Synthesis and Evaluation of Dinitroanilines for Treatment of Cryptosporidiosis

Abstract

The efficacy of a series of dinitroaniline herbicide derivatives for the treatment of Cryptosporidium parvum infections has been studied. The lead compounds oryzalin (compound 1) and trifluralin (compound 2) have low water solubility (<3 ppm) which was alleged to be a major contributor to their poor pharmacokinetic availability. Derivatives of compounds 1 and 2 were synthesized. In these derivatives the functionality at the C-1 amine position or the C-4 position was substituted with groups with various hydrophilicities to determine if a direct relation existed between water solubility and overall activity. The chlorinated precursors of these derivatives were also examined and were found to be less active in the C. parvum assays, a result in direct contrast to earlier work with Leishmania. Enhanced water solubility alone did not overcome the drug availability problem; however, several candidates with similar activities but with toxicities lower than those of the lead compounds were produced.

Evidence of the presence of minor tautomeric forms in selected nitroanilines

“…Many compounds of this family, such as Oryzalin, Pendimethalin, Prodiamine, and Trifluarin, are used as herbicides to control grass and other weeds 8–10 . Their mode of action involves the inhibition of root elongation by blocking tubulin production and producing mitosis interruption 11 . Furthermore, Pendimethalin has been shown to significantly increase both the mitotic index and the frequency of chromosomal aberrations in onion and corn plants 12…”

“…[8][9][10] Their mode of action involves the inhibition of root elongation by blocking tubulin production and producing mitosis interruption. 11 Furthermore, Pendimethalin has been shown to significantly increase both the mitotic index and the frequency of chromosomal aberrations in onion and corn plants. 12 Nitro compounds can be involved in fast tautomeric equilibria, and the occurrence of nitro-aci tautomerism in aliphatic compounds is well known (Scheme 1).…”

Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials

“…Certain dinitroaniline herbicides, (Figure ) and their analogues, which are photo‐labile, also exhibit activity against Leishmaniasis, a disease endemic to tropical and sub‐tropical regions, both in culture and in vivo ,. These compounds have also exhibited activity against a range of parasites commonly infecting humans and domesticated animals, including Plasmodium, [10] Cryptosporidium , Leishmania ,, Entamoeba , Babesia [14] and Toxoplasma . One such nitroaromatic compound, trifluralin 1 (Figure ), a widely used commercial pre‐emergent herbicide, was initially considered the active agent against leishmaniasis .…”

A comparison of the effects of two dinitroanilines againstCryptosporidium parvumin vitro and in vivo in neonatal mice and rats

“…The dinitroanilines are tubulin‐binding agents that were originally recognised for their herbicidal properties. More recently, a number of in vitro studies have compared the anti‐cryptosporidial effects of several dinitroanilines as well as dinitroaniline analogues [7–9]. However, as far as we are aware, no previous studies have examined the in vivo efficacy of these compounds against C. parvum .…”