{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T11:38:33Z","timestamp":1777894713437,"version":"3.51.4"},"reference-count":55,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,22]],"date-time":"2022-05-22T00:00:00Z","timestamp":1653177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Major Projects for \u201cMajor New Drugs Innovation and Development\u201d","award":["2018ZX09735001-003"],"award-info":[{"award-number":["2018ZX09735001-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in the treatment of human diseases. To avoid such side effects, researchers are searching for novel ZBGs that may be used for the synthesis of HDAC6 inhibitors. In this study, a series of stereoisomeric compounds were designed and synthesized to discover non-hydroxamate HDAC6 inhibitors using \u03b1-amino amide as zinc-ion-chelating groups, along with a pair of enantiomeric isomers with inverted L-shaped vertical structure as cap structures. The anti-proliferative activities were determined against HL-60, Hela, and RPMI 8226 cells, and 7a and its stereoisomer 13a exhibited excellent activities against Hela cells with IC50 = 0.31 \u00b5M and IC50 = 5.19 \u00b5M, respectively. Interestingly, there is a significant difference between the two stereoisomers. Moreover, an evaluation of cytotoxicity toward human normal liver cells HL-7702 indicated its safety for normal cells. X-ray single crystal diffraction was employed to increase insights into molecule structure and activities. It was found that the carbonyl of the amide bond is on the different side from the amino and pyridine nitrogen atoms. To identify possible protein targets to clarify the mechanism of action and biological activity of 7a, a small-scale virtual screen using reverse docking for HDAC isoforms (1\u201310) was performed and the results showed that HDAC6 was the best receptor for 7a, suggesting that HDAC6 may be a potential target for 7a. The interaction pattern analysis showed that the \u03b1-amino amide moiety of 7a coordinated with the zinc ion of HDAC6 in a bidentate chelate manner, which is similar to the chelation pattern of hydroxamic acid. Finally, the molecular dynamics simulation approaches were used to assess the docked complex\u2019s conformational stability. In this work, we identified 7a as a potential HDAC6 inhibitor and provide some references for the discovery of non-hydroxamic acid HDAC6 inhibitors.<\/jats:p>","DOI":"10.3390\/molecules27103335","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T02:57:02Z","timestamp":1653274622000},"page":"3335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New \u03b1-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Yangrong","family":"Xu","sequence":"first","affiliation":[{"name":"National Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hangjun","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yijie","family":"Xu","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialin","family":"Guo","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China"},{"name":"China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingguo","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junhai","family":"Xiao","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for the Emergency Drug, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Verza, F.A., Das, U., Fachin, A.L., Dimmock, J.R., and Marins, M. 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