Synthesis and biological evaluation of 1,4-benzodiazepin-2-ones with antitrypanosomal activity

doi:10.1016/j.bmc.2011.01.010

Bioorganic & Medicinal Chemistry

Volume 19, Issue 5, 1 March 2011, Pages 1802-1815

https://doi.org/10.1016/j.bmc.2011.01.010 Get rights and content

Abstract

A library of 1,4-benzodiazepines has been synthesized and evaluated against Trypanosoma brucei, a causative parasite of Human African trypanosomiasis. Benzodiazepines possessing a P2- transporter motif were found to have MIC values as low as 0.78 μM.

Graphical abstract

A library of 1,4-benzodiazepines has been synthesized and displays MIC values as low as 0.78 μM against Trypanosoma brucei.

Introduction

Human African Trypanosomiasis (HAT or sleeping sickness) is caused by two subspecies of the parasite T. brucei, namely Trypanosoma brucei rhodesiense (causing East African sleeping sickness) or Trypanosoma brucei gambiense (causing West African sleeping sickness).1, 2, 3, 4, 5 Approximately 50,000 people are reported with this disease annually although over 300,000 are infected but have not been diagnosed or treated.

Current therapies for HAT have been in use for several decades (Fig. 1)1, 2, 3, 4, 5 and, not surprisingly, have many shortcomings viz. high toxicity, prohibitive costs, undesirable routes of administration as well as poor efficacy. Melaminophenyl arsenicals, for example, melarsoprol, and diamidines, including pentamidine, possess amino-purine transporter (termed P2-) recognition motifs to facilitate access to the parasite; loss of this transporter accounts for added complications of drug resistance.⁵

There is an urgent need for more effective treatments for HAT. We recently reported a series of 1,4-benzodiazepin-2,5-diones (Fig. 2) structurally related to the paullone nucleus,⁶ which inter alia were tractable for parallel synthesis, drug discovery and lead generation with antileishmanial and antitrypanosomal activities.⁷ Given the structural similarity of this series with 1,4-benzodiazepine-2-ones⁸ (BZDs), we will describe the synthesis and biological evaluation of a library of the latter and their evaluation as antitrypanosomal agents.

Section snippets

Results and discussion

C3 and C5 substituted BZDs 5–12 were synthesised from readily available 2-amino phenylketones 1–4 in a three step process, often without the need for purification.8, 9 The nitro analogue 14 was synthesised by treatment of 13 with KNO₃ in concentrated H₂SO₄ (Scheme 1, Table 1). N1-Substituted BZD analogues 17–40 were synthesised by treating BZDs 5–16 with sodium hydride and alkylation with the appropriate alkyl or benzyl halide.

All of the synthesised compounds were screened for antitrypanosomal

Conclusion

A library of BZDs has been synthesised and shown to have moderate to good trypanocidal activity. The presence of a guanidine moiety often confers substantial trypanocidal activity to the benzodiazepine although the introduction of such a potential P2- transporter motif is not a guaranteed prerequisite for trypanocidal activity since 67 exhibited poor HAT activity. Although the uptake of guanidine-benzodiazepine derivatives (8, 58, 64) into trypanosomes appeared to occur via the P2- and/or HAPT1

Experimental

NMR, MS and general experimental details are as outlined in previous publications.^8a DCM = dichloromethane.

Acknowledgements

The School of Science, University of Greenwich, and GRE are thanked for a Ph.D. studentship (to RPR) and for providing a CHN analysis apparatus. Swansea University (EPSRC Mass Spectrometry Service Centre) are gratefully acknowledged for HRMS measurements.

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Synthesis and biological evaluation of 1,4-benzodiazepin-2-ones with antitrypanosomal activity

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

Experimental

Acknowledgements

Adv. Parasitol.

Lancet

J. Neuroimmunol.

Biochem. Pharmacol.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Tetrahedron

Future Med. Chem.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

J. Org. Chem.

J. Org. Chem.

Bioorg. Med. Chem. Lett.

Tetrahedron

Tetrahedron Lett.