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Drug Res (Stuttg) 2021; 71(06): 335-340
DOI: 10.1055/a-1349-1256
Original Article

In-vitro Anti-trypanosomal and Cytotoxicity Evaluation of 3-methyl-3,4-dihydroquinazolin-2(1H)-one Derivatives

Omobolanle J. Jesumoroti 
1   Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
,
Richard M. Beteck
1   Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
,
Lesetja J. Legoabe
1   Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
› Author Affiliations Funding: The bioassay component of the project was funded by the South African Medical Research Council (MRC) with funds from National Treasury under its Economic Competitiveness and Support Package awarded to Prof. Heinrich Hoppe, Rhodes University. The authors are grateful to North-West University for financial support.
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Correction: In-vitro Anti-trypanosomal and Cytotoxicity Evaluation of 3-methyl-3,4-dihydroquinazolin-2(1H)-one DerivativesDrug Res (Stuttg) 2021; 71(06): e1-e1
DOI: 10.1055/a-1387-6035

Abstract

Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein current treatments suffer from several drawbacks such as toxicity, low activity, and poor pharmacokinetic properties, and hence the need for alternative treatment is apparent. To this effect, we screened in vitro a library of 2-quinazolinone derivatives for antitrypanosomal activity against T.b. brucei and cytotoxicity against HeLa cells. Seven compounds having no overt cytotoxicity against HeLa cells exhibited antitrypanosomal activity in the range of 0.093–45 µM were identified. The activity data suggests that the antitrypanosomal activity of this compound class is amenable to substituents at N1 and C6 positions. Compound 14 having a molecular weight of 238Da, ClogP value of 1 and a total polar surface area of 49 was identified as the most active, exhibiting an IC50 value of 0.093 µM [Graphical Abstract].

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Graphical Abstract.

Key words

sleeping sickness - 2-quinazolinone - hit - antitrypanosomal - cross screening

Supplementary Material



Publication History

Received: 20 November 2020

Accepted: 05 January 2021

Article published online:
03 February 2021

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Brun R, Schumacher R, Schmid C. et al. The phenomenon of treatment failures in human African trypanosomiasis. Trop Med Int Health 2001; 6: 906-914
    CrossrefPubMedGoogle Scholar
  • 2 Barrett M, Burchmore R, Stich A. et al. The trypanosomiases. Lancet 2003; 362: 1469-1480
    CrossrefPubMedGoogle Scholar
  • 3 Beteck R, Legoabe L, Isaacs M. et al. In vitro anti-trypanosomal activities of indanone-based chalcones. Drug Research 2019; 69: 337-341
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 http://www.who.int/gho/neglected_diseases/human_african_trypanosomiasis/en/ Accessed on 06.11.2020
    PubMed
  • 5 Kuepfer I, Hhary E, Allan M. et al. Clinical presentation of T.b. rhodesiense sleeping sickness in second stage patients from Tanzania and Uganda. PLoS Negl Trop Dis 2011; 5: e968
    CrossrefPubMedGoogle Scholar
  • 6 Simarro P, Cecchi G, Franco J. et al. Estimating and mapping the population at risk of sleeping sickness. PLOS Neglected Tropical Diseases 2012; 6: e1859
    CrossrefPubMedGoogle Scholar
  • 7 Franco J, Simarro P, Diarra A. et al. Epidemiology of human African trypanosomiasis. Clin Epidemiol 2014; 6: 257-275
    PubMedGoogle Scholar
  • 8 Kaiser M, Bray M, Cal M. et al. Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrobial Agents and Chemotherapy 2011; 55: 5602-5608
    CrossrefPubMedGoogle Scholar
  • 9 MacLean L, Reiber H, Kennedy P. et al. Stage progression and neurological symptoms in Trypanosoma brucei rhodesience sleeping sickness: Role of the CNS inflammatory response. PLOS Negl Trop Dis 2012; 6: e1857
    CrossrefPubMedGoogle Scholar
  • 10 Kennedy PG. Human African trypanosomiasis of the CNS: Current issues and challenges. J Clin Invest 2004; 113: 496-504
    CrossrefPubMedGoogle Scholar
  • 11 Stich A, Abel P, Krishna S. Human African trypanosomiasis. BMJ 2002; 325: 203-206
    CrossrefPubMedGoogle Scholar
  • 12 Checchi F, Filipe J, Haydon D. et al. Estimates of the duration of the early and late stage of gambiense sleeping sickness. Infect Dis 2008; 8: 1-10
    PubMedGoogle Scholar
  • 13 https://www.who.int/news-room/fact-sheets/detail/trypanosomiasis-human-african-(sleeping-sickness) Accessed on 06:11:2020
    PubMed
  • 14 Berninger M, Schmidt I, Ponte-Sucre A. et al. Novel lead compounds in pre-clinical development against African Sleeping Sickness. Med Chem Commun 2017; 8: 1872-1890
    CrossrefPubMedGoogle Scholar
  • 15 Babokhov P, Sanyaolu AO, Oyibo WA. et al. A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis. Pathog Glob Health 2013; 107: 242-252
    CrossrefPubMedGoogle Scholar
  • 16 Mesu V, Kalonji B, Bardonneau W. et al. Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: A pivotal multicentre, randomised, non-inferiority trial. The Lancet 2018; 391: 144-154
    CrossrefPubMedGoogle Scholar
  • 17 Deeks ED. Fexinidazole: first global approval. Drugs 2019; 79: 215-220
    CrossrefPubMedGoogle Scholar
  • 18 Lindner A, Lejon V, Chappuis F. et al. New WHO guidelines for treatment of gambiense human African trypanosomiasis including fexinidazole: Substantial changes for clinical practice. The Lancet Infectious Diseases 2020; 20: e38-e46
    CrossrefPubMedGoogle Scholar
  • 19 Chappuis F. Oral fexinidazole for human African trypanosomiasis. The Lancet 2018; 391: 100-102
    CrossrefPubMedGoogle Scholar
  • 20 Steverding D. The development of drugs for treatment of sleeping sickness: A historical review. Parasit Vectors 2010; 3: 1-9
    CrossrefPubMedGoogle Scholar
  • 21 Marais L, Petzer A, Petzer JP. et al. The monoamine oxidase inhibition properties of C6‑ and N1‑substituted 3‑methyl‑3,4‑dihydroquinazolin‑2(1H)‑one derivatives. Molecular Diversity 2019; 24: 391-406
    PubMedGoogle Scholar
  • 22 Burri C. Chemotherapy against human African trypanosomiasis; Is there a road to success?. Parasitol 2010; 137: 1987-1994
    CrossrefPubMedGoogle Scholar
  • 23 Babokhov P, Sanyaolu A, Oyibo A. et al. A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis. Pathogens and Global Health 2013; 107: 242-252
    CrossrefPubMedGoogle Scholar
  • 24 Ahmed M, Youns M. Synthesis and Biological evaluation of a novel series of 6, 8-D ibromo-4 (3 H) quinazolinone derivatives as anticancer agents. Archiv der Pharmazie 2013; 346: 610-617
    CrossrefPubMedGoogle Scholar
  • 25 Field M, Horn D, Fairlamb A. et al. Antitrypanosomatid drug discovery: An ongoing challenge and a continuing need. Nat Rev Microbiol 2017; 15: 217-231
    CrossrefPubMedGoogle Scholar
  • 26 Asif M. Chemical characteristics, synthetic methods, and biological potential of quinazoline and quinazolinone derivatives. International Journal of Medicinal Chemistry 2014; DOI: 10.1155/2014/395637.
    CrossrefPubMedGoogle Scholar
  • 27 Noureldin N, Kothayer H, Lashine E. et al. Synthesis, anticonvulsant activity, and SAR study of novel 4-quinazolinone derivatives. Archiv der Pharmazie 2017; 350: 1600332
    CrossrefPubMedGoogle Scholar
  • 28 Mohamed M, Kamel M, Kassem E. et al. Synthesis, biological evaluation and molecular docking of quinazoline-4 (1H)-one derivatives as anti-inflammatory and analgesic agents. Acta Pol Pharm. Drug Res 2011; 68: 665-675
    PubMedGoogle Scholar
  • 29 Zayed M, Hassan M. Synthesis and biological evaluation studies of novel quinazolinone derivatives as antibacterial and anti-inflammatory agents. Saudi Pharmaceutical Journal 2014; 22: 157-162
    CrossrefPubMedGoogle Scholar
  • 30 Gatadi S, Lakshmi T, Nanduri S. 4 (3H)-Quinazolinone derivatives: Promising antibacterial drug leads. European Journal of Medicinal Chemistry 2019; 170: 157-172
    CrossrefPubMedGoogle Scholar
  • 31 Eissa A, El-Metwally A, El-Hashash M. et al. Synthesis and Biological Evaluation of Some New2-propyl-4 (3H)-Quinazolinone Derivatives as Anti-bacteria. Journal of the Korean Chemical Society 2008; 52: 328-337
    CrossrefPubMedGoogle Scholar
  • 32 Zhang J, Liu J, Ma Y. et al. One-pot synthesis and antifungal activity against plant pathogens of quinazolinone derivatives containing an amide moiety. Bioorganic Medicinal Chemistry Letters 2016; 26: 2273-2277
    CrossrefPubMedGoogle Scholar
  • 33 Ahmed M, Youns M. Synthesis and Biological Evaluation of a novel series of 6, 8-D ibromo-4 (3 H) quinazolinone derivatives as anticancer agents. Archiv der Pharmazie 2013; 346: 610-617
    CrossrefPubMedGoogle Scholar
  • 34 Birhan Y, Bekhit A, Hymete A. In vivo antimalarial evaluation of some 2, 3-disubstituted-4 (3 H)-quinazolinone derivatives. BMC Research Notes 2015; 8: 1-6
    CrossrefPubMedGoogle Scholar
  • 35 Wong WA. Weak spot in multiple protozoan parasites. J Structure 2017; 25: 1641-1643
    CrossrefPubMedGoogle Scholar
  • 36 Pandey R, Kumbhar B, Srivastava S. et al. Febrifugine analogues as Leishmania donovani trypanothione reductase inhibitors: Binding energy analysis assisted by molecular docking, ADMET and molecular dynamics simulation. Journal of Biomolecular Structure 2017; 35: 141-158
    CrossrefPubMedGoogle Scholar
  • 37 Scovill J, Blank E, Konnick E. et al. Antitrypanosomal activities of tryptanthrins. Antimicrobial Agents and Chemotherapy 2002; 882-883
    CrossrefPubMedGoogle Scholar
  • 38 Bukachi S, Wandibba S, Nyamongo I. The socio-economic burden of human African trypanosomiasis and the coping strategies of households in the South Western Kenya foci. PLoS Negl Trop Dis 2017; 11: e0006002
    CrossrefPubMedGoogle Scholar
  • 39 Marais L, Petzer A, Petzer JP. et al. The monoamine oxidase inhibition properties of C6-and N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives. Molecular Diversity 2019; 24: 391-406
    CrossrefPubMedGoogle Scholar
  • 40 Devine W, Woodring JL, Swaminathan U. et al. Protozoan parasite growth inhibitors discovered by cross-screening yield potent scaffolds for lead discovery. J Med Chem 2015; 58: 5522-5537
    CrossrefPubMedGoogle Scholar
  • 41 Monti L, Wang S, Oukoloff K. et al. Brain-penetrant, triazolopyrimidine and phenylpyrimidine microtubule-stabilizers as potential leads to treat Human African Trypanosomiasis. ChemMedChem 2018; 13: 1751-1754
    CrossrefPubMedGoogle Scholar
  • 42 Beteck R, Legoabe L, Isaacs M. et al. Anti-Trypanosomal and antimalarial properties of tetralone derivatives and structurally related benzocycloalkanones. Medicina (Kaunas) 2019; 55: 206
    CrossrefPubMedGoogle Scholar
  • 43 Troeberg L, Chen X, Flaherty T. et al. Chalcone, acyl hydrazide, and related amides kill cultured Trypanosoma brucei brucei. Mol Med 2000; 6: 660-669
    CrossrefPubMedGoogle Scholar
  • 44 Veale C, Hoppe H. Screening of the Pathogen Box reveals new starting points for anti-trypanosomal drug discovery. Med Chem Commun 2018; 9: 2037-2044 . DOI: 10.1039/C8MD00319J
    CrossrefPubMedGoogle Scholar
  • 45 Field M, Horn D, Fairlamb A. et al. Antitrypanosomatid drug discovery: an ongoing challenge and a continuing need. Nat Rev Microbiol 2017; 15: 217-231
    CrossrefPubMedGoogle Scholar
  • 46 Beteck R, Isaacs M, Hoppe H. et al. Synthesis, in vitro cytotoxicity and trypanocidal evaluation of novel 1,3,6-substituted non-fluoroquinolones. S Afr J Chem 2018; 71: 188-195 DOI: 10.17159/0379-4350/2018.
    CrossrefPubMedGoogle Scholar
  • 47 Bollini M, Bruno A, Niño M. et al. Synthesis, 2D-QSAR studies and biological evaluation of quinazoline derivatives as potent anti-trypanosoma cruzi agents. J Medicinal Chemistry 2019; 15: 265-276
    CrossrefPubMedGoogle Scholar