Novel Bisbenzamidines as Potential Drug Candidates for the Treatment of Pneumocystis Carinii Pneumonia

[en] A series of pentamidine congeners has been synthesized and screened for their in vitro activity against Pneumocystis carinii. Among the tested compounds, bisbenzamidines linked by a flexible pentanediamide or hexanediamide chain (7 and 9) emerged as exceptionally potent agents that were more effective and less toxic than pentamidine in the assays described in this study.

Disciplines :

Chemistry

Author, co-author :

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

Mayence, A.

Huang, T.L.

Collins, M.S.

Rebholz, S.

Walzer, P.D.

Cushion, M.T.

Language :

English

Title :

Novel Bisbenzamidines as Potential Drug Candidates for the Treatment of Pneumocystis Carinii Pneumonia

Publication date :

06 September 2004

Journal title :

Bioorganic and Medicinal Chemistry Letters

ISSN :

0960-894X

Publisher :

Elsevier, United Kingdom

Volume :

Issue :

Pages :

4545 - 4548

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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Bibliography

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N,N′-Bis[4-(aminoiminomethyl)phenyl] hexane-1,6-dicarboxamide, dihydrochloride salt, (9) was obtained by heating under reflux for 1 h a mixture of 4-aminobenzamidine monohydrochloride (20, 0.86 g, 5 mmol), adipoyl dichloride (0.37 mL, 2.5 mmol), and pyridine (4 mL, 50 mmol) in N,N-dimethyl formamide (20 mL). The precipitate was filtered and thoroughly washed successively with water and acetone. Yield: 40%. Mp: 294-295°C (decomp.). 1H NMR (DMSO-d6): 10.6 (s, 2H); 9.2 (s, 4H); 9.0 (s, 4H); 7.8 (dd, 8H); 2.4 (br m, 4H); 1.7 (br m, 4H) ppm. IR: 3096, 1671, 1611, 1523, 1483, 1256 cm-1. Anal. Calcd for C 20 H24N6O2·2HCl (452.15): C, 52.98; H, 5.78; N, 18.54. Found: C, 52.91; H, 5.65; N, 18.31. (M-H-W Laboratories, Phoenix, AZ)
Bis(4-aminoiminomethylphenyl) benzene-1,4-dicarboxylate, dihydrochloride salt, (10) was obtained by heating under reflux for 8 h a mixture of 4-hydroxybenzamidine hydrochloride (19, 1.72 g, 10 mmol), terephthaloyl chloride (18, 1.01 g, 5 mmol), and pyridine (1.6 mL, 20 mmol) in dioxane (50 mL). The precipitate was filtered and washed successively with water and ethanol. Yield: 45%. Mp: 273-277°C. 1H NMR (DMSO-d6): 9.5 (s, 4 H); 9.3 (s, 4 H); 8.4 (s, 4 H); 8.0 (d, 4H, J=8 Hz); 7.6 (d, 4H, J=8 Hz) ppm. IR: 3600-2400 (br), 3030, 1743, 1721, 1668, 1607, 1487, 1176, 1071 cm-1. Anal. Calcd for C22H18N4O4· 2HCl (475.32): C, 55.59; H, 4.24; N, 11.79. Found: C, 55.34; H, 4.42; N, 11.53. (M-H-W Laboratories, Phoenix, AZ)
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Pneumocystis carinii were obtained from chronically immunosuppressed Long Evans and Brown Norway rats housed under conventional conditions at the Cincinnati VA medical Center (VAMC) or from CD rats (Charles River Laboratories, Hollister, CA) inoculated intratracheally with P. carinii and maintained under barrier conditions at the University of Cincinnati Laboratory Animal Medicine Unit (Cincinnati, OH). P. carinii were extracted and purified from the lungs of rats after 8-12 weeks of immunosuppression, enumerated, cryopreserved and stored in liquid nitrogen. Typically, infected rat lungs yield up to 2 × 10 10 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. Each concentration of every compound is assayed in triplicate wells and the results expressed as the average relative light units. Triplicate runs for each compound concentration are run using different organism isolation batches
Walzer P.D., Ashbaugh A., Collins M., Cushion M.T. Antimicrob. Agents Chemother. 45:2001;3234