{"doi":"10.3390/molecules27206835","title":"Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease","abstract":"Sickle cell disease (SCD) is caused by a single-point mutation, and the ensuing deoxygenation-induced polymerization of sickle hemoglobin (HbS), and reduction in bioavailability of vascular nitric oxide (NO), contribute to the pathogenesis of the disease. In a proof-of-concept study, we successfully incorporated nitrate ester groups onto two previously studied potent antisickling aromatic aldehydes, TD7 and VZHE039, to form TD7-NO and VZHE039-NO hybrids, respectively. These compounds are stable in buffer but demonstrated the expected release of NO in whole blood in vitro and in mice. The more promising VZHE039-NO retained the functional and antisickling activities of the parent VZHE039 molecule. Moreover, VZHE039-NO, unlike VZHE039, significantly attenuated RBC adhesion to laminin, suggesting this compound has potential in vivo RBC anti-adhesion properties relevant to vaso-occlusive events. Crystallographic studies show that, as with VZHE039, VZHE039-NO also binds to liganded Hb to make similar protein interactions. The knowledge gained during these investigations provides a unique opportunity to generate a superior candidate drug in SCD with enhanced benefits.","journal":"Molecules","year":2022,"id":284130,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235968,"name":"Mohini S. Ghatge","orcid":"0000-0002-1146-536X","position":1,"is_corresponding":false},{"id":899869,"name":"Akua K. Donkor","orcid":"0000-0002-2563-3002","position":2,"is_corresponding":false},{"id":385892,"name":"Faik N. Musayev","orcid":"0000-0002-7969-1590","position":3,"is_corresponding":false},{"id":957892,"name":"Tanvi Deshpande","orcid":"0000-0001-8621-2781","position":4,"is_corresponding":false},{"id":961406,"name":"Mohammed A. AlAwadh","orcid":"0000-0002-1126-5886","position":5,"is_corresponding":false},{"id":958291,"name":"Rana T. Alhashimi","orcid":null,"position":6,"is_corresponding":false},{"id":961407,"name":"Hongmei Zhu","orcid":"0000-0002-6935-8284","position":7,"is_corresponding":false},{"id":504458,"name":"Abdelsattar M. Omar","orcid":"0000-0002-9825-3465","position":8,"is_corresponding":false},{"id":25026,"name":"Marilyn J. Telen","orcid":"0000-0003-3809-1780","position":9,"is_corresponding":false},{"id":331988,"name":"Yan Zhang","orcid":"0000-0001-8934-7016","position":10,"is_corresponding":false},{"id":690715,"name":"T. McMahon","orcid":"0000-0002-3404-3223","position":11,"is_corresponding":false},{"id":376404,"name":"Osheiza Abdulmalik","orcid":"0000-0003-2497-4291","position":12,"is_corresponding":false},{"id":235969,"name":"Martin K. Safo","orcid":"0000-0002-9536-1743","position":13,"is_corresponding":false},{"id":331985,"name":"Boshi Huang","orcid":"0000-0003-2243-1947","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T00:29:32.702533Z","pmid":"36296435","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}