| Summary: | Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The <i>N</i>-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative <b>1</b>, which has already been experimentally shown to inhibit thr with a K<sub>i</sub> value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of <b>1</b> was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental K<sub>i</sub> values, which were found equal to 0.058 and 6.95 μM for <i>ee</i>AChE and <i>eq</i>BChE, respectively. Thirty analogs of <b>1</b> were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.
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