima APCDA, Kim YV, Lonsdale-Eccles JD, Fukuma T, Scharfstein J, et al. Blood-brain barrier traversal by African Trypanosomes requires calcium signaling induced by parasite cysteine protease. J Clin Invest. 2006;116:2739–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Grab DJ, Garcia-Garcia JC, Nikolskaia OV, Kim YV, Brown A, Pardo CA, et al. Protease activated receptor signaling is required for African trypanosome traversal of human brain microvascular endothelial cells. PLoS Negl Trop Dis. 2009;3:e479.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Steverding D, Sexton DW, Wang X, Gehrke SS, Wagner GK, Caffrey CR. Trypanosoma Brucei: chemical evidence that cathepsin L is essential for survival and a relevant drug target. Int J Parasitol. 2012;42:481–8.

    Article  CAS  PubMed  Google Scholar 

  29. Ettari R, Tamborini L, Angelo IC, Micale N, Pinto A, Micheli C, et al. Inhibition of Rhodesain as a novel therapeutic modality for human African Trypanosomiasis. J Med Chem. 2013;56:5637–58.

    Article  CAS  PubMed  Google Scholar 

  30. Johé P, Jaenicke E, Neuweiler H, Schirmeister T, Kersten C, Hellmich UA. Structure, interdomain dynamics, and PH-dependent autoactivation of pro-Rhodesain, the main lysosomal cysteine protease from African Trypanosomes. J Biol Chem. 2021;296:100565.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nascimento IJ, dos S, Aquino TM, de; Silva-Júnior EF. da. Cruzain and Rhodesain inhibitors: last decade of advances in seeking for new compounds against American and African Trypanosomiases. Curr Top Med Chem. 2021;21:1871–99.

    Article  Google Scholar 

  32. Alvarez VE, Iribarren PA, Niemirowicz GT, Cazzulo JJ. Update on relevant trypanosome peptidases: validated targets and future challenges. Biochim Biophys Acta - Proteins Proteom. 2021;1869:140577.

    Article  CAS  PubMed  Google Scholar 

  33. Petri GL, Di Martino S, De Rosa M. Peptidomimetics: an overview of recent medicinal chemistry efforts toward the discovery of novel small. Mol Inhib J Med Chem. 2022;65:7438–75.

    Article  Google Scholar 

  34. El-Faham A, de la Torre BG, Albericio F. Latest advances on synthesis, purification, and characterization of peptides and their applications. Appl Sci. 2021;11:5593.

    Article  CAS  Google Scholar 

  35. Palmer JT, Rasnick D, Klaus JL, Bromme D. Vinyl sulfones as mechanism-based cysteine protease inhibitors. J Med Chem. 1995;38:3193–6.

    Article  CAS  PubMed  Google Scholar 

  36. Kerr ID, Lee JH, Farady CJ, Marion R, Rickert M, Sajid M, et al. Vinyl sulfones as antiparasitic agents and a structural basis for drug design. J Biol Chem 2009;284:25697–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Royo S, Rodríguez S, Schirmeister T, Kesselring J, Kaiser M, González FV. Dipeptidyl enoates as potent rhodesain inhibitors that display a dual mode of action. ChemMedChem. 2015;10:1484–7.

    Article  CAS  PubMed  Google Scholar 

  38. Royo S, Schirmeister T, Kaiser M, Jung S, Rodríguez S, Bautista JM, et al. Antiprotozoal and cysteine proteases inhibitory activity of dipeptidyl enoates. Bioorg Med Chem. 2018;26:4624–34.

    Article  CAS  PubMed  Google Scholar 

  39. Schirmeister T, Kesselring J, Jung S, Schneider TH, Weickert A, Becker J, et al. Quantum chemical-based protocol for the rational design of covalent inhibitors. J Am Chem Soc. 2016;138:8332–5.

    Article  CAS  PubMed  Google Scholar 

  40. Latorre A, Schirmeister T, Kesselring J, Jung S, Johé P, Hellmich UA, et al. Dipeptidyl nitroalkenes as potent reversible inhibitors of cysteine proteases rhodesain and cruzain. ACS Med Chem Lett. 2016;7:1073–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jung S, Fuchs N, Johe P, Wagner A, Diehl E, Yuliani T, et al. Fluorovinylsulfones and -sulfonates as potent covalent reversible inhibitors of the trypanosomal cysteine protease rhodesain: structure-activity relationship, inhibition mechanism, metabolism, and in vivo studies. J Med Chem. 2021;64:12322–58.

    Article  CAS  PubMed  Google Scholar 

  42. Jung S, Fuchs N, Grathwol C, Hellmich UA, Wagner A, Diehl E, et al. New peptidomimetic rhodesain inhibitors with improved selectivity towards human cathepsins. Eur J Med Chem. 2022;238:114460.

    Article  CAS  PubMed  Google Scholar 

  43. Previti S, Ettari R, Cosconati S, Amendola G, Chouchene K, Wagner A, et al. Development of novel peptide-based Michael acceptors targeting rhodesain and falcipain-2 for the treatment of neglected tropical diseases (NTDs). J Med Chem. 2017;60:6911–23.

    Article  CAS  PubMed  Google Scholar 

  44. Ettari R, Previti S, Maiorana S, Amendola G, Wagner A, Cosconati S, et al. Optimization strategy of novel peptide-based Michael acceptors for the treatment of human African Trypanosomiasis. J Med Chem. 2019;62:10617–29.

    Article  CAS  PubMed  Google Scholar 

  45. Jaishankar P, Hansell E, Zhao DM, Doyle PS, McKerrow JH, Renslo AR. Potency and selectivity of P2/P3-modified inhibitors of cysteine proteases from trypanosomes. Bioorg Med Chem Lett. 2008;18:624–8.

    Article  CAS  PubMed  Google Scholar 

  46. Mott BT, Ferreira RS, Simeonov A, Jadhav A, Ang KKH, Leister W, et al. Identification and optimization of inhibitors of trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB. J Med Chem. 2010;53:52–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang PY, Wang M, Li L, Wu H, He CY, Yao SQ. Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-trypanosoma Brucei agents. Chemistry. 2012;18:6528–41.

    Article  CAS  PubMed  Google Scholar 

  48. Di Chio C, Previti S, Amendola G, Ravichandran R, Wagner A, Cosconati S, et al. Development of novel dipeptide nitriles as inhibitors of rhodesain of Trypanosoma Brucei Rhodesiense. Eur J Med Chem. 2022;236:114328.

    Article  PubMed  Google Scholar 

  49. Schirmeister T, Schmitz J, Jung S, Schmenger T, Krauth-Siegel RL, Gütschow M. Evaluation of dipeptide nitriles as inhibitors of rhodesain, a major cysteine protease of trypanosoma brucei. Bioorg Med Chem Lett. 2017;27:45–50.

    Article  CAS  PubMed  Google Scholar 

  50. Maiorana S, Ettari R, Previti S, Amendola G, Wagner A, Cosconati S, et al. Peptidyl vinyl ketone irreversible inhibitors of rhodesain: modifications of the P2 fragment. ChemMedChem. 2020;15:1552–61.

    Article  CAS  PubMed  Google Scholar 

  51. Ettari R, Pinto A, Previti S, Tamborini L, Angelo IC, La Pietra V, et al. Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation. Bioorg Med Chem. 2015;23:7053–60.

    Article  CAS  PubMed  Google Scholar 

  52. Ettari R, Tamborini L, Angelo IC, Grasso S, Schirmeister T, Lo Presti L, et al. Development of rhodesain inhibitors with a 3-bromoisoxazoline warhead. ChemMedChem. 2013;8:2070–6.

    Article  CAS  PubMed  Google Scholar 

  53. Ettari R, Zappalà M, Micale N, Schirmeister T, Gelhaus C, Leippe M, et al. Synthesis of novel peptidomimetics as inhibitors of protozoan cysteine proteases falcipain-2 and rhodesain. Eur J Med Chem. 2010;45:3228–33.

    Article  CAS  PubMed  Google Scholar 

  54. Ettari R, Pinto A, Tamborini L, Angelo IC, Grasso S, Zappalà M, et al. Synthesis and biological evaluation of papain-family cathepsin L-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antiprotozoal agents. ChemMedChem. 2014;9:1817–25.

    Article  CAS  PubMed  Google Scholar 

  55. Ettari R, Micale N, Schirmeister T, Gelhaus C, Leippe M, Nizi E, et al. Novel peptidomimetics containing a vinyl ester moiety as highly potent and selective falcipain-2 inhibitors. J Med Chem. 2009;52:2157–60.

    Article  CAS  PubMed  Google Scholar 

  56. Bova F, Ettari R, Micale N, Carnovale C, Schirmeister T, Gelhaus C, et al. Constrained peptidomimetics as antiplasmodial falcipain-2 inhibitors. Bioorg Med Chem. 2010;18:4928–38.

    Article  CAS  PubMed  Google Scholar 

  57. Ettari R, Previti S, Cosconati S, Maiorana S, Schirmeister T, Grasso S, et al. Development of novel 1,4-benzodiazepine-based Michael acceptors as antitrypanosomal agents. Bioorg Med Chem Lett. 2016;26:3453–6.

    Article  CAS  PubMed  Google Scholar 

  58. Ettari R, Previti S, Cosconati S, Kesselring J, Schirmeister T, Grasso S, et al. Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors. J Enzyme Inhib Med Chem. 2016;31:1184–91.

    Article  CAS  PubMed  Google Scholar 

  59. Giroud M, Dietzel U, Anselm L, Banner D, Kuglstatter A, Benz J, et al. Repurposing a library of human cathepsin L ligands: identification of macrocyclic lactams as potent rhodesain and trypanosoma brucei inhibitors. J Med Chem. 2018;61:3350–69.

    Article  CAS  PubMed  Google Scholar 

  60. Giroud M, Kuhn B, Saint-Auret S, Kuratli C, Martin RE, Schuler F, et al. 2H-1,2,3-triazole-based dipeptidyl nitriles: potent, selective, and trypanocidal rhodesain inhibitors by structure-based design. J Med Chem. 2018;61:3370–88.

    Article  CAS  PubMed  Google Scholar 

  61. Roman D, Raguž L, Keiff F, Meyer F, Barthels F, Schirmeister T, et al. Modular solid-phase synthesis of antiprotozoal barnesin derivatives. Org Lett. 2020;22:3744–8.

    Article  CAS  PubMed  Google Scholar 

  62. Klein P, Barthels F, Johe P, Wagner A, Tenzer S, Distler U, et al. Naphthoquinones as covalent reversible inhibitors of cysteine proteases — studies on inhibition mechanism and kinetics. Molecules. 2020;25:2064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Vicik R, Busemann M, Gelhaus C, Stiefl N, Scheiber J, Schmitz W, et al. Aziridide-based inhibitors of cathepsin L: synthesis, inhibition activity, and docking studies. ChemMedChem. 2006;1:1126–41.

    Article  CAS  PubMed  Google Scholar 

  64. Klein P, Johe P, Wagner A, Jung S, Kühlborn J, Barthels F, et al. New cysteine protease inhibitors: electrophilic (Het)Arenes and unexpected prodrug identification for the trypanosoma protease rhodesain. Molecules. 2020;25:1451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fonseca NC, da Cruz LF, Villela FdaS, Pereira GADN, de Siqueira-Neto JL, Kellar D, et al. Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and schistosoma mansoni cathepsin B1. Antimicrob Agents Chemother. 2015;59:2666–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang H, Collins J, Nyamwihura R, Ware S, Kaiser M, Ogungbe IV. Discovery of a quinoline-based phenyl sulfone derivative as an antitrypanosomal agent. Bioorg Med Chem Lett. 2018;28:1647–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang H, Collins J, Nyamwihura R, Crown O, Ajayi O, Ogungbe IV. Vinyl sulfone-based inhibitors of trypanosomal cysteine protease rhodesain with improved antitrypanosomal activities. Bioorg Med Chem Lett. 2020;30:127217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ferreira RS, Simeonov A, Jadhav A, Eidam O, Mott BT, Keiser MJ, et al. Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors. J Med Chem. 2010;53:4891–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pereira GAN, Santos LH, Wang SC, Martins LC, Villela FS, Liao W, et al. Benzimidazole inhibitors of the major cysteine protease of trypanosoma brucei. Future Med Chem. 2019;11:1537–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pereira GAN, Silva EB, Braga SFP, Leite PG, Martins LC, Vieira RP, et al. Discovery and characterization of trypanocidal cysteine protease inhibitors from the ‘Malaria Box. Eur J Med Chem. 2019;179:765–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Silva LR, Guimarães AS, do Nascimento J, do Santos Nascimento IJ, da Silva EB, McKerrow JH, et al. Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases. Bioorg Med Chem. 2021;41:116213.

    Article  CAS  PubMed  Google Scholar 

  72. Morello A, Pavani M, Garbarino JA, Chamy maríaC, Frey C, Mancilla J, et al. Effects and mode of action of 1,4-naphthoquinones isolated from calceolaria sessilis on tumoral cells and trypanosoma parasites. Comp Biochem Physiol. 1995;112C:119–28.

    CAS  Google Scholar 

  73. Delarmelina M, Daltoé RD, Cerri MF, Madeira KP, Rangel LBA, Lacerda Júnior V, et al. Synthesis, antitumor activity and docking of 2,3-(substituted)-1,4-naphthoquinone derivatives containing nitrogen, oxygen and sulfur. J Braz Chem Soc. 2015;26:1804–16.

    CAS  Google Scholar 

  74. Braga SFP, Martins LC, da Silva EB, Sales Júnior PA, Murta SMF, Romanha AJ, et al. Synthesis and biological evaluation of potential inhibitors of the cysteine proteases cruzain and rhodesain designed by molecular simplification. Bioorg Med Chem. 2017;25:1889–1900.

    Article  CAS  PubMed  Google Scholar 

  75. Pires DEV, Blundell TL, Ascher DB. PkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem 2015;58:4066–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pires DEV, Bundle TL, Ascher DB. pkCSM - pharmacokinetics home page. Melbourne (AU): 2015. biosig.lab.uq.edu.au/pkcsm/ (Accessed Mar 14, 2023).

  77. Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov. 2007;6:881–90.

    Article  CAS  PubMed  Google Scholar 

  78. Curatolo W. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm Sci Technol Today. 1998;1:387–93.

    Article  CAS  Google Scholar 

  79. Wenlock MC, Barton P. In silico physicochemical parameter predictions. Mol Pharm. 2013;10:1224–35.

    Article  CAS  PubMed  Google Scholar 

  80. Tetko IV. Computing chemistry on the web. Drug Discov Today. 2005;10:1497–500.

    Article  PubMed  Google Scholar 

  81. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46:3–26.

    Article  CAS  PubMed  Google Scholar 

  82. Zuniga ES, Early J, Parish T. The future for early-stage tuberculosis drug discovery. Future Microbiol. 2015;10:217–29.

    Article  CAS  PubMed  Google Scholar 

  83. Manjunatha UH, Smith PW. Perspective: challenges and opportunities in TB drug discovery from phenotypic screening. Bioorg Med Chem. 2015;23:5087–97.

    Article  CAS  PubMed  Google Scholar 

  84. Waring MJ. Lipophilicity in drug discovery. Expert Opin Drug Discov. 2010;5:235–48.

    Article  CAS  PubMed  Google Scholar 

  85. Tarcsay Á, Keserú GM. Contributions of molecular properties to drug promiscuity. J Med Chem. 2013;56:1789–95.

    Article  CAS  PubMed  Google Scholar 

  86. Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013;58:388–96.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) under Grant: 2020/13279-7; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) under Grant: 302689/2020-6]; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001 and Pró-Reitoria de Pesquisa (PROPe)–UNESP (Edital PROPe 01/2023).

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  1. School of Pharmaceutical Science, State University of São Paulo (Unesp), Araraquara, 14800-903, Brazil

    Diego Eidy Chiba, Jean Leandro dos Santos & Cauê Benito Scarim

  2. University College London (UCL), 20 Gordon Street, WC1H 0AJ, London, UK

    Guilherme Felipe dos Santos Fernandes

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D.E.C. and C.B.S. designed the review, analyzed the literature data, and performed the analyses, as well as wrote the manuscript, with input from G.F.S.F and J.L.S. All authors reviewed the manuscript.

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Correspondence to Cauê Benito Scarim.

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Chiba, D.E., dos Santos Fernandes, G.F., dos Santos, J.L. et al. Exploring the latest breakthroughs in rhodesain inhibitors for African trypanosomiasis. Med Chem Res 33, 354–369 (2024). https://doi.org/10.1007/s00044-024-03189-0

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