Trypanocidal Activity of Conformationally Restricted Pentamidine Congeners

Abstract

A series of conformationally restricted congeners of pentamidine in which the flexible pentyl bridge of pentamidine was replaced by trans-1,2-bismethylenecyclopropyl, phenyl, pyridinyl, piperazinyl, homopiperazinyl, and piperidinyl groups were synthesized. The compounds were evaluated for trypanocidal activity in vitro and in vivo against one drug-sensitive and three drug-resistant trypanosome isolates. The DNA binding affinity of the compounds was also studied using calf thymus DNA and poly(dA-dT). The nature of the linker influenced the DNA binding affinity as well as the trypanocidal activity of the compounds. trans-1,2-Bis(4-amidinophenoxymethylene)cyclopropane (1) was over 25-fold more potent than pentamidine against the drug-resistant isolate KETRI 243As-10-3, albeit with comparable DNA binding affinity. N,N'-Bis(4-amidinophenyl)homopiperazine (8) was the most potent trypanocide in vitro against all four trypanosome isolates studied, but N,N'-bis(4-amidinophenyl)piperazine (6) was the most effective agent in vivo against both drug-sensitive and drug-resistant trypanosomes.

Bisguanidine, Bis(2-aminoimidazoline), and Polyamine Derivatives as Potent and Selective Chemotherapeutic Agents against Trypanosoma brucei rhodesiense. Synthesis and in Vitro Evaluation

“…[48][49][50] In a recent article, Donkor et al studied the trypanocidal activity of a series of conformationally restricted congeners of pentamidine. 15 Although a direct correlation between the DNA binding affinity and the trypanocidal activity was not observed, the authors concluded that compounds with strong DNA affinity generally showed good trypanocidal activity in that series. In particular, N,N'-bis(4-amidinophenyl)piperazine (Figure 1) and N,N'-bis(4-imidazolinophenyl)piperazine were the most potent trypanocides and also the strongest DNA binders in this series.…”

“…[26][27][28] Moreover, some of the alkanediguanidine [1, 8-octanediguanidine (1b), 29 1,12-dodecanediguanidine (1d), 6,30,31 bis(guanidinopropyl)amine (6a) 32 trypanosomal agent in vivo. 15 Hence, in the search for new HAT chemotherapy, we decided to carry out an in vitro screening against the parasite T. brucei rhodesiense of a total of 62 compounds (Tables 1-5) taken from our in-house library and structurally related to the trypanocidal agents synthalin (1,10-decanediguanidine) and 4,4'-diguanidinodiphenylmethane (31b), and the polyamine N 1 -(3-amino-propyl)-propane-1,3-diamine respectively. We also describe here the original synthesis of 21 molecules which had not been previously reported.…”

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

“…1A). We have been interested (12,24,25,31,34) in determining the effect of restricting the conformational flexibility of pentamidine congeners on their anti-P. carinii and antiparasitic activity. Based on these recent studies, we identified 4,4Ј-(1,4-piperazinediyl)bisbenzenecarboximidamide (compound 19, Table 1) as a promising lead compound.…”

Novel pentamidine derivatives: Synthesis, anti-tumor properties and polynucleotide-binding activities

“…Amidinophenyl substituted benzo and pyridine dicarboxamides were prepared and tested for their antimicrobial activity or cytotoxic activity against several human cancer cell lines [12][13][14][15]. Although they showed moderate activity against P. carinii and Plasmodium falciparum, their poor antitumor activity was poor [6,14,16].…”