{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:18:59Z","timestamp":1760239139066,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,22]],"date-time":"2020-09-22T00:00:00Z","timestamp":1600732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Peptidyl enzyme inhibitors containing an internal aminomethylphosphinic bond system (P(O)(OH)-CH2-NH) can be termed extended transition state analogs by similarity to the corresponding phosphonamidates (P(O)(OH)-NH). Phosphonamidate pseudopeptides are broadly recognized as competitive mechanism-based inhibitors of metalloenzymes, mainly hydrolases. Their practical use is, however, limited by hydrolytic instability, which is particularly restricting for dipeptide analogs. Extension of phosphonamidates by addition of the methylene group produces a P-C-N system fully resistant in water conditions. In the current work, we present a versatile synthetic approach to such modified dipeptides, based on the three-component phospha-Mannich condensation of phosphinic acids, formaldehyde, and N-benzylglycines. The last-mentioned component allowed for simple and versatile introduction of functionalized P1\u2032 residues located on the tertiary amino group. The products demonstrated moderate inhibitory activity towards porcine and plant metalloaminopeptidases, while selected derivatives appeared very potent with human alanyl aminopeptidase (Ki = 102 nM for 6a). Analysis of ligand-protein complexes obtained by molecular modelling revealed canonical modes of interactions for mono-metallic alanyl aminopeptidases, and distorted modes for di-metallic leucine aminopeptidases (with C-terminal carboxylate, not phosphinate, involved in metal coordination). In general, the method can be dedicated to examine P1\u2032-S1\u2032 complementarity in searching for non-evident structures of specific residues as the key fragments of perspective ligands.<\/jats:p>","DOI":"10.3390\/molecules25184334","type":"journal-article","created":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T03:03:39Z","timestamp":1600916619000},"page":"4334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["N-Benzyl Residues as the P1\u2032 Substituents in Phosphorus-Containing Extended Transition State Analog Inhibitors of Metalloaminopeptidases"],"prefix":"10.3390","volume":"25","author":[{"given":"Kamila","family":"Janiszewska","sequence":"first","affiliation":[{"name":"Department of Bioorganic Chemistry, Wroc\u0142aw University of Science and Technology, Wybrze\u017ce Wyspia\u0144skiego 27, 50-370 Wroc\u0142aw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8902-097X","authenticated-orcid":false,"given":"Micha\u0142","family":"Talma","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry, Wroc\u0142aw University of Science and Technology, Wybrze\u017ce Wyspia\u0144skiego 27, 50-370 Wroc\u0142aw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bartosz","family":"Oszywa","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3382-9697","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Pawe\u0142czak","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8019-4797","authenticated-orcid":false,"given":"Pawe\u0142","family":"Kafarski","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry, Wroc\u0142aw University of Science and Technology, Wybrze\u017ce Wyspia\u0144skiego 27, 50-370 Wroc\u0142aw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artur","family":"Mucha","sequence":"additional","affiliation":[{"name":"Department of Bioorganic Chemistry, Wroc\u0142aw University of Science and Technology, Wybrze\u017ce Wyspia\u0144skiego 27, 50-370 Wroc\u0142aw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,22]]},"reference":[{"key":"ref_1","unstructured":"Kukhar, V.P., and Hudson, H.R. 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