{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T16:18:47Z","timestamp":1793636327569,"version":"4.5.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T00:00:00Z","timestamp":1691020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>Derivative synthesis has been a crucial method for altering the effects of already-approved medications, especially to lessen adverse effects and enhance results. Making use of this multi-target approach, a series of naproxen-sulfa drug conjugates was designed and synthesized. The newly designed conjugates were confirmed by spectroscopic techniques like IR, <jats:sup>1<\/jats:sup>HNMR, <jats:sup>13<\/jats:sup>CNMR, and elemental analysis. The conjugates were screened for anti-inflammatory, urease, and cyclooxygenase-2 (COX-2) inhibition. Naproxen conjugated with sulfanilamide, sulfathiazole, and sulfaguanidine was found potent and showed a competitive mode of urease inhibition, with IC<jats:sub>50<\/jats:sub> (\u00b5M) values 6.69 \u00b1 0.11, 5.82 \u00b1 0.28, 5.06 \u00b1 0.29, respectively. When compared to other screened conjugates, the naproxen-sulfamethoxazole conjugation showed better anti-inflammatory action by inhibiting induced edema by 82.8%, which is comparable to the medication indomethacin (86.8% inhibition). Whereas it exhibited 75.4% inhibition of COX-2 at 10\u00a0\u00b5M concentration which is comparable with the reference drug (celecoxib, 77.1% inhibition). Moreover, the binding modes of competitive inhibitors with the urease and COX-2 receptor were predicted through molecular docking studies and their stability analysis through MD simulations showed that these compounds made stable complexes with the respective targets and there were no conformational changes that occurred during simulation. The obtained results showed that the conjugates of approved therapeutic molecules may lead to the development of novel types of pharmacological agents in the treatment of several pathological disorders where urease and COX-2 enzymes are involved.<\/jats:p>","DOI":"10.3389\/fchem.2023.1206380","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T10:02:54Z","timestamp":1691056974000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Exploring the potential of propanamide-sulfonamide based drug conjugates as dual inhibitors of urease and cyclooxygenase-2: biological and their in silico studies"],"prefix":"10.3389","volume":"11","author":[{"given":"Saghir","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Abdul Qadir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmood","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Imran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Numan","family":"Yousaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanveer A.","family":"Wani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema","family":"Zargar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ijaz","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Muddassar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2015\/524056","article-title":"Amidine sulfonamides and benzene sulfonamides: Synthesis and their biological evaluation","volume":"2015","author":"Abdul Qadir","year":"","journal-title":"J. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2015\/938486","article-title":"Synthesis, characterization, and antibacterial activities of novel sulfonamides derived through condensation of amino group containing drugs, amino acids, and their analogs","volume":"2015","author":"Abdul Qadir","year":"","journal-title":"BioMed Res. Int."},{"key":"B3","doi-asserted-by":"publisher","first-page":"128740","DOI":"10.1016\/j.molstruc.2020.128740","article-title":"Benzenesulfonohydrazides inhibiting urease: Design, synthesis, their in vitro and in silico studies","volume":"1220","author":"Ahmed","year":"2020","journal-title":"J. Mol. Struct."},{"key":"B4","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.bbrc.2017.06.059","article-title":"Azomethines, isoxazole, N-substituted pyrazoles and pyrimidine containing curcumin derivatives: Urease inhibition and molecular modeling studies","volume":"490","author":"Ahmed","year":"2017","journal-title":"Biochem. biophysical Res. Commun."},{"key":"B5","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.bioorg.2017.11.015","article-title":"Sulfonamides containing curcumin scaffold: Synthesis, characterization, carbonic anhydrase inhibition and molecular docking studies","volume":"76","author":"Ahmed","year":"","journal-title":"Bioorg. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1111\/cbdd.13076","article-title":"Screening of curcumin\u2010derived isoxazole, pyrazoles, and pyrimidines for their anti\u2010inflammatory, antinociceptive, and cyclooxygenase\u20102 inhibition","volume":"91","author":"Ahmed","year":"","journal-title":"Chem. Biol. Drug Des."},{"key":"B7","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.arabjc.2016.11.017","article-title":"Synthesis, characterization, biological activities and molecular modeling of Schiff bases of benzene sulfonamides bearing curcumin scaffold","volume":"12","author":"Ahmed","year":"2019","journal-title":"Arabian J. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3210","DOI":"10.1039\/d2ra08284e","article-title":"Flavonoids and related privileged scaffolds as potential urease inhibitors: A review","volume":"13","author":"Al-Rooqi","year":"2023","journal-title":"RSC Adv."},{"key":"B9","first-page":"10","volume-title":"Combined 3D-QSAR, molecular docking and dynamics simulations studies to model and design TTK inhibitors","author":"Ashraf","year":"2022"},{"key":"B10","volume-title":"Amber 2021: Reference manual","author":"Case","year":"2021"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"Case","year":"2005","journal-title":"Amber Biomol. Simul. programs"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.3390\/molecules22081352","article-title":"Sulfonamide-linked ciprofloxacin, sulfadiazine and amantadine derivatives as a novel class of inhibitors of jack bean urease; synthesis, kinetic mechanism and molecular docking","volume":"22","author":"Channar","year":"2017","journal-title":"Molecules"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.3390\/polym14081609","article-title":"Inhibition of carrageenan-induced acute inflammation in mice by the microgramma vacciniifolia frond lectin (MvFL)","volume":"14","author":"de Siqueira Patriota","year":"2022","journal-title":"Polymers"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1002\/jcc.10349","article-title":"A point\u2010charge force field for molecular mechanics simulations of proteins based on condensed\u2010phase quantum mechanical calculations","volume":"24","author":"Duan","year":"2003","journal-title":"J. Comput. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"114412","DOI":"10.1016\/j.ejmech.2022.114412","article-title":"Development of 4-((3-oxo-3-phenylpropyl) amino) benzenesulfonamide derivatives utilizing tail\/dual-tail approaches as novel carbonic anhydrase inhibitors","volume":"238","author":"Elbadawi","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"117194","DOI":"10.1016\/j.bmc.2023.117194","article-title":"The most common linkers in bioactive molecules and their bioisosteric replacement network","volume":"81","author":"Ertl","year":"2023","journal-title":"Bioorg. Med. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1002\/pro.3923","article-title":"The Bio3D packages for structural bioinformatics","volume":"30","author":"Grant","year":"2021","journal-title":"Bio3D Packag. Struct. Bioinforma."},{"key":"B18","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"Vmd: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"VMD Vis. Mol. Dyn."},{"key":"B19","doi-asserted-by":"publisher","first-page":"16061","DOI":"10.1039\/d0ra02363a","article-title":"Identification of novel bacterial urease inhibitors through molecular shape and structure based virtual screening approaches","volume":"10","author":"Imran","year":"2020","journal-title":"RSC Adv."},{"key":"B20","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":", RW Impey, ML Klein."},{"key":"B21","doi-asserted-by":"publisher","first-page":"106406","DOI":"10.1016\/j.bioorg.2023.106406","article-title":"Switching of newly synthesized linker-based derivatives of non-steroidal anti-inflammatory drugs toward anti-inflammatory and anticancer activity","volume":"133","author":"Kaur","year":"2023","journal-title":"Bioorg. Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"7129","DOI":"10.3390\/molecules27207129","article-title":"Synthesis, in vitro anti-microbial analysis and molecular docking study of aliphatic hydrazide-based benzene sulphonamide derivatives as potent inhibitors of \u03b1-glucosidase and urease","volume":"27","author":"Khan","year":"2022","journal-title":"Molecules"},{"key":"B23","doi-asserted-by":"publisher","first-page":"254","DOI":"10.3390\/ph16020254","article-title":"An understanding of mechanism-based approaches for 1, 3, 4-oxadiazole scaffolds as cytotoxic agents and enzyme inhibitors","volume":"16","author":"Kumar","year":"2023","journal-title":"Pharmaceuticals"},{"key":"B24","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1134\/s0026893308040195","article-title":"Radius of gyration as an indicator of protein structure compactness","volume":"42","author":"Lobanov","year":"2008","journal-title":"Mol. Biol. Los. Angel."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1016\/j.bcp.2003.12.014","article-title":"Cyclooxygenase-2 (COX-2)-dependent and-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells","volume":"67","author":"Maier","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.ejps.2018.06.003","article-title":"Safer anti-inflammatory therapy through dual COX-2\/5-LOX inhibitors: A structure-based approach","volume":"121","author":"Manju","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e0138616","DOI":"10.1371\/journal.pone.0138616","article-title":"Mitotic checkpoint kinase Mps1 has a role in normal physiology which impacts clinical utility","volume":"10","author":"Martinez","year":"2015","journal-title":"PLoS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3775","DOI":"10.1021\/acsomega.1c06694","article-title":"Synthesis and evaluation of 1,3,5-triaryl-2-pyrazoline derivatives as potent dual inhibitors of urease and \u03b1-glucosidase together with their cytotoxic, molecular modeling and drug-likeness studies","volume":"7","author":"Mehmood","year":"2022","journal-title":"ACS omega"},{"key":"B29","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.bioorg.2018.10.021","article-title":"Biology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico study of S-naproxen derivatives","volume":"83","author":"Mohiuddin","year":"2019","journal-title":"Bioorg. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"264","DOI":"10.2174\/1570180815666180820144621","article-title":"Cephalosporin conjugated sulfonamides: Synthesis, characterization and anticancer activities","volume":"17","author":"Nadeem","year":"2020","journal-title":"Lett. Drug Des. Discov."},{"key":"B31","doi-asserted-by":"publisher","first-page":"107860","DOI":"10.1016\/j.pharmthera.2021.107860","article-title":"Deciphering the key heterocyclic scaffolds in targeting microtubules, kinases and carbonic anhydrases for cancer drug development","volume":"225","author":"Peerzada","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"044130","DOI":"10.1063\/5.0014475","article-title":"Scalable molecular dynamics on CPU and GPU architectures with NAMD","volume":"153","author":"Phillips","year":"2020","journal-title":"NAMD"},{"key":"B33","first-page":"719","article-title":"Synthesis and biological evaluation of amino terminal modified new sulfonamides of contemporary drugs","volume":"34","author":"Qadir","year":"2015","journal-title":"Lat. Am. J. Pharm."},{"key":"B34","doi-asserted-by":"publisher","first-page":"123639","DOI":"10.1016\/j.jssc.2022.123639","article-title":"Exploring the potential of anti-inflammatory activity of berberine chloride-loaded mesoporous silica nanoparticles in carrageenan-induced rat paw edema model","volume":"317","author":"Rathod","year":"2023","journal-title":"J. Solid State Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1021\/acs.jctc.7b00028","article-title":"How molecular size impacts RMSD applications in molecular dynamics simulations","volume":"13","author":"Sargsyan","year":"2017","journal-title":"J. Chem. Theory Comput."},{"key":"B36","first-page":"2017","volume-title":"Schr\u00f6dinger","year":"2017"},{"key":"B37","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s11030-019-10032-x","article-title":"Biology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico studies on ibuprofen derivatives","volume":"25","author":"Seraj","year":"2021","journal-title":"Mol. Divers."},{"key":"B38","doi-asserted-by":"publisher","first-page":"42983","DOI":"10.1039\/d0ra09051d","article-title":"Folic acid-sulfonamide conjugates as antibacterial agents: Design, synthesis and molecular docking studies","volume":"10","author":"Shahzad","year":"2020","journal-title":"RSC Adv."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2553","DOI":"10.1021\/ct300203w","article-title":"Improving the prediction of absolute solvation free energies using the next generation OPLS force field","volume":"8","author":"Shivakumar","year":"2012","journal-title":"OPLS force field"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.3390\/molecules23071527","article-title":"Investigations of structural requirements for BRD4 inhibitors through ligand- and structure-based 3D QSAR approaches","volume":"23","author":"Tahir","year":"2018","journal-title":"Molecules"},{"key":"B41","doi-asserted-by":"publisher","first-page":"130226","DOI":"10.1016\/j.molstruc.2021.130226","article-title":"Levofloxacin and sulfa drugs linked via Schiff bases: Exploring their urease inhibition, enzyme kinetics and in silico studies","volume":"1235","author":"Tirmazi","year":"2021","journal-title":"J. Mol. Struct."},{"key":"B42","doi-asserted-by":"publisher","first-page":"135077","DOI":"10.1016\/j.molstruc.2023.135077","article-title":"A novel series of thiosemicarbazone hybrid scaffolds: Design, Synthesis, DFT studies, metabolic enzyme inhibition properties, and molecular docking calculations","volume":"1280","author":"Yakan","year":"2023","journal-title":"J. Mol. Struct."},{"key":"B43","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/s41467-023-35829-1","article-title":"Discovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors","volume":"14","author":"Yu","year":"2023","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2023.1206380\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T10:03:04Z","timestamp":1691056984000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2023.1206380\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,3]]},"references-count":43,"alternative-id":["10.3389\/fchem.2023.1206380"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2023.1206380","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,3]]},"article-number":"1206380"}}