Estrogenic Activity of Tetrazole Derivatives Bearing Bisphenol Structures: Computational Studies, Synthesis, and In Vitro Assessment

The classification of bisphenol A
(BPA) as an industrial endocrine
disruptor has led to a ban of this ubiquitous critical starting material
from food and medical applications. Thus, scientists worldwide are
researching to develop non-ER binding starting compounds to fulfill
unmet market needs. In line with this trending research topic, the
current paper highlights the development of tetrazole derivatives
bearing a bisphenol structure (TbB) as a novel weak binder or potential
inactive to the estrogen receptor (ER) and androgen receptor (AR).
The structure and ligand-based approach supported by binding affinity
analysis, electrostatic complementarity, ADMET prediction, and in
silico studies identified TbBs as privileged substitutes for BPA.
Five TbB ligands were successfully synthesized and subjected to biological
testing comprising radioligand competitive binding and functional
cellular assays. The measured IC50 value for BPA was found
to be 0.24 μM, whereas all the inhibitions were less than 15%
for the two TbB ligands, 223-2 and 223-3. As these TbB ligands did
not meet the established acceptance criteria of 50% inhibition, they
are considered as extremely weak binders to ERα. Steric clashes,
the desolvation effect, and the increased total polar surface area
(TPSA) of TbB ligands in the hydrophobic binding site are hypothesized
to be possible reasons for low binding. Modeling studies complemented
by bioassays highlight TbB compounds as privileged prospective BPA
replacements. However, more research on TbB ligand toxicity is needed
to understand and substantiate that the adverse effects on the hormonal
system, for example, via metabolic activation, are not elicited.