{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:08:15Z","timestamp":1788055695337,"version":"build-2784847793"},"reference-count":74,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["602666"],"award-info":[{"award-number":["602666"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["201506220185"],"award-info":[{"award-number":["201506220185"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["602666"],"award-info":[{"award-number":["602666"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201506220185"],"award-info":[{"award-number":["201506220185"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.<\/jats:p>","DOI":"10.3390\/ijms24076817","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T03:59:55Z","timestamp":1680753595000},"page":"6817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?"],"prefix":"10.3390","volume":"24","author":[{"given":"Yang","family":"Zheng","sequence":"first","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Schroeder","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgi K.","family":"Kanev","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanaa S.","family":"Botros","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza 12411, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0521-1734","authenticated-orcid":false,"given":"Samia","family":"William","sequence":"additional","affiliation":[{"name":"Parasitology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza 12411, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel-Nasser A.","family":"Sabra","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza 12411, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2324-9509","authenticated-orcid":false,"given":"Louis","family":"Maes","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-3202","authenticated-orcid":false,"given":"Guy","family":"Caljon","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3882-6081","authenticated-orcid":false,"given":"Carmen","family":"Gil","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biologicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2707-8110","authenticated-orcid":false,"given":"Ana","family":"Martinez","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biologicas (CIB-CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene G.","family":"Salado","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5203-4339","authenticated-orcid":false,"given":"Koen","family":"Augustyns","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewald","family":"Edink","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten","family":"Sijm","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"de Heuvel","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwan J. P.","family":"de Esch","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"van der Meer","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Siderius","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert Jan","family":"Sterk","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Brown","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1354-2848","authenticated-orcid":false,"given":"Rob","family":"Leurs","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1016\/S0140-6736(18)32335-3","article-title":"Global, Regional, and National Disability-Adjusted Life-Years (DALYs) for 359 Diseases and Injuries and Healthy Life Expectancy (HALE) for 195 Countries and Territories, 1990\u20132017: A Systematic Analysis for the Global Burden of Disease Study 2017","volume":"392","author":"Kyu","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1016\/S0140-6736(12)61689-4","article-title":"Disability-Adjusted Life Years (DALYs) for 291 Diseases and Injuries in 21 Regions, 1990\u20132010: A Systematic Analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Murray","year":"2012","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S1473-3099(15)00066-3","article-title":"Spatial Distribution of Schistosomiasis and Treatment Needs in Sub-Saharan Africa: A Systematic Review and Geostatistical Analysis","volume":"15","author":"Lai","year":"2015","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.molbiopara.2014.06.002","article-title":"Schistosomiasis Control: Praziquantel Forever?","volume":"195","author":"Cioli","year":"2014","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.actatropica.2017.08.002","article-title":"Schistosomiasis: Drugs Used and Treatment Strategies","volume":"176","author":"Fontes","year":"2017","journal-title":"Acta Trop."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e02582-16","DOI":"10.1128\/AAC.02582-16","article-title":"Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance","volume":"61","author":"Vale","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.ijpara.2005.02.005","article-title":"Current Status of Sensitivity to Praziquantel in a Focus of Potential Drug Resistance in Egypt","volume":"35","author":"Botros","year":"2005","journal-title":"Int. J. Parasitol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1146\/annurev.nutr.18.1.353","article-title":"Cyclic amp signaling and gene regulation","volume":"18","author":"Daniel","year":"1998","journal-title":"Annu. Rev. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.clinthera.2011.12.008","article-title":"Roflumilast: A Phosphodiesterase-4 Inhibitor for the Treatment of Severe Chronic Obstructive Pulmonary Disease","volume":"34","author":"Pinner","year":"2012","journal-title":"Clin. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0140-6736(09)61255-1","article-title":"Roflumilast in Symptomatic Chronic Obstructive Pulmonary Disease: Two Randomised Clinical Trials","volume":"374","author":"Calverley","year":"2009","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1056\/NEJM199111213252103","article-title":"Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure","volume":"325","author":"Packer","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_12","first-page":"47","article-title":"Sildenafil: An Orally Active Type 5 Cyclic GMP-Specific Phosphodiesterase Inhibitor for the Treatment of Penile Erectile Dysfunction","volume":"8","author":"Boolell","year":"1996","journal-title":"Int. J. Impot. Res."},{"key":"ref_13","first-page":"147","article-title":"Roflumilast: First Phosphodiesterase 4 Inhibitor Approved for Treatment of COPD","volume":"4","author":"Giembycz","year":"2010","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.4155\/fmc.11.77","article-title":"Phosphodiesterase Inhibitors as a New Generation of Antiprotozoan Drugs: Exploiting the Benefit of Enzymes That Are Highly Conserved between Host and Parasite","volume":"3","author":"Seebeck","year":"2011","journal-title":"Future Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1096\/fj.06-6818com","article-title":"The Trypanosoma Brucei CAMP Phosphodiesterases TbrPDEBl and TbrPDEB2: Flagellar Enzymes That Are Essential for Parasite Virulence","volume":"21","author":"Oberholzer","year":"2007","journal-title":"FASEB J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8745","DOI":"10.1021\/jm301059b","article-title":"Catechol Pyrazolinones as Trypanocidals: Fragment-Based Design, Synthesis, and Pharmacological Evaluation of Nanomolar Inhibitors of Trypanosomal Phosphodiesterase B1","volume":"55","author":"Orrling","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2579","DOI":"10.1016\/j.bmcl.2012.01.119","article-title":"Synthesis and Evaluation of Human Phosphodiesterases (PDE) 5 Inhibitor Analogs as Trypanosomal PDE Inhibitors. Part 1. Sildenafil Analogs","volume":"22","author":"Wang","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3870","DOI":"10.1021\/acs.jmedchem.7b01670","article-title":"Targeting a Subpocket in Trypanosoma Brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity","volume":"61","author":"Blaazer","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4013","DOI":"10.1016\/j.bmc.2019.06.026","article-title":"Alkynamide Phthalazinones as a New Class of TbrPDEB1 Inhibitors (Part 2)","volume":"27","author":"Singh","year":"2019","journal-title":"Bioorg. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3998","DOI":"10.1016\/j.bmc.2019.06.027","article-title":"Alkynamide Phthalazinones as a New Class of TbrPDEB1 Inhibitors","volume":"27","author":"Singh","year":"2019","journal-title":"Bioorg. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/j.1365-2958.2007.05976.x","article-title":"Crystal Structure of the Leishmania Major Phosphodiesterase LmjPDEB1 and Insight into the Design of the Parasite-Selective Inhibitors","volume":"66","author":"Wang","year":"2007","journal-title":"Mol. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1021\/cb501004q","article-title":"Identification of Potent Phosphodiesterase Inhibitors That Demonstrate Cyclic Nucleotide-Dependent Functions in Apicomplexan Parasites","volume":"10","author":"Howard","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kunz, S., Balmer, V., Sterk, G.J., Pollastri, M.P., Leurs, R., M\u00fcller, N., Hemphill, A., and Spycher, C. (2017). The Single Cyclic Nucleotide-Specific Phosphodiesterase of the Intestinal Parasite Giardia Lamblia Represents a Potential Drug Target. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005891"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.exppara.2009.12.021","article-title":"The Identification of Inhibitors of Schistosoma mansoni Miracidial Transformation by Incorporating a Medium-Throughput Small-Molecule Screen","volume":"125","author":"Taft","year":"2010","journal-title":"Exp. Parasitol."},{"key":"ref_25","unstructured":"(2022, November 06). Final Report Summary\u2014PDE4NPD. Available online: https:\/\/cordis.europa.eu\/project\/id\/602666\/reporting."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Munday, J.C., Kunz, S., Kalejaiye, T.D., Siderius, M., Schroeder, S., Paape, D., Alghamdi, A.H., Abbasi, Z., Huang, S.X., and Donachie, A.-M. (2020). Cloning and Functional Complementation of Ten Schistosoma mansoni Phosphodiesterases Expressed in the Mammalian Host Stages. PLoS Negl. Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0008447"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Long, T., Rojo-Arreola, L., Shi, D., El-Sakkary, N., Jarnagin, K., Rock, F., Meewan, M., Rasc\u00f3n, A.A., Lin, L., and Cunningham, K.A. (2017). Phenotypic, Chemical and Functional Characterization of Cyclic Nucleotide Phosphodiesterase 4 (PDE4) as a Potential Anthelmintic Drug Target. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005680"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1517\/13543770903313753","article-title":"PDE4 Inhibitors: A Review of Current Developments (2005\u20132009)","volume":"19","author":"Lehner","year":"2009","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1016\/j.jaad.2017.11.056","article-title":"Phosphodiesterase 4 Inhibitors","volume":"78","author":"Zebda","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.4155\/fmc-2018-0592","article-title":"Discovery of Novel Schistosoma mansoni PDE4A Inhibitors as Potential Agents against Schistosomiasis","volume":"11","author":"Schroeder","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1093\/bioinformatics\/bty419","article-title":"NGL Viewer: Web-Based Molecular Graphics for Large Complexes","volume":"34","author":"Rose","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1126\/science.288.5472.1822","article-title":"Atomic Structure of PDE4: Insights into Phosphodiesterase Mechanism and Specificity","volume":"288","author":"Xu","year":"2000","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11788","DOI":"10.1074\/jbc.M111.326777","article-title":"Biological and Structural Characterization of Trypanosoma Cruzi Phosphodiesterase C and Implications for Design of Parasite Selective Inhibitors","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1021\/jm3017877","article-title":"Discovery of Novel Trypanosoma Brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure","volume":"56","author":"Jansen","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7029","DOI":"10.1021\/acs.jmedchem.5b01813","article-title":"PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design","volume":"59","author":"Jansen","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1016\/j.str.2004.10.004","article-title":"Structural Basis for the Activity of Drugs That Inhibit Phosphodiesterases","volume":"12","author":"Card","year":"2004","journal-title":"Structure"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107793","DOI":"10.1016\/j.exppara.2019.107793","article-title":"The Phosphodiesterase-4 Inhibitor Roflumilast Impacts Schistosoma mansoni Ovipositing in Vitro but Displays Only Modest Antischistosomal Activity In Vivo","volume":"208","author":"Botros","year":"2020","journal-title":"Exp. Parasitol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0014-2999(98)00439-7","article-title":"Phosphodiesterase Inhibitors Suppress A2-Adrenoceptor-Mediated 5-Hydroxytryptamine Release from Tracheae of Newborn Rabbits","volume":"354","author":"Freitag","year":"1998","journal-title":"Eur. J. Pharmacol."},{"key":"ref_40","unstructured":"Fredholm, B.B. (2011). Handbook of Experimental Pharmacology, Springer."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0163-7258(91)90039-O","article-title":"Cyclic Nucleotide Phosphodiesterases: Pharmacology, Biochemistry and Function","volume":"51","author":"Thompson","year":"1991","journal-title":"Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nrd2058","article-title":"Phosphodiesterases in the CNS: Targets for Drug Development","volume":"5","author":"Menniti","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_43","unstructured":"Bell, A.S., and Terrett, N.K. (1999). Pyrazolo[4,3-d]Pyrimidine Derivatives and Pharmaceutical Compositions Containing Them. (EP0911333A1), Patent."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nrd4228","article-title":"Advances in Targeting Cyclic Nucleotide Phosphodiesterases","volume":"13","author":"Maurice","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1016\/0024-3205(82)90095-9","article-title":"HL 725, an Extremely Potent Inhibitor of Platelet Phosphodiesterase and Induced Platelet Aggregation in Vitro","volume":"31","author":"Ruppert","year":"1982","journal-title":"Life Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1021\/jm00122a011","article-title":"Cardiotonic Agents. 9. Synthesis and Biological Evaluation of a Series of (E)-4,5-Dihydro-6-[2-[4-(1H-Imidazol-1-Yl)Phenyl]Ethenyl]-3(2H)-Pyridazinones: A Novel Class of Compounds with Positive Inotropic, Antithrombotic, and Vasodilatory Activities for Th","volume":"32","author":"Sircar","year":"1989","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0006-2952(99)00346-9","article-title":"Potent Effects of Novel Anti-Platelet Aggregatory Cilostamide Analogues on Recombinant Cyclic Nucleotide Phosphodiesterase Isozyme Activity","volume":"59","author":"Sudo","year":"2000","journal-title":"Biochem. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"690","DOI":"10.3109\/10715762.2012.669040","article-title":"Piclamilast Inhibits the Pro-Apoptotic and Anti-Proliferative Responses of A549 Cells Exposed to H2O2 via Mechanisms Involving AP-1 Activation","volume":"46","author":"Mata","year":"2012","journal-title":"Free Radic. Res."},{"key":"ref_49","unstructured":"Sterk, G.J., Hatzelmann, A., Barsig, J., Marx, D., Kley, H.-P., Christiaans, J.A.M., and Menge, W.M.P.B. (2005). Pyrrolidinedione Substituted Piperidine-Phthalazones as Pde4. (PL373645A1), Inhibitors. Patent."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"203","DOI":"10.2174\/156720511795256053","article-title":"EHT0202 in Alzheimers Disease: A 3-Month, Randomized, Placebo- Controlled, Double-Blind Study","volume":"8","author":"Vellas","year":"2011","journal-title":"Curr. Alzheimer Res."},{"key":"ref_51","unstructured":"Sterk, G.J., Hatzelmann, A., Marx, D., and Steinhilber, W. (2004). Phthalazinones Derivatives Useful as Pde4\/7. (SK14342003A3), Inhibitors. Patent."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1093\/infdis\/jir857","article-title":"Pharmacological Validation of Trypanosoma Brucei Phosphodiesterases as Novel Drug Targets","volume":"206","author":"Gould","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_53","unstructured":"Weinbrenner, S., Dunkern, T., Marx, D., Schmidt, B., Stenget, T., Flockerzi, D., Kautz, U., Hauser, D., Diefenbach, J., and Christiaans, J.A.M. (2008). 6-Benzyl-2,3,4,7-Tetrahydro-Indolo[2,3-c]Quinoline Compounds Useful as Pde5. (WO2008095835A1), Inhibitors. Patent."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.1016\/j.bmcl.2005.05.090","article-title":"Comparison of Different Heterocyclic Scaffolds as Substrate Analog PDE5 Inhibitors","volume":"15","author":"Haning","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/jnr.10102","article-title":"Zaprinast, an Inhibitor of CGMP-Selective Phosphodiesterases, Enhances the Secretion of TNF-\u03b1 and IL-1\u03b2 and the Expression of INOS and MHC Class II Molecules in Rat Microglial Cells","volume":"67","author":"Choi","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1679LP","DOI":"10.1124\/mol.104.002246","article-title":"Discovery of BRL 50481 [3-(&lt;Em&gt;N,N&lt;\/Em&gt;-Dimethylsulfonamido)-4-Methyl-Nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8&lt;Sup&gt;+&lt;\/Sup&gt; T-Lymphocytes","volume":"66","author":"Smith","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3274","DOI":"10.1021\/jm201720d","article-title":"Effect of Phosphodiesterase 7 (PDE7) Inhibitors in Experimental Autoimmune Encephalomyelitis Mice. Discovery of a New Chemically Diverse Family of Compounds","volume":"55","author":"Redondo","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8590","DOI":"10.1021\/jm501090m","article-title":"Modulation of CAMP-Specific PDE without Emetogenic Activity: New Sulfide-Like PDE7 Inhibitors","volume":"57","author":"Brea","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3095","DOI":"10.1016\/j.bmcl.2011.03.022","article-title":"1,5-Substituted Nipecotic Amides: Selective PDE8 Inhibitors Displaying Diastereomer-Dependent Microsomal Stability","volume":"21","author":"DeNinno","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"7621","DOI":"10.1021\/jm2009138","article-title":"Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors","volume":"54","author":"Malamas","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.chembiol.2011.12.010","article-title":"Identification of Biologically Active PDE11-Selective Inhibitors Using a Yeast-Based High-Throughput Screen","volume":"19","author":"Ceyhan","year":"2012","journal-title":"Chem. Biol."},{"key":"ref_62","unstructured":"(2023, March 31). Integrated DNA Technologies Tool. Available online: https:\/\/www.idtdna.com\/CodonOpt."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/gkm047","article-title":"A Versatile Ligation-Independent Cloning Method Suitable for High-Throughput Expression Screening Applications","volume":"35","author":"Berrow","year":"2007","journal-title":"Nucleic Acids. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1107\/S0907444910045749","article-title":"Overview of the CCP4 Suite and Current Developments","volume":"67","author":"Winn","year":"2011","journal-title":"Acta Crystallogr. Sect. D"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: Model-Building Tools for Molecular Graphics","volume":"60","author":"Emsley","year":"2004","journal-title":"Acta Crystallogr. Sect. D"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"483","DOI":"10.4269\/ajtmh.1967.16.483","article-title":"An Improved Perfusion Technique for Recovering Adult Schistosomes from Laboratory Animals","volume":"16","author":"Duvall","year":"1967","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.ijpara.2003.12.003","article-title":"Sex- and Stage-Related Sensitivity of Schistosoma mansoni to In Vivo and In Vitro Praziquantel Treatment","volume":"34","author":"Cioli","year":"2004","journal-title":"Int. J. Parasitol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.ijpara.2005.05.002","article-title":"Effect of Praziquantel on the Immature Stages of Schistosoma haematobium","volume":"35","author":"Botros","year":"2005","journal-title":"Int. J. Parasitol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1021\/jm00037a021","article-title":"Selective Type IV Phosphodiesterase Inhibitors as Antiasthmatic Agents. The Syntheses and Biological Activities of 3-(Cyclopentyloxy)-4-Methoxybenzamides and Analogues","volume":"37","author":"Ashton","year":"1994","journal-title":"J. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1007\/s11164-012-0742-3","article-title":"A Convenient Method for the Synthesis of Roflumilast","volume":"39","author":"Lin","year":"2013","journal-title":"Res Chem. Intermed."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5893","DOI":"10.1021\/jm500378a","article-title":"Discovery and Early Clinical Development of 2-{6-[2-(3,5-Dichloro-4- Pyridyl)Acetyl]-2,3-Dimethoxyphenoxy}- N -Propylacetamide (LEO 29102), a Soft-Drug Inhibitor of Phosphodiesterase 4 for Topical Treatment of Atopic Dermatitis","volume":"57","author":"Felding","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"8188","DOI":"10.1021\/jm201148s","article-title":"Pharmacological Validation of Trypanosoma Brucei Phosphodiesterases B1 and B2 as Druggable Targets for African Sleeping Sickness","volume":"54","author":"Bland","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_73","unstructured":"Yao, L., and Xiao, Z. (2016). Preparation Method of Roflumilast N-Oxide. (106256820A), C.N. Patent."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.ejmech.2016.08.052","article-title":"Development of Highly Potent Phosphodiesterase 4 Inhibitors with Anti-Neuroinflammation Potential: Design, Synthesis, and Structure-Activity Relationship Study of Catecholamides Bearing Aromatic Rings","volume":"124","author":"Zhou","year":"2016","journal-title":"Eur. J. Med. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6817\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:10:55Z","timestamp":1760123455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6817"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,6]]},"references-count":74,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24076817"],"URL":"https:\/\/doi.org\/10.3390\/ijms24076817","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,6]]}}}