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Synthesis and antitubercular activity of imidazo[2,1-b]thiazoles

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Abstract

A number of selected imidazo[2,1-b]thiazoles entered the screening at the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) and one of these compounds, 2-chloro-6-phenylimidazo[2,1-b]thiazole, showed antitubercular activity. On this basis we planned the synthesis of new analogues bearing a substituted ring at the 6 position. For one compound only (2-chloro-6-p-chlorophenylimidazo[2,1-b]thiazole) the 5-nitroso derivative was also prepared. The antitubercular activity of these compounds was compared with the known analogues lacking the chlorine at the 2 position. 5-Nitroso-6-p-chlorophenylimidazo[2,1-b]thiazole showed potent antitubercular activity.

Introduction

Despite the ready availability of effective treatments, tuberculosis remains a major public health threat worldwide. The emergence of drug resistant strains of Mycobacterium tuberculosis, particularly multiple drug resistant strains [1], [2], [3], [4] has complicated treatment protocols and raises the concern that tuberculosis may once again become an incurable disease. For this reason it is critical to discover new drugs acting with a mechanism different from those of presently used antitubercular drugs. The numerous reviews recently reported in the literature are a proof of the renewed interest towards this pathology [5], [6], [7], [8], [9], [10], [11].

A number of selected imidazo[2,1-b]thiazoles entered the screening at the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) and one of these compounds, 2-chloro-6-phenylimidazo[2,1-b]thiazole (3a) (figure 1) showed antitubercular activity. On this basis we planned the synthesis of new analogues bearing a substituted ring at the 6 position. For one compound only (3c), the 5-nitroso derivative was also prepared (4c). The antitubercular activity of these compounds was compared with the known analogues lacking the chlorine at the 2 position.

Section snippets

Chemistry

The 2-chloroimidazothiazoles 3 were prepared by the reaction of 2-amino-5-chlorothiazole (1a) with the appropriate bromoacetophenones 2. Only the 6-p-aminophenyl derivative 3n was obtained from 2-chloro-6-p-nitrophenylimidazo[2,1-b]thiazole (3m) by reduction with iron in acetic acid. The 5-nitroso derivative 4c was prepared by treating 2-chloro-6-p-chlorophenylimidazo[2,1-b]thiazole (3c) with sodium nitrite in acetic acid. All the new 2-chloro derivatives 3 and 4 are reported in Table I, Table

Biological results

Seven of the 14 compounds showed inhibitory activity >0% at the screening concentration of 6.25 μg mL−1. The antitubercular profile of these compounds is reported in table III, in comparison with the analogues lacking the chlorine at the 2 position. It is interesting to note that the 2-chloro derivatives showed moderate to good increases in activity in almost every case with only two exceptions (3k vs. 5k and 4c vs. 6c). Compound 6c, one of the exceptions, showed significant antitubercular

Discussion

For this series of imidazo[2,1-b]thiazoles and the corresponding 2-chloro derivatives, several compounds demonstrated significant antitubercular activity. For five out of the seven pairs (2-H vs. 2-Cl substituted), the 2-chloro analogue showed modest to good increases in activity versus its 2-H counterpart. There may be several explanations for this increased activity including greater hydrophobicity, an electron withdrawing effect on the imidazo[2,1-b]thiazole ring system, or a specific

Chemistry

The melting points are uncorrected. Analyses (C, H, N) were within ±0.4% of the theoretical values. Bakerflex plates (silica gel IB2-F) were used for TLC and Kieselgel 60 (Merck) for column chromatography: the eluent was petroleum ether–acetone in various proportions. The IR spectra were recorded in Nujol on a Nicolet Avatar 320 ESP; νmax is expressed in cm−1 (table I). The 1H-NMR spectra were recorded in (CD3)2SO on a Varian Gemini (300 MHz) spectrometer; the chemical shift (referenced to

Acknowledgements

Antimycobacterial data were provided by TAACF through a research and development contract with the US National Institute of Allergy and Infectious Diseases.

References (22)

  • B Heym et al.

    Int. J. Antimicrob. Agents

    (1997)
  • C.E Barry

    Biochem. Pharmacol.

    (1997)
  • A Andreani et al.

    Eur. J. Med. Chem.

    (1991)
  • A Andreani et al.

    Eur. J. Med. Chem.

    (1992)
  • L.A Basso et al.

    Adv. Exp. Med. Biol.

    (1998)
  • A Telenti et al.

    Drugs

    (2000)
  • C Loiez-Durocher et al.

    Ann. Biol. Clin.

    (2000)
  • K Duncan

    J. Pharm. Pharmacol.

    (1997)
  • K Duncan

    Expert Opin. Ther. Pat.

    (1997)
  • C Grassi

    Expert Opin. Invest. Drugs

    (1997)
  • K Duncan

    Expert Opin. Ther. Pat.

    (1998)
  • Cited by (0)

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