{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T18:43:31Z","timestamp":1782758611205,"version":"3.54.5"},"reference-count":0,"publisher":"Bentham Science Publishers Ltd.","issue":"3","content-domain":{"domain":["eurekaselect.com"],"crossmark-restriction":true},"short-container-title":["CAD"],"published-print":{"date-parts":[[2021,7,15]]},"abstract":"<jats:sec>\n<jats:title>Background:<\/jats:title>\n<jats:p> Leflunomide (LFM) and its active metabolite, teriflunomide (TFM), have\ndrawn a lot of attention for their anticancer activities, treatment of rheumatoid arthritis and malaria due\nto their capability to inhibit dihydroorotate dehydrogenase (DHODH) and Plasmodium falciparum dihydroorotate\ndehydrogenase (PfDHODH) enzyme. In this investigation, the strength of intramolecular\nhydrogen bond (IHB) in five analogs of TFM (ATFM) was analyzed employing density functional theory\n(DFT) using B3LYP\/6-311++G (d, p) level and molecular orbital analysis in the gas phase and water\nsolution. A detailed electronic structure study was performed using the quantum theory of atoms in\nmolecules (QTAIM) and the hydrogen bond energies (EHB) of stable conformer obtained in the range of\n76-97 kJ\/mol, as a medium hydrogen bond. The effect of substitution on the IHB nature was studied by\nnatural bond orbital analysis (NBO). <jats:sup>1<\/jats:sup>H NMR calculations showed an upward trend in the proton\nchemical shift of the enolic proton in the chelated ring (14.5 to 15.7ppm) by increasing the IHB\nstrength. All the calculations confirmed the strongest IHB in 5-F-ATFM and the weakest IHB in 2-FATFM.\nMolecular orbital analysis, including the HOMO-LUMO gap and chemical hardness, was performed\nto compare the reactivity of inhibitors. Finally, molecular docking analysis was carried out to\nidentify the potency of inhibition of these compounds against PfDHODH enzyme.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title\/>\n<jats:p>TFM acts as an inhibitor of dihydroorotate dehydrogenase (DHODH) and Plasmodium falciparum dihydroorotate\ndehydrogenase (PfDHODH) enzyme. Leflunomide and its active metabolite teriflunomide\nhave been identified as drugs for treatment of some diseases, such as multiple sclerosis (MS), rheumatoid\narthritis (RA), malaria, and cancer. Hydrogen bonds play a key role in the interaction between\ndrugs and enzymes.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Objective:<\/jats:title>\n<jats:p>The aim of the present work is to investigate the effect of the strength of intramolecular hydrogen\nbonds (IHBs) in the active metabolite analogs of leflunomide or analogs of teriflunomide (ATFMs)\nand study the interaction of these inhibitors against the PfDHODH enzyme using quantum mechanical\nmethods.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods:<\/jats:title>\n<jats:p>At first, intramolecular hydrogen bonds in five ATFMs were evaluated by the DFT method,\nquantum theory of atoms in molecules (QTAIM), nuclear magnetic resonance (NMR), natural bond orbital\n(NBO), and molecular orbital (MO) analyses. Then, the interaction of these inhibitors against the\nPfDHODH enzyme were compared using molecular docking study.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results:<\/jats:title>\n<jats:p>All the computed results confirm the following trend in the intramolecular hydrogen bond\nstrength in five mono-halo-substituted 2-cyano-3-hydroxy-N-phenylbut-2-enamide (ATFM): 5-FATFM&gt;\n4-Br-ATFM \u2248 3-Br-ATFM&gt;3-Cl-ATFM&gt;TFM-Z&gt;2-F-ATFM which is in agreement with\nQTAIM, NMR, and NBO results. Docking results show that 5-F-ATFM (E<jats:sub>HB<\/jats:sub>=97kJ\/mol) has the minimum\nMolDock score due to its considerable IHB strength.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion:<\/jats:title>\n<jats:p>For strong IHBs (E<jats:sub>HB<\/jats:sub>&gt;100kJ\/mol), C=O and O\u2013H group are involved in the intramolecular\ninteractions and do not contribute to the external interactions. Also, the docking study revealed maximum\nbinding energy between TFM-Z and PfDHODH enzyme.<\/jats:p>\n<\/jats:sec>","DOI":"10.2174\/1573409916666200527133126","type":"journal-article","created":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T16:08:06Z","timestamp":1590595686000},"page":"480-491","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effect of the Intramolecular Hydrogen Bond on the Active Metabolite Analogs of Leflunomide for Blocking the Plasmodium falciparum Dihydroorotate Dehydrogenase Enzyme: QTAIM, NBO, and Docking Study"],"prefix":"10.2174","volume":"17","author":[{"given":"Reihaneh","family":"Heidarian","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Physics and Chemistry, Alzahra University, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansoureh","family":"Zahedi-Tabrizi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Physics and Chemistry, Alzahra University, Tehran, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"965","container-title":["Current Computer-Aided Drug Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/eurekaselect.com\/article\/download\/182309","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.eurekaselect.com\/182309\/article","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/eurekaselect.com\/article\/download\/182309","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T14:13:36Z","timestamp":1626963216000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.eurekaselect.com\/182309\/article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,15]]},"references-count":0,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,7,15]]}},"alternative-id":["LiveAll1"],"URL":"https:\/\/doi.org\/10.2174\/1573409916666200527133126","relation":{},"ISSN":["1573-4099"],"issn-type":[{"value":"1573-4099","type":"print"}],"subject":[],"published":{"date-parts":[[2021,7,15]]},"assertion":[{"value":"Peer Reviewed","order":0,"name":"review_status","label":"Review Status","group":{"name":"peer_review_details","label":"Peer Review Details"}},{"value":"Single blind","order":1,"name":"review_process","label":"Review Process","group":{"name":"peer_review_details","label":"Peer Review Details"}},{"value":"Checked with iThenticate","order":0,"name":"screening_status","label":"Screening Status","group":{"name":"plagiarism_screening","label":"Plagiarism Screening"}},{"value":"2019-12-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-17","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}