On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors

Abstract

Aldehyde peptide like compounds display a bivalent reactive profile and improved antichagasic potency.

Nitriles: an attractive approach to the development of covalent inhibitors

“…Still, the order of reactivity generally remains amidst studies. 38,[49][50][51] The reactivity of different warheads (electrophiles) with thiol-based compounds (nucleophiles) can be rationalized in terms of their intrinsic electrophilicity, as well as the nucleophilicity and polarizability of reacting chemical species. Thus, the principle of hard and soft acids and bases (HSAB) defined by Pearson 52 is of great value, since the anionic cysteine sulfhydryl is a highly polarizable group (soft base), due to the high energy of the 3sp 3 orbitals and large ionic radius.…”

Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases

“…Accordingly, an emerging trend is the development of reversible covalent inhibitors which provide potent inhibition of the desired target, but will not permanently inactivate off-target proteins . Among the reversible covalent warheads explored for cruzain to date, an aldehyde group often, if not always, affords outstanding inhibitory potency compared to α-keto amides, nitriles, oximes, heterocycles, and so on. − On the other hand, the inherent electrophilicity of aldehydes contributes to their rapid metabolism, immunotoxicities, and untoward drug–drug interactions, which have all but disqualified their use in drug design. Theoretically, these issues can be mitigated by confining the exposure of the aldehyde solely to the germane protein target while eschewing off-target proteins; however, such approaches have been challenging to implement …”

Promoting GAINs (Give Attention to Limitations in Assays) over PAINs Alerts: no PAINS, more GAINs

“…In addition, compounds that undergo reversible covalent interaction may not show signal perturbation in ALARM NMR. In this case, time‐based monitoring using NMR spectroscopy or HPLC with model thiols such as GSH or cysteamine at appropriate concentrations may enable one to directly observe and/or quantify the reversibility of a covalent interaction [61,63–67] …”

“…In this case, time-based monitoring using NMR spectroscopy or HPLC with model thiols such as GSH or cysteamine at appropriate concentrations may enable one to directly observe and/or quantify the reversibility of a covalent interaction. [61,[63][64][65][66][67]…”