Molecular factors governing inhibition of arylimidamides against Leishmania: Conservative computational modeling to improve chemotherapies

Abstract

A dataset of 55 compounds with inhibitory activity against L. donovani axenic amastigotes and L. amazonensis intracellular parasites was examined through three-dimensional quantitative structure-activity relationship modeling employing molecular descriptors from both rigid and flexible compound alignments. For training and testing purposes, the compounds were divided into two datasets of 45 and 10 compounds, respectively. Statistically significant models were constructed and validated via the internal and external predictions. For all models employing steric, electrostatic, hydrophobic, H-donor and H-acceptor molecular descriptors, the R2 values were greater than 0.90 and the SEE values were less than 0.22. The models obtained from rigid and flexible compounds were employed together to obtain a conservative method for predictions. This method minimized under predictions. Molecular descriptors from the models were then extrapolated, for the overall predictive devices and the individual compounds, and examined with regard to inhibitory activity. Information gained from the molecular descriptors is useful in the design of novel compounds. The models obtained can be employed to predict activities of the compounds designed and/or form predictions for compounds that exist and have not yet been examined with biological inhibitory assays.

Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas' Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies

“…Nonetheless, the AIAs remain among the most active classes of compounds against intracellular Leishmania and T. cruzi. Our efforts to improve the efficacy and reduce the toxicity of AIAs have resulted in the synthesis and testing of additional AIAs containing shorter linkers (unpublished data) and AIAs containing one AIA group (mono-AIAs), as opposed to the two AIA groups found in DB1955, DB1960, and other AIAs reported thus far (8,22). Within the class of AIAs containing shorter linkers, the active compounds are toxic, with administration to mice resulting in acute, immediate toxicity (unpublished data), unlike the compounds examined here.…”

“…Our previous efforts have identified arylimidamides (AIAs) as compounds with outstanding in vitro antileishmanial (8,22) and anti-T. cruzi (12,18,19) activities. In addition to excellent in vitro antileishmanial potency, the AIA hydrochloride salt 2,5-bis[2-(2-propoxy)-4-(2-pyridylimino)aminophenyl]furan (DB766) displayed good efficacy in both murine and hamster models of VL (27), was as active as Bz in experimental models of T. cruzi infection (3), was not mutagenic in the Ames test, and did not have an effect on the serum chemistry of mice when given orally at a dose of 100 mg/kg/day ϫ 5, although higher dose levels were not tested due to the limited aqueous solubility of DB766 (27).…”

Structure‐Dependent Binding of Arylimidamides to the DNA Minor Groove

“…They underwent a short MD simulation of 1 ns at a constant temperature and volume (NTV). [52] Briefly, 1) the system temperature was set to 300 K with a coupling constant of 100 fs, 2) a Maxwell-Boltzmann distribution was employed for initial atom velocities, 3) the nonbonded pair list was updated every 25 fs, and 4) the duration of the MD simulations in vacuo was 1 ns with a time step of 100 fs and a snapshot every 1000 fs. Snapshots from the MD simulation displayed several lowenergy structures.…”

Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations

“…Although it possesses many favorable qualities as an antileishmanial candidate, DB766 does not display the therapeutic index needed to progress further for development as monotherapy against VL. While many other bis-AIAs have been synthesized, none are superior to DB766 (3)(4)(5)(6). As part of an investigation into the mechanism of action of DB766, L. donovani axenic amastigotes resistant to this compound were raised through DB766 pressure in culture.…”