Elsevier

Bioorganic & Medicinal Chemistry

Volume 16, Issue 21, 1 November 2008, Pages 9546-9553
Bioorganic & Medicinal Chemistry

Synthesis and antitubercular activity of ferrocenyl diaminoalcohols and diamines

https://doi.org/10.1016/j.bmc.2008.09.030Get rights and content

Abstract

A total of 21 ferrocenyl and benzyl diaminoalcohols and diamines were synthesized and evaluated against Mycobacterium tuberculosis H37Rv. Interestingly, ferrocenyl diamines exhibit better activities than ferrocenyl diaminoalcohols.

Graphical abstract

Ferrocenyl and benzyl diaminoalcohols and diamines were synthesized and evaluated against Mycobacterium tuberculosis H37Rv.

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Introduction

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, still remains the leading cause of worldwide death among infectious diseases.1 Two billion people are infected with latent TB and are at risk for developing the active disease, and annually, approximately eight million of these infected people develop active TB more. TB kills nearly two million people over the world every year. Even though improved methods of prevention, detection, diagnosis and treatment have greatly reduced the number of people who contract the disease and unfortunately die from it, the emergence of multidrug-resistant (MDR) strains and the global human immunodeficiency virus (HIV) pandemic have amplified the incidence of TB. Currently, TB chemotherapy is composed by a cocktail of the first-line drugs, isoniazid (INH), rifampin (RIF), pyrazinamide (PZA) and ethambutol (EMB), given for six months. The increasing problem of MDR-TB has focused attention on developing new drugs that are not only active against drug resistant TB, but also shorten the lengthy therapy. Consequently, there is urgent need and significant interest in developing new TB drugs.2, 3, 4

Despite its modest efficiency against M. tuberculosis, ethambutol (EMB) (Fig. 1) is still a first-line drug used against TB in part because its very low toxicity and its chemical simplicity.5 Studies concerning the structural modification of EMB have focused on the diamine or diaminoalcohol analogues with enhanced efficiency compared to EMB.6, 7, 8, 9, 10, 11 Among diamines, compounds SQ 109, SQ 775 and SQ 786 (Fig. 1) exhibit enhanced activities in comparison to EMB.7, 8

The use of metal complexes capable of enhancing the activity of biological compounds has become a relevant strategy of research in both communities of organometallic chemists and biologists.12 Ferroquine (SSR97193), resulting from the incorporation of a metallocenic moiety into chloroquine, proved to be a new effective drug with a powerful antimalarial activity in vitro and in vivo.13, 14 In particular, the high lipophilicity and electrochemical behaviour (redox potential of the ferrocene/ferrocinium couple, E0 = +0.400V vs saturated calomel electrode) of ferrocene render it very attractive for designing antimalarial drugs.15 This strategy, which consists of incorporate a ferrocenyl moiety into a ‘standard’ drug offers new possibilities in therapeutic applications and reversal of drug resistances.16, 17, 18

In a preliminary communication, we reported the synthesis of ferrocenyl diamines and the evaluation of their antitubercular activity.19 Herein we describe the full details of our investigations. A strategy based on the modification of ethambutol is presented here: insertion of ferrocene between the two amine functions, insertion of ferrocene between alcohol and amine, replacement of alcohol by ferrocene: synthesis of diamines (Fig. 2).

Section snippets

Synthesis of ferrocenyl amino alcohols

The racemic ferrocenyl diamino alcohols 46 were synthesized according to the reported procedure (Scheme 1). Racemic 2-N,N-dimethylaminomethylferrocenecarbox-aldehyde 1 was first reacted with acetic anhydride to give 2 in 89% yield. The saponification of ester 2 was carried out in the presence of sodium hydroxide in methanol providing 3 in 89% yield after work-up.20

The ferrocenyl amino alcohols were then obtained in two steps. First, the hydroxy aldehyde 3 was reacted in CH2Cl2 with

Conclusion

In conclusion we have synthesized and evaluated a series of ferrocenyl diamines and diaminoalcohols as inhibitors of M. tuberculosis H37Rv. This study has revealed that the presence of a ferrocenyl moiety in the structure of diamines is essential for a good antimycobacterial activity. The best activity was obtained for ferrocenyl diamines having only a two or three carbon atoms spacer between the two amino functions. Other studies are currently underway in our laboratories to better understand

General methods

The 1H and 13C NMR spectra were recorded on a Bruker AC300 spectrometer using tetramethylsilane (TMS) as the internal standard and CDCl3, MeOH-d4 or DMSO-d6 as the solvents. MS-MALDI TOF spectra were obtained using a Vision 2000 time-of-flight instrument (Finnigan MAT, Bremen, Germany) equipped with a nitrogen laser operating at wavelength of 337 nm. The matrix used was trihydroxyacetophenone (thap). Thin layer chromatography (TLC) was carried out on aluminium-baked Macherey-Nagel silica gel 60.

Acknowledgements

The authors are thankful to the ‘Ministère des Affaires Etrangères’, the ‘Centre National de la Recherche Scientifique’ and the ‘Ambassade de France à Madagascar’ for financial support and Francine Agbossou-Niedercorn for helpful discussions.

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