Anti- Pneumocystis Activities of Aromatic Diamidoxime Prodrugs

Abstract

Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

Dicationic DNA Minor Groove Binders as Antimicrobial Agents

“…administration, several diamidinocarbazoles were very effective against P. carinii pneumonia in an animal model. The dicationic carbazoles were inactive when given orally; however, they were considered good candidates for amidoxime pro-drugs [44,106,108]. Unexpectedly, as can be noted from Tab.…”

“…The in vivo conversion of pentamidine dioxime to pentamidine has been noted [107]. However, on oral administration of pentamidine dioxime in the immunosuppressed rat model for PCP it was only moderately effective [106]. We have reported that the bisamidoxime and bis-O-methylamidoxime of furamidine (17) were quite effective anti-PCP agents in the rat model on both oral and intravenous administration (see Tab. 16.13) [108].…”

“…While numerous reports exist on the pro-drug modification of many functional groups [99][100][101][102][103], very few reports have appeared describing pro-drug approaches for aryl amidines [104,105]. It has been reported by our laboratories and others that amidoximes can be used as orally active pro-drugs for the corresponding diamidines [44,[106][107][108]. The amidoximes are true pro-drugs in that they are inactive in vitro against microorganisms and must be converted to amidines to exert an antimicrobial effect.…”

“…The amidoximes are true pro-drugs in that they are inactive in vitro against microorganisms and must be converted to amidines to exert an antimicrobial effect. Aromatic amidoximes have pK a values in the range of 2-6 and are readily absorbed from the gastrointestinal tract and then metabolically converted to the active amidines [106][107][108]. The conversion of amidoxime-type pro-drugs to amidines is discussed in more detail in the following section on furamidines.…”

“…Therefore, for these types of compounds to have the greatest public health impact it is essential that they are effective on oral administration. Consequently, we have undertaken a parallel study of using pro-drug approaches as a means to effectively deliver these dicationic molecules on oral administration [106,108,111]. Specifically, we have demonstrated that amidoxime and phenylcarbamate derivatives of furamidine are effective when given by oral administration in a rat model for Pneumocystis carinii pneumonia [108,111] and amidoximes are effective in a mouse model for trypanosomiasis (J. E. Hall, unpublished results).…”