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Synthesis and antiproliferative activity of 3-aryl-2-(1H-benzotriazol-1-yl)acrylonitriles. Part III

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Abstract

A new series of 30 3-aryl-2-(1H-benzotriazol-1-yl)acrylonitriles were synthesized and tested for biological activity as part of our research in the antimicrobial and antitumor fields. In particular, title compounds were evaluated in vitro against representative strains of Gram-positive and Gram-negative bacteria (S. aureus, Salmonella spp), mycobacteria (M. fortuitum, M. smegmatis ATCC 19420 and M. tuberculosis ATCC 27294), yeast and mould (C. albicans ATCC 10231 and A. fumigatus). Furthermore, their antiretroviral activity against HIV-1 was determined in MT-4 cells together with cytotoxicity. In these assays title compounds and 47 additional derivatives described previously (P. Sanna, A. Carta, M.E. Rahbar Nikookar, Eur. J. Med. Chem. 35 (2000) 535–543; P. Sanna, A. Carta, L. Gherardini, M.E. Rahbar Nikookar, Farmaco 57 (2002) 79–87) were tested for their capability to prevent MT-4 cell growth. All compounds resulted devoid of antibacterial, antifungal and anti-HIV-1 activity. In anti-mycobacterial assays several compounds resulted active (MIC50=6.0–70 μM) against M. tuberculosis. However, since they showed cytotoxicity against MT-4 cells at lower concentrations (CC50=0.05–25 μM), their anti-mycobacterial activity was not selective. For this reason, the most cytotoxic compounds were also evaluated for antiproliferative activity against a panel of human cell lines derived from both hematological and solid tumors. Compound 34 resulted the most potent compound against the above human tumor-derived cell lines.

Introduction

Recently, we reported the synthesis and the anti-mycobacterial activity of over 50 3-substituted-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles, prop-2-enamides and propenoic acids [1], [2]. Several compounds showed an interesting activity in a preliminary screening against M. tuberculosis within an international program with the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF). As part of our antimicrobial and antitumor research programs [3], [4], [5], [6] we synthesized a new series of 30 3-aryl-2-(1H-benzotriazol-1-yl)acrylonitriles and evaluated their biological activity in order to extend previous SAR studies. Substituents at position 4 in the phenyl moiety (I, OCH3 and CN) were chosen with the aim to complete the previous series. Furthermore, the substituents typical of previous derivatives (F, Cl, Br, CF3 and NO2), along with new substituents such as I, OCH3 and CN, were introduced either at positions 2 or 3, whereas F, Cl and CF3 were contemporaneously introduced at two different positions. Both the previously synthesized [1], [2] and the new derivatives were evaluated for cytotoxicity against MT-4 cells, carried out in parallel with anti-HIV-1 activity, in order to determine whether the compounds were endowed with selective antimicrobial/antiviral activity.

Due to the relevant cytotoxicity shown by many derivatives, we studied in detail their potential antiproliferative activity against a panel of cell lines derived from hematological and solid tumors.

Section snippets

Chemistry

The synthesis of compounds 417, 4873, and 7578 has been previously reported [1], [2] and their chemical structures are shown in Fig. 1 and Table 1. The synthesis of the new series of 3-aryl-2-(1H-benzotriazol-1-yl)acrylonitriles 1847, depicted in Fig. 1 and Table 1, was accomplished as previously reported [1], [2] by straightforward condensation of the key intermediate 2-(benzotriazol-1-yl)acetonitrile (1) [1] with the appropriate commercially available aldehydes, or prepared as reported in

Microbiology

The new compounds were evaluated in vitro against representative strains of Gram-positive and Gram-negative bacteria (S. aureus, Salmonella spp), various mycobacterial strains (M. fortuitum, M. smegmatis ATCC 19420 and M. tuberculosis ATCC 27294), and yeast and mould strain (C. albicans ATCC 10231 and A. fumigatus). Streptomycin, Ciprofloxacin, Ofloxacin, Isoniazid, Rifampicin and Miconazole were used as reference drugs. Title compounds were also evaluated for anti-HIV-1 activity in MT-4 cells.

Results and discussion

The new compounds 1847 reported in Fig. 1 and Table 1 were evaluated against representative strains of Gram-positive, Gram-negative bacteria, mycobacteria, yeasts and moulds. Because of an ongoing screening program carried out to identify new antiretroviral compounds, the new derivatives were also evaluated for anti-HIV-1 activity in MT-4 cells. However, none of these compounds showed antibacterial and antifungal activity or the capability to protect the HIV-1-infected cells from the

Conclusion

Acrylonitrile derivatives are endowed with potent antiproliferative activity, whereas, as far as the anti-mycobacterial activity is concerned, it does not appear to be selective. Since compound 34 resulted active against both hematological and solid human tumors, it might represent a new lead compound which could be further optimized.

Experimental

Melting points were determined by a Kofler hot stage or Digital Electrothermal apparatus, and are uncorrected. Infrared spectra are for Nujol mulls and were recorded using a Perkin–Elmer 781 spectrophotometer. UV spectra are qualitative and were recorded in nm for solutions in EtOH with a Perkin–Elmer Lambda 5 spectrophotometer. The abbreviations used are as follows: sh for shoulder, infl for inflection. 1H-NMR spectra were recorded on a Varian XL-200 (200 MHz) instrument, using TMS as internal

Acknowledgements

The authors thank Prof. Giuseppe Paglietti for fruitful discussion and the review of the manuscript.

References (10)

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    Eur. J. Med. Chem.

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    Farmaco

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    Farmaco

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  • A. Carta et al.

    Farmaco

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    Farmaco

    (2002)
There are more references available in the full text version of this article.

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1

Unfortunately Professor Paolo Sanna died on the 28th March, 2002 during preparation of this paper.

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