{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T22:44:15Z","timestamp":1769121855659,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T00:00:00Z","timestamp":1604275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005725","name":"National Plan for Science, Technology and Innovation","doi-asserted-by":"publisher","award":["14-BIO80-03"],"award-info":[{"award-number":["14-BIO80-03"]}],"id":[{"id":"10.13039\/501100005725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Aromatic aldehydes that bind to sickle hemoglobin (HbS) to increase the protein oxygen affinity and\/or directly inhibit HbS polymer formation to prevent the pathological hypoxia-induced HbS polymerization and the subsequent erythrocyte sickling have for several years been studied for the treatment of sickle cell disease (SCD). With the exception of Voxelotor, which was recently approved by the U.S. Food and Drug Administration (FDA) to treat the disease, several other promising antisickling aromatic aldehydes have not fared well in the clinic because of metabolic instability of the aldehyde moiety, which is critical for the pharmacologic activity of these compounds. Over the years, our group has rationally developed analogs of aromatic aldehydes that incorporate a stable Michael addition reactive center that we hypothesized would form covalent interactions with Hb to increase the protein affinity for oxygen and prevent erythrocyte sickling. Although, these compounds have proven to be metabolically stable, unfortunately they showed weak to no antisickling activity. In this study, through additional targeted modifications of our lead Michael addition compounds, we have discovered other novel antisickling agents. These compounds, designated MMA, bind to the \u03b1-globin and\/or \u03b2-globin to increase Hb affinity for oxygen and concomitantly inhibit erythrocyte sickling with significantly enhanced and sustained pharmacologic activities in vitro.<\/jats:p>","DOI":"10.3390\/biom10111508","type":"journal-article","created":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T19:51:31Z","timestamp":1604346691000},"page":"1508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9825-3465","authenticated-orcid":false,"given":"Abdelsattar M.","family":"Omar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2497-4291","authenticated-orcid":false,"given":"Osheiza","family":"Abdulmalik","sequence":"additional","affiliation":[{"name":"Division of Hematology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohini S.","family":"Ghatge","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosra A.","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1143-9890","authenticated-orcid":false,"given":"Steven D.","family":"Paredes","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7932-2226","authenticated-orcid":false,"given":"Moustafa E.","family":"El-Araby","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9536-1743","authenticated-orcid":false,"given":"Martin K.","family":"Safo","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/ajh.21162","article-title":"Prevalence and risk factors for pulmonary artery systolic hypertension among sickle cell disease patients in Nigeria","volume":"83","author":"Aliyu","year":"2008","journal-title":"Am. J. Hematol."},{"key":"ref_2","first-page":"305","article-title":"Sickle Cell Disease","volume":"377","author":"Piel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.jsb.2016.04.003","article-title":"Crystal structure of carbonmonoxy sickle hemoglobin in R-state conformation","volume":"194","author":"Ghatge","year":"2016","journal-title":"J. Struct. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/jmr.698","article-title":"Crowding and the polymerization of sickle hemoglobin","volume":"17","author":"Ferrone","year":"2004","journal-title":"J. Mol. Recognit."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1006\/jmbi.1993.1195","article-title":"Double strand packing in hemoglobin S fibers","volume":"230","author":"Cretegny","year":"1993","journal-title":"J. Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0065-3233(08)60287-9","article-title":"Sickle cell hemoglobin polymerization","volume":"40","author":"Eaton","year":"1990","journal-title":"Adv. Protein Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1006\/jmbi.1997.1253","article-title":"The high resolution crystal structure of deoxyhemoglobin S","volume":"272","author":"Harrington","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_8","unstructured":"Bunn, F. (1986). Molecular, Genetic and Clinical Aspects. Hemoglobin, W. B. Saunders Company."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/jcp.22195","article-title":"Sickle cell anemia and vascular dysfunction: The nitric oxide connection","volume":"224","author":"Akinsheye","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"ref_10","first-page":"e2009024","article-title":"Pathophisiology of sickle cell disease and new drugs for the treatment","volume":"1","year":"2009","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3953","DOI":"10.1182\/blood-2002-10-3313","article-title":"Transgenic sickle mice have vascular inflammation","volume":"101","author":"Belcher","year":"2003","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1182\/bloodadvances.2018GS110347","article-title":"Increasing hydroxyurea use in children with sickle cell disease at Kamuzu Central Hospital, Malawi","volume":"2","author":"Mvalo","year":"2018","journal-title":"Blood Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1586\/ehm.10.22","article-title":"Hydroxyurea use in sickle cell disease: The battle with low prescription rates, poor patient compliance and fears of toxicities","volume":"3","author":"Brandow","year":"2010","journal-title":"Expert Rev. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sinha, C.B., Bakshi, N., Ross, D., and Krishnamurti, L. (2018). From trust to skepticism: An in-depth analysis across age groups of adults with sickle cell disease on their perspectives regarding hydroxyurea. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199375"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1002\/phar.2329","article-title":"Systematic Review of l-glutamine for Prevention of Vaso-occlusive Pain Crisis in Patients with Sickle Cell Disease","volume":"39","author":"Hutcherson","year":"2019","journal-title":"Pharmacotherapy"},{"key":"ref_16","unstructured":"(2018). L-glutamine (Endari) for sickle cell disease. Med. Lett. Drugs Ther., 60, 21\u201322."},{"key":"ref_17","first-page":"620","article-title":"Pharmaceutical approval update: L-glutamine oral powder (Endari)","volume":"42","author":"Kaufman","year":"2017","journal-title":"Pharm. Therapeut."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ataga, K.I., Kutlar, A., Kanter, J., Liles, D., Cancado, R., Friedrisch, J., Guthrie, T.H., Knight-Madden, J., Alvarez, O.A., and Gordeuk, V.R. (2017). Crizanlizumab for the prevention of pain crises in sickle cell disease. N. Engl. J. Med., 376.","DOI":"10.1056\/NEJMoa1611770"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJMoa1903212","article-title":"A Phase 3 randomized trial of voxelotor in sickle cell disease","volume":"381","author":"Vichinsky","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1021\/acsmedchemlett.6b00491","article-title":"Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin","volume":"8","author":"Metcalf","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1111\/bjh.14214","article-title":"GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease","volume":"175","author":"Oksenberg","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3233\/CH-170340","article-title":"GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions","volume":"70","author":"Dufu","year":"2018","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.bbapap.2011.02.013","article-title":"Hemoglobin-ligand binding: Understanding Hb function and allostery on atomic level","volume":"1814","author":"Safo","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.hoc.2013.11.001","article-title":"Therapeutic strategies to alter the oxygen affinity of sickle hemoglobin","volume":"28","author":"Safo","year":"2014","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/978-3-030-41769-7_14","article-title":"Hemoglobin: Structure, Function and Allostery","volume":"94","author":"Ahmed","year":"2020","journal-title":"Subcell. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/bjh.14264","article-title":"New developments in anti-sickling agents: Can drugs directly prevent the polymerization of sickle haemoglobin in vivo?","volume":"175","author":"Oder","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Mozzarelli, A., and Bettati, S. (2011). Allosteric Effectors of Hemoglobin: Past, Present and Future. Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood, John Wiley & Sons, Ltd.","DOI":"10.1002\/9781119975427"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/j.1365-2141.2004.05332.x","article-title":"5-Hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells","volume":"128","author":"Abdulmalik","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1021\/acs.molpharmaceut.7b00553","article-title":"Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease","volume":"14","author":"Xu","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4665","DOI":"10.1021\/jm0498001","article-title":"Structural Basis for the Potent Antisickling Effect of a Novel Class of Five-Membered Heterocyclic Aldehydic Compounds","volume":"47","author":"Safo","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1107\/S0907444911036353","article-title":"Crystallographic analysis of human hemoglobin elucidates the structural basis of the potent and dual antisickling activity of pyridyl derivatives of vanillin","volume":"67","author":"Abdulmalik","year":"2011","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.1016\/j.bmc.2018.04.015","article-title":"Rational design of pyridyl derivatives of vanillin for the treatment of sickle cell disease","volume":"26","author":"Pagare","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1107\/S2059798318009919","article-title":"Rational modification of vanillin derivatives to stereospecifically destabilize sickle hemoglobin polymer formation","volume":"74","author":"Deshpande","year":"2018","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1021\/acs.molpharmaceut.8b00108","article-title":"A Triazole Disulfide Compound Increases the Affinity of Hemoglobin for Oxygen and Reduces the Sickling of Human Sickle Cells","volume":"15","author":"Nakagawa","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2318","DOI":"10.1021\/cb500230b","article-title":"Identification of a small molecule that increases hemoglobin oxygen affinity and reduces SS erythrocyte sickling","volume":"9","author":"Nakagawa","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6353","DOI":"10.1039\/C5OB00367A","article-title":"Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents","volume":"13","author":"Omar","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1039\/C9MD00291J","article-title":"Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents","volume":"10","author":"Omar","year":"2019","journal-title":"Medchemcomm"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/009841099157764","article-title":"Distribution and metabolism of (5-hydroxymethyl)furfural in male F344 rats and B6C3F1 mice after oral administration","volume":"57","author":"Godfrey","year":"1999","journal-title":"J. Toxicol. Environ. Health Part A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1046\/j.1432-1327.1998.2510549.x","article-title":"Human aldehyde dehydrogenase gene family","volume":"251","author":"Yoshida","year":"1998","journal-title":"Eur. J. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0009-2797(00)00211-8","article-title":"Role of aldehyde dehydrogenases in endogenous and xenobiotic metabolism","volume":"129","author":"Vasiliou","year":"2000","journal-title":"Chem. Biol. Interact."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1021\/jm00368a001","article-title":"Design, synthesis, and testing of potential antisickling agents. 3. Ethacrynic acid","volume":"27","author":"Kennedy","year":"1984","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1182\/blood.V77.6.1334.1334","article-title":"Vanillin, a potential agent for the treatment of sickle cell anemia","volume":"77","author":"Abraham","year":"1991","journal-title":"Blood"},{"key":"ref_43","unstructured":"Obied, T., and Venitz, J. (2009). 5-hydroxy methyl furfural (5-HMF) metabolism in hepatic cytosol from mice, rats, dogs, and humans. Proceedings of the 23 rd Annual Meeting, The AAPS Journal 11."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4105","DOI":"10.1016\/S0021-9258(18)62890-X","article-title":"Kinetics of the reaction of the \u201cmasked\u201d and \u201cfree\u201d sulfhydryl groups of human hemoglobin with p-mercuribenzoate","volume":"245","author":"Chiancone","year":"1970","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"107386","DOI":"10.1016\/j.jsb.2019.09.003","article-title":"Structural analysis of glutathionyl hemoglobin using native mass spectrometry","volume":"208","author":"Muralidharan","year":"2019","journal-title":"J. Struct. Biol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/11\/1508\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:28:20Z","timestamp":1760178500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/11\/1508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,2]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["biom10111508"],"URL":"https:\/\/doi.org\/10.3390\/biom10111508","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,2]]}}}