{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T21:01:57Z","timestamp":1779310917623,"version":"3.51.4"},"reference-count":65,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003336","name":"Bulgarian National Science Fund","doi-asserted-by":"crossref","award":["K\u041f-06-M83\/3"],"award-info":[{"award-number":["K\u041f-06-M83\/3"]}],"id":[{"id":"10.13039\/501100003336","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Virtual screening is a widely adopted technique for the discovery of novel pharmacologically active compounds; however, the risk of identifying false positive hits remains a major challenge. Aim: The aim of this study was to perform a validated structure-based drug design screening to discover multitarget pyrrole-based molecules as selective dual-acting monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors. Methods: The study employed validated docking protocols using Glide (Schr\u00f6dinger) and GOLD (CCDC), integrating ligand enrichment analysis and robust Molecular Mechanics\/Generalized Born Surface Area (MM\/GBSA) rescoring. These methods were applied to a custom-designed database of pyrrole-based compounds. The top-ranked hits were synthesized and validated through in vitro tests, demonstrating significant inhibitory activities against MAO-A, MAO-B, AChE, and Butyrylcholinesterase (BChE). Results: The docking protocols achieved favorable hit rates, with 25.93% for AChE inhibitors and 44.44% for MAO-B inhibitors. Additionally, structure\u2013activity relationship analysis revealed key substituent effects that significantly influence binding affinity and selectivity. Two compounds, EM-DC-19 (2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2H-imidazol-4-yl)propanoic acid) and EM-DC-27 ([4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]acetic acid), were identified as selective MAO-B inhibitors with additional moderate AChE inhibitory activity, demonstrating IC50 values of 0.299 \u00b1 0.10 \u00b5M and 0.344 \u00b1 0.10 \u00b5M against MAO-B, and 76.15 \u00b1 6.12 \u00b5M and 375.20 \u00b1 52.99 \u00b5M against AChE, respectively. The absence of statistically significant inhibitory effects of these lead compounds on MAO-A and BChE (IC50 &gt; 100 \u00b5M) underscores their selective inhibitory activity towards MAO-B and AChE. Furthermore, both compounds demonstrated low neurotoxicity and significant neuroprotective and antioxidant effects in rat brain synaptosomes, mitochondria, and microsomes. These effects were particularly evident in models of 6-hydroxydopamine-induced neurotoxicity (6-OHDA) and oxidative stress induced by tert-butyl hydroperoxide and Fe2+\/ascorbic acid. Conclusions: The findings suggest that these multitarget compounds hold promise for further development, with potential for structural modifications to enhance their enzyme inhibitory and neuroprotective properties.<\/jats:p>","DOI":"10.3390\/ph18111677","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T16:09:47Z","timestamp":1762358987000},"page":"1677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Design, Synthesis, and Evaluation of Pyrrole-Based Selective MAO-B Inhibitors with Additional AChE Inhibitory and Neuroprotective Properties Identified via Virtual Screening"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5885-7213","authenticated-orcid":false,"given":"Emilio","family":"Mateev","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University\u2014Sofia, 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2344-5101","authenticated-orcid":false,"given":"Samir","family":"Chtita","sequence":"additional","affiliation":[{"name":"Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Casablanca 20100, Morocco"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7679-4221","authenticated-orcid":false,"given":"Ekaterina","family":"Pavlova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University\u2014Sofia, 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8977-3303","authenticated-orcid":false,"given":"Ali","family":"Irfan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1708-1287","authenticated-orcid":false,"given":"Diana","family":"Tzankova","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University\u2014Sofia, 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9657-6623","authenticated-orcid":false,"given":"Shubham","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Chemistry, GLA University, Mathura 281406, Uttar Pradesh, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borislav","family":"Georgiev","sequence":"additional","affiliation":[{"name":"Institute of Biodiversity and Ecosystem Research, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1905-7130","authenticated-orcid":false,"given":"Alexandrina","family":"Mateeva","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University\u2014Sofia, 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-7089","authenticated-orcid":false,"given":"Georgi","family":"Momekov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University\u2014Sofia, 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4752-5002","authenticated-orcid":false,"given":"Maya","family":"Georgieva","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University\u2014Sofia, 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1695-8454","authenticated-orcid":false,"given":"Alexander","family":"Zlatkov","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University\u2014Sofia, 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Kondeva-Burdina","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University\u2014Sofia, 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"ref_1","unstructured":"Parkinson Study Group (2002). 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