biostudies-literaturePurgatorio RMinistero dell'Istruzione, dell'Università e della RicercaMinistero dell’Istruzione, dell’Università e della Ricerca5208https://www.ebi.ac.uk/biostudies/studies/S-EPMC8434007biostudies-literatureUnknown26(17)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_i 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_i 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.Molecules (Basel, Switzerland)First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease.PMC8434007PRIN, Grant 2017RPHBCW_002PRIN, Grant 201744BN5T_004Altomare CDRullo MPurgatorio RNicolotti Ode Candia MGambacorta NPisani LCatto MfalseFirst-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease.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_i 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_i 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.2021-01-01T00:00:00Z2021 Aug2026-04-08T06:49:56.91Z2022-02-11T10:59:05.939ZS-EPMC84340073450064010.3390/molecules26175208