Novel Bisbenzimidazoles With Antileishmanial Effectiveness

[en] A small library of 2,2'-[(alpha,omega-alkanediylbis(oxyphenylene)]bis-1H-benzimidazoles has been prepared and screened in vitro against Pneumocystis carinii, Trypanosoma brucei rhodesiense, and Leishmania donovani. Among the six tested compounds two derivatives emerged as promising hits characterized by IC(50) values lower than that determined for pentamidine against L. donovani.

Disciplines :

Chemistry

Author, co-author :

Mayence, A.

Pietka, A.

Collins, M.S.

Cushion, M.T.

Tekwani, B.L.

Huang, T.L.

Vanden Eynde, Jean-Jacques ; Université de Mons > Faculté des Sciences > Synthèse et spectrométrie de masse organiques

Language :

English

Title :

Novel Bisbenzimidazoles With Antileishmanial Effectiveness

Publication date :

15 April 2008

Journal title :

Bioorganic and Medicinal Chemistry Letters

ISSN :

0960-894X

Publisher :

Elsevier, United Kingdom

Volume :

Issue :

Pages :

2658 - 2661

Peer reviewed :

Peer Reviewed verified by ORBi

Research unit :

S836 - Synthèse et spectrométrie de masse organiques

Available on ORBi UMONS :

since 10 June 2010

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General procedure. A mixture of an hydroxybenzaldehyde (5.12 g; 42 mmol), a dibromoalkane (20 mmol), and potassium carbonate (2.76 g; 20 mmol) in ethanol (10 ml) was heated under reflux for 8 h. After cooling, the precipitate was filtered and successively washed with water, ethanol, and ether. The bisbenzaldehyde was pure enough to be engaged in the second step. A mixture of the bisbenzaldehyde (3 mmol), sodium pyrosulfite (0.57 g; 3 mmol), ortho-phenylenediamine (6 mmol), and water (3 ml) in ethanol (9 ml) was irradiated in a microwave oven (Biotage) for 15 min at 140 °C. After cooling the precipitate was filtered and thoroughly washed with water, ethanol, and ether. 4,4′-[1,5-Pentanediyl(oxy)]bisbenzaldéhyde: IR (KBr, cm-1): 2945, 1692, 1604, 1576, 1510. 1H NMR (DMSO-d6, ppm): 9.9 (s, 2H, CHO); 7.9 (d, 4H, J = 8 Hz, C6H4:H2,H6); 7.1 (d, 4H, J = 8 Hz, C6H4:H3,H5); 4.2 (t, 4H, J = 6 Hz, O-CH2-CH2-CH2); 1.8 (m, 4H, J = 6 Hz, O-CH2-CH2-CH2); 1.5 (m, 2H, J = 6 Hz, O-CH2-CH2-CH2). Mp (°C): 90.7-94.5 °C. Yield: 90%. 2,2′-[1,5-Pentanediylbis(oxy-1,4-phenylène)]bis-1H-benzimidazole (8): IR (KBr, cm-1): 3623-2400 (N-H bz), 1762, 1611,1500, 1254. 1H NMR (DMSO-d6, ppm): 8.1 (d, 4H, J = 9 Hz, C6H4:H2′,H6′); 7.6 (AA′BB′, 4H, benz: H4,H7); 7.2 (AA′BB′, 4H, benz: H5,H6); 7.1 (d, 4H, J = 9 Hz, C6H4:H3′,H5′); 4.1 (t, 4H, J = 6 Hz, O-CH2-CH2-CH2); 1.8 (m.large, 4H, O-CH2-CH2-CH2); 1.6 (m.large, 2H, O-CH2-CH2-CH2). HRMS (ESI-ToF) MH+C31H29N4O2: MW experimental: m/z 489.2275; MW calculated: m/z 489.2291. Mp (°C): >300 °C. Yield: 94%.
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Reported values are means of 2-4 determinations.
Pneumocystis carinii were obtained from chronically immunocompressed Long Evans and Brown Norway rats. Typically, infected rat lungs yielded up to 2 × 1010 organism nuclei with the vast majority (about 95%) of the life cycle forms present as trophic forms with the remainder (about 5%) being composed of cysts. P. carinii preparations were evaluated for microbial contamination, ATP content, karyotype, and host cell content prior to use in the ATP assay. See,. Cushion M.T., Walzer P.D., Collins M.S., Rebholz S., Vanden Eynde J.J., Mayence A., and Huang T.L. Antimicrob. Agents Chemother. 48 (2004) 4209
Assays were performed in 96-well microtiter plates, each well containing 100 μl of culture medium with 8 × 103 bloodstream-form trypomastigotes of the strain Trypanosoma brucei rhodesiense STIB 900, which is known to be susceptible to all currently drugs. After 3 days of incubation, parasite growth is assessed fluorimetrically after the addition of resazurin. Fluorescence is measured after 24 h at 37 °C. See, http://www.who.int/tdr/grants/workplans/pdf/.
The compounds were dissolved in DMSO at the concentration of 2 mg ml-1 and diluted with the culture medium to obtain the desired final concentrations. The solutions were added, in a 96-well microplate assay, to the L. donovani promastigotes culture (2 × 106 cells/ml). Controls with corresponding dilutions of DMSO indicated that growth of the parasite was not altered under those experimental conditions. The plates were incubated at 26 °C for 72 h and growth of Leishmania promastigotes was determined by Alamar blue assay. See,. Mikus J., and Steverding D. Parasitol. Int. 48 (2000) 265
The compounds were tested on Vero cells (monkey kidney fibroblast) by a Neutral Red assay. See,. Babich H., and Borenfreund E. Appl. Environ. Microbiol. 57 (1991) 2101