Paulo J. Costa

Empirical force field methods typically rely on point charges to describe the electrostatic interactions, which is problematic when anisotropy needs to be considered, as in the case of the electrostatic potential of covalently bound halogens that possess a positive site, termed [Formula: see text]-hole, surrounded by a large negative belt. To address this, an off-center point charge (extra point, EP) is usually placed at a given distance from the halogen to emulate the [Formula: see text]-hole and commonly used implementations are based on the restrained electrostatic potential (RESP) procedure to fit atomic charges, being one of the most used charge models. In this context, no specific Merz–Singh–Kollman (MK) radius for iodine is available in the literature, which is an essential parameter in the RESP fitting procedure. In this work, we explored the impact of the iodine MK radius on the obtained RESP charges for a set of 12 iodinated molecules. We verified that the relative root mean square (RRMS) values obtained with and without an EP kept decreasing with increasing radii for most compounds, thus impairing optimization using such a procedure. Nevertheless, the use of an iodine MK radius lower than 2 Å is not advisable since the RRMS kept decreasing considerably until this value was reached. Moreover, the performance of three iodine MK radii was studied with the estimation of the free energy of hydration ([Formula: see text]) values using alchemical free energy calculations, which are particularly sensitive to the charges used. Despite the usage of different radii not leading to remarkable differences, our results indicate that using a value of 2.70 Å leads to lower mean absolute errors (MAE) and root mean squared error (RMSE) values when comparing the calculated with the experimental [Formula: see text] values.

The synthesis and biological evaluation of novel guanidino sugars as isonucleoside analogs is described. 5‐Guanidino xylofuranoses containing 3‐ O ‐saturated/unsaturated hydrocarbon or aromatic‐containing moieties were accessed from 5‐azido xylofuranoses via reduction followed by guanidinylation with N , N ′‐bis( tert ‐butoxycarbonyl)‐ N ′′‐triflylguanidine. Molecules comprising novel types of isonucleosidic structures including 5‐guanidino 3‐ O ‐methyl‐branched N ‐benzyltriazole isonucleosides and a guanidinomethyltriazole 3′‐ O ‐dodecyl xylofuranos‐5′‐yl isonucleoside were accessed. The guanidinomethyltriazole derivative and a 3‐ O ‐dodecyl ( N ‐Boc)guanidino xylofuranose were revealed as selective inhibitors of acetylcholinesterase ( K i =22.87 and 7.49 μM, respectively). The latter also showed moderate antiproliferative effects in chronic myeloid leukemia (K562) and breast cancer (MCF‐7) cells. An aminomethyltriazole 5’‐isonucleoside was the most potent molecule with low micromolar GI 50 values in both cells (GI 50 =6.33 μM, 8.45 μM), similar to that of the drug 5‐fluorouracil in MCF‐7 cells. Moreover, the most bioactive compounds showed low toxicity in human fibroblasts, further indicating their interest as promising lead molecules.