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Synthesis, multi-target enzyme inhibition, and in silico evaluation of phthalimide derivatives with relevance to tuberculosis-associated pathophysiology.

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Τίτλος: Synthesis, multi-target enzyme inhibition, and in silico evaluation of phthalimide derivatives with relevance to tuberculosis-associated pathophysiology.
Συγγραφείς: Khushal A; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan., Khan S; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan; Department of Chemistry, Pennsylvania State University, University Park 16802, PA, USA. Electronic address: sarakhan@cuiatd.edu.pk., Farooq U; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan. Electronic address: umarf@cuiatd.edu.pk., Khan MN; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan., Hafeez M; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan., Sarwar R; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan.
Πηγή: Bioorganic chemistry [Bioorg Chem] 2026 Oct 15; Vol. 182, pp. 110441. Date of Electronic Publication: 2026 Aug 31.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE
Imprint Name(s): Publication: Amsterdam : Elsevier
Original Publication: New York, London, Academic Press.
Ιατρικοί όροι (MeSH): Phthalimides*/pharmacology , Phthalimides*/chemical synthesis , Phthalimides*/chemistry , Enzyme Inhibitors*/chemical synthesis , Enzyme Inhibitors*/pharmacology , Enzyme Inhibitors*/chemistry , Mycobacterium tuberculosis*/enzymology , Mycobacterium tuberculosis*/drug effects , Urease*/antagonists & inhibitors , Urease*/metabolism , Xanthine Oxidase*/antagonists & inhibitors , Xanthine Oxidase*/metabolism , Tuberculosis*/drug therapy , Tuberculosis*/physiopathology, Butyrylcholinesterase/metabolism ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; Humans ; Molecular Docking Simulation
Περίληψη: Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a significant global health concern requiring innovative therapeutic approaches. Urease is a bacterial enzyme involved in nitrogen acquisition and phagosomal alkalinization in Mtb, whereas thymidine phosphorylase (TP), xanthine oxidase (XO), and butyrylcholinesterase (BChE) are host enzymes associated with nucleotide metabolism, oxidative stress, and cholinergic/immune regulation, respectively, and were included to explore enzyme-inhibitory profiles with potential relevance to tuberculosis-associated pathophysiology. In this study, a new series of phthalimide derivatives was synthesized and structurally characterized through 1H NMR and 13C NMR, with further optimization performed at the DFT level (B3LYP/6-31G). Enzyme inhibition assays demonstrated inhibitory activity across the four targets. Compound C15 emerged as the most effective multitarget enzyme inhibitor, showing strong activity against urease (IC₅₀ = 2.90 ± 0.11 μM), XO (IC₅₀ = 5.61 ± 0.14 μM), and BChE (IC₅₀ = 9.49 ± 0.18 μM), whereas compound C17 displayed the greatest potency towards TP (IC₅₀ = 3.24 ± 0.28 μM). UV-Visible spectrophotometric analysis was conducted to examine enzyme-ligand interactions, revealing concentration-dependent changes consistent with complex formation. Among the series, C17 exhibited the strongest binding affinity towards TP and urease, whereas C15 showed the strongest affinity towards XO. Structure-activity relationship analysis identified benzothiazole, halogen, nitro, sulphonamide, and carboxylic acid functionalities as important contributors to enzyme-inhibitory activity. Collectively, these findings identify C15 and C17 as promising lead compounds for further optimization as multitarget enzyme inhibitors.
(Copyright © 2026 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Binding constant, dissociation constant; Mycobacterium tuberculosis; Phthalimides; Thymidine phosphorylase; UV–Vis absorption; Urease; Xanthine oxidase
Substance Nomenclature: 0 (Phthalimides)
0 (Enzyme Inhibitors)
EC 3.5.1.5 (Urease)
EC 3.1.1.8 (Butyrylcholinesterase)
EC 1.17.3.2 (Xanthine Oxidase)
1J6PQ7YI80 (phthalimide)
Entry Date(s): Date Created: 20260901 Date Completed: 20261008 Latest Revision: 20261008
Update Code: 20261008
DOI: 10.1016/j.bioorg.2026.110441
PMID: 42679740
Βάση Δεδομένων: MEDLINE
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  Data: Synthesis, multi-target enzyme inhibition, and in silico evaluation of phthalimide derivatives with relevance to tuberculosis-associated pathophysiology.
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  Data: <searchLink fieldCode="AU" term="%22Khushal+A%22">Khushal A</searchLink>; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan.<br /><searchLink fieldCode="AU" term="%22Khan+S%22">Khan S</searchLink>; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan; Department of Chemistry, Pennsylvania State University, University Park 16802, PA, USA. Electronic address: sarakhan@cuiatd.edu.pk.<br /><searchLink fieldCode="AU" term="%22Farooq+U%22">Farooq U</searchLink>; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan. Electronic address: umarf@cuiatd.edu.pk.<br /><searchLink fieldCode="AU" term="%22Khan+MN%22">Khan MN</searchLink>; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan.<br /><searchLink fieldCode="AU" term="%22Hafeez+M%22">Hafeez M</searchLink>; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan.<br /><searchLink fieldCode="AU" term="%22Sarwar+R%22">Sarwar R</searchLink>; Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, KPK, Pakistan.
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  Data: <searchLink fieldCode="MM" term="%22Phthalimides%22">Phthalimides*</searchLink>/<searchLink fieldCode="MM" term="%22Phthalimides+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Phthalimides%22">Phthalimides*</searchLink>/<searchLink fieldCode="MM" term="%22Phthalimides+chemical+synthesis%22">chemical synthesis</searchLink> <br /><searchLink fieldCode="MM" term="%22Phthalimides%22">Phthalimides*</searchLink>/<searchLink fieldCode="MM" term="%22Phthalimides+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Enzyme+Inhibitors%22">Enzyme Inhibitors*</searchLink>/<searchLink fieldCode="MM" term="%22Enzyme+Inhibitors+chemical+synthesis%22">chemical synthesis</searchLink> <br /><searchLink fieldCode="MM" term="%22Enzyme+Inhibitors%22">Enzyme Inhibitors*</searchLink>/<searchLink fieldCode="MM" term="%22Enzyme+Inhibitors+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Enzyme+Inhibitors%22">Enzyme Inhibitors*</searchLink>/<searchLink fieldCode="MM" term="%22Enzyme+Inhibitors+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Mycobacterium+tuberculosis%22">Mycobacterium tuberculosis*</searchLink>/<searchLink fieldCode="MM" term="%22Mycobacterium+tuberculosis+enzymology%22">enzymology</searchLink> <br /><searchLink fieldCode="MM" term="%22Mycobacterium+tuberculosis%22">Mycobacterium tuberculosis*</searchLink>/<searchLink fieldCode="MM" term="%22Mycobacterium+tuberculosis+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Urease%22">Urease*</searchLink>/<searchLink fieldCode="MM" term="%22Urease+antagonists+%26+inhibitors%22">antagonists & inhibitors</searchLink> <br /><searchLink fieldCode="MM" term="%22Urease%22">Urease*</searchLink>/<searchLink fieldCode="MM" term="%22Urease+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Xanthine+Oxidase%22">Xanthine Oxidase*</searchLink>/<searchLink fieldCode="MM" term="%22Xanthine+Oxidase+antagonists+%26+inhibitors%22">antagonists & inhibitors</searchLink> <br /><searchLink fieldCode="MM" term="%22Xanthine+Oxidase%22">Xanthine Oxidase*</searchLink>/<searchLink fieldCode="MM" term="%22Xanthine+Oxidase+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Tuberculosis%22">Tuberculosis*</searchLink>/<searchLink fieldCode="MM" term="%22Tuberculosis+drug+therapy%22">drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Tuberculosis%22">Tuberculosis*</searchLink>/<searchLink fieldCode="MM" term="%22Tuberculosis+physiopathology%22">physiopathology</searchLink><br /><searchLink fieldCode="MH" term="%22Butyrylcholinesterase%22">Butyrylcholinesterase</searchLink>/<searchLink fieldCode="MH" term="%22Butyrylcholinesterase+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Structure-Activity+Relationship%22">Structure-Activity Relationship</searchLink> ; <searchLink fieldCode="MH" term="%22Molecular+Structure%22">Molecular Structure</searchLink> ; <searchLink fieldCode="MH" term="%22Dose-Response+Relationship%2C+Drug%22">Dose-Response Relationship, Drug</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Molecular+Docking+Simulation%22">Molecular Docking Simulation</searchLink>
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  Label: Abstract
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  Data: Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a significant global health concern requiring innovative therapeutic approaches. Urease is a bacterial enzyme involved in nitrogen acquisition and phagosomal alkalinization in Mtb, whereas thymidine phosphorylase (TP), xanthine oxidase (XO), and butyrylcholinesterase (BChE) are host enzymes associated with nucleotide metabolism, oxidative stress, and cholinergic/immune regulation, respectively, and were included to explore enzyme-inhibitory profiles with potential relevance to tuberculosis-associated pathophysiology. In this study, a new series of phthalimide derivatives was synthesized and structurally characterized through <superscript>1</superscript>H NMR and <superscript>13</superscript>C NMR, with further optimization performed at the DFT level (B3LYP/6-31G). Enzyme inhibition assays demonstrated inhibitory activity across the four targets. Compound C15 emerged as the most effective multitarget enzyme inhibitor, showing strong activity against urease (IC₅₀ = 2.90 ± 0.11 μM), XO (IC₅₀ = 5.61 ± 0.14 μM), and BChE (IC₅₀ = 9.49 ± 0.18 μM), whereas compound C17 displayed the greatest potency towards TP (IC₅₀ = 3.24 ± 0.28 μM). UV-Visible spectrophotometric analysis was conducted to examine enzyme-ligand interactions, revealing concentration-dependent changes consistent with complex formation. Among the series, C17 exhibited the strongest binding affinity towards TP and urease, whereas C15 showed the strongest affinity towards XO. Structure-activity relationship analysis identified benzothiazole, halogen, nitro, sulphonamide, and carboxylic acid functionalities as important contributors to enzyme-inhibitory activity. Collectively, these findings identify C15 and C17 as promising lead compounds for further optimization as multitarget enzyme inhibitors.<br /> (Copyright © 2026 Elsevier Inc. All rights reserved.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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  Data: <i>Keywords: </i>Binding constant, dissociation constant; Mycobacterium tuberculosis; Phthalimides; Thymidine phosphorylase; UV–Vis absorption; Urease; Xanthine oxidase
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  Data: 0 (Phthalimides)<br />0 (Enzyme Inhibitors)<br />EC 3.5.1.5 (Urease)<br />EC 3.1.1.8 (Butyrylcholinesterase)<br />EC 1.17.3.2 (Xanthine Oxidase)<br />1J6PQ7YI80 (phthalimide)
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        Value: 10.1016/j.bioorg.2026.110441
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        Text: English
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        Type: general
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      – SubjectFull: Mycobacterium tuberculosis enzymology
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      – SubjectFull: Tuberculosis drug therapy
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      – SubjectFull: Tuberculosis physiopathology
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