Synthesis and properties of new substituted 1,2,4-triazoles: potential antitumor agents

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Abstract

Cycloaddition of the reactive intermediates 4 with 1-(cyanomethyl)benzotriazole (5) and its N-2 isomer 9 furnished, after spontaneous rearrangements, the 1,2,4-triazole derivatives 8 and 10. Analogously, reaction of 4 with ethyl cyanoacetate lead to the 1,3,5-trisubstituted 1,2,4-triazoles 12, which gave on treatment with hydrazine the corresponding hydrazides 13. Treatment of 13d with galactose or phenyl isothiocayanate gave the 1-d-galactose-acylhydrazone 14 and the 1,2,4-triazole derivative 15, respectively. Compounds 8c; 10b,c; 13a,c and 14 were selected for the antitumor screening, whereby 8c, 13a, and 13c showed remarkable activity against leukemia, ovarian, renal and lung cancers (8c with Gl50 of 0.70 μM, 0.07 μM against leukemia (CCRF-CEM and RPMI-8226), 0.02 μM against ovarian (OVCAR-3) and 0.60 μM against renal (CARKI-1) and lung cancers, respectively).

The title compounds were prepared by cycloaddition reactions. Six of the new compounds were screened against a variety of tumor cell lines.

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Introduction

The 1H-benzotriazol compounds possess important pharmacological activities such as anti-inflammatory,1 antiviral,2 antifungal,3 antineoplastic4 and antidepressant5 effects. Such compounds are Metronidazole and analogues used as drugs for the treatment of trichomoniasis and amoebicis, as well as Fluconazole and Miconazole, which are useful antifungal agents.6, 7, 8, 9 Recently, Moon et al.10 reported the synthesis and biological activity of the new benzotriazolium Cephalosporins 1, which exhibited remarkable activity against Pseudomonas aeruginosa and other bacteria, depending on the group attached to the benzotriazole backbone. Furthermore, some 2-alkyl-5-aminobenzotriazoles 211, 12 showed interesting antimicrobial activities against Gram-positive, Gram-negative bacteria and Candida albicans. More examples, such as 1-and 2-[3-(1-piperazinyl)propyl]-benzotriazoles showed in vitro remarkable antiserotonergic, antiadrenergic and antihistaminic activity, as well as in vivo analgesic action.13 In addition, the benzotriazoles 5 and 9 are themself active against Leishmania.14 In respect with the potential activity of these molecules and the structurally related benzo-fused-imidazoles (rifaximin,15 as antineoplastic and anticancer agents), we focused our interest in designing a novel type of trisubstituted 1,2,4-triazoles bearing methyl benzotriazole residues in the 2-positions, starting with 5 and its N-2 isomer 9, to give compounds 8 and 10, respectively. These compounds can be considered as alkylating agents interfering with the metabolism, in vivo, as demonstrated in malignant diseases such as haematological and solid malignancies,16 for which Dacarbazine®17 is a good example. In the same respect, some substituted hydrazine compounds, like Procarbazine®,19 was found to possess antineolpastic activity particularly in the treatment of Hodgkins‘ disease.18 These biological data prompted us to synthesize new trisubstituted-1,2,4-triazoles bearing an acetohydrazide functionality which was further modified by a sugar or a 2-(1,2,4-triazolylthione) derivative. Recently, Katritzky et al.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and other laboratories28, 29, 30, 31, 32 reported the synthesis of numerous examples of benzotriazole bearing diverse heterocycles.

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Results and Discussion

Recently, the short-lived reactive intermediates 1-(chloroalkyl)-1-aza-2-azoniaallene salts Scheme 1, Scheme 2 were used by Jochims and co-workers32 in the synthesis of various 1,2,4-triazole compounds via cycloaddition reaction with various unsaturated precursors in the presence of SbCl5. In our recent work, these cations have been utilized in the synthesis of new type of 1,2,4-triazole compounds such as C-ribonucleosides,33, 34 acyclic C-nucleosides35 and homo-C-analogues,35 C-nucleosides of d

Preparation of 1,3-5-trisubstituted 1,2,4-triazoles bearing a 3-(benzotriazolylmethylene) or 3-(ethoxycarbonylmethyl) group (8, 10 and 12)

A solution of SbCl5 (1.5 g, 4.0 mmol) in CH2Cl2 (10 mL) was added dropwise to a stirred, cold solution (−60 °C) of 332 (4.0 mmol) in dry CH2Cl2 (30 mL) followed directly by the addition of the nitriles 5, 9 or 11 (3.0 mmol). After stirring for 2 h at −60 °C, 1 h at 0 °C, and 10 min at 23 °C, pentane (60 mL) was added and the residue was filtered and dissolved in CH3CN (60 mL). The solution was treated after cooling to 0 °C with an aqueous solutions of NaHCO3 (3.36 g, 40 mmol) in H2O (40 mL) and NH3

Acknowledgements

We thank Dr. V. L. Narayanan and Dr. E. Sauville (Drugs Synthesis and Chemistry Branch, National Cancer Institute (NCI), Maryland, USA) for the antitumor screening. The hospitality and laboratory facilities of Professor U. Beifuß of Chemistry Department, University of Göttingen, Germany for Y. Al-Soud is highly acknowledged. We thank also Professor W. Pfleiderer of Konstanz University for helpful discussion.

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