N-Substituted (Hexahydro)-1H-isoindole-1,3(2H)-dione Derivatives: New Insights into Synthesis and Characterization

Novel phthalimide derivatives, namely N-(1,3-dioxoisoindolin-2-yl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide (1a) and N-(1,3-dioxoisoindolin-2-yl)thiophene-2-carboxamide (1b), and hexahydrophthalimide derivative N-(1,3-dioxohexahydro-1H-isoindol-2(3H)-yl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide (2), have been synthesized. The phthalimide derivatives were synthesized from phthalic anhydride and 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetohydrazide or thiophene-2-carbohydrazide, and the hexahydrophthalimide derivative has been synthesized from hexahydrophthalic anhydride and 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetohydrazide. The chemical structures of the compounds are elucidated by Nuclear Magnetic Resonance (NMR) and Infrared (IR) spectra. The new in vitro antioxidant activities of the obtained substances were evaluated using the DPPH method. All tested compounds showed antioxidative activity, the most active compound being 1b. Bioinformatics tools were used for the prediction of pharmacokinetics and pharmacodynamics profiles. Our results showedthat all compounds have a suitable intestinal absorption rate, good BBB and CNS permeabilities and have as molecular targets MAO B, COX-2 and NF-KB, important for antioxidant activities.

[1]  S. Avram,et al.  Target Prediction of 5,10,15,20-Tetrakis(4′-Sulfonatophenyl)-Porphyrin Using Molecular Docking , 2022, Pharmaceutics.

[2]  Amit Kumar,et al.  Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase. , 2022, European journal of medicinal chemistry.

[3]  A. Saeed,et al.  Synthesis of New Substituted Thiophene Derivatives and Evaluating their Antibacterial and Antioxidant Activities , 2022, Polycyclic Aromatic Compounds.

[4]  M. Chifiriuc,et al.  In Silico and Experimental Investigation of the Biological Potential of Some Recently Developed Carprofen Derivatives , 2022, Molecules.

[5]  M. Konuş,et al.  Synthesis of Ethynyl‐Thiophene Derivatives, Antioxidant Properties and ADME Analysis , 2022, ChemistrySelect.

[6]  Nitin Kumar,et al.  Thiophene and its Analogs as Prospective Antioxidant Agents: A Retrospect. , 2021, Mini reviews in medicinal chemistry.

[7]  J. Pagés,et al.  Quinazoline Derivatives Designed as Efflux Pump Inhibitors: Molecular Modeling and Spectroscopic Studies , 2021, Molecules.

[8]  G. Grădișteanu Pîrcălăbioru,et al.  Laser-Irradiated Chlorpromazine as a Potent Anti-Biofilm Agent for Coating of Biomedical Devices , 2020, Coatings.

[9]  M. Chifiriuc,et al.  Design, Synthesis and In Vitro Characterization of Novel Antimicrobial Agents Based on 6-Chloro-9H-carbazol Derivatives and 1,3,4-Oxadiazole Scaffolds , 2020, Molecules.

[10]  Z. A. Bhat,et al.  Possible Pathways of Hepatotoxicity Caused by Chemical Agents. , 2019, Current drug metabolism.

[11]  M. Chifiriuc,et al.  Evaluating the biological potential of some new cobalt (II) complexes with acrylate and benzimidazole derivatives , 2019, Applied Organometallic Chemistry.

[12]  R. Kaur,et al.  Click Chemistry Approach to Isoindole-1,3-dione Tethered 1,2,3-Triazole Derivatives , 2019, SynOpen.

[13]  R. Bărăţoiu,et al.  Synthesis and structural characterization of some novel methoxyamino derivatives with acid-base and redox behavior , 2018, Journal of Molecular Structure.

[14]  Ahmed T Negmeldin,et al.  Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors , 2018, Journal of enzyme inhibition and medicinal chemistry.

[15]  E. Bagci,et al.  Advanced Structure-activity Relationships Applied to Mentha spicata L. Subsp. spicata Essential Oil Compounds as AChE and NMDA Ligands, in Comparison with Donepezil, Galantamine and Memantine - New Approach in Brain Disorders Pharmacology. , 2017, CNS & neurological disorders drug targets.

[16]  N. C. Silva,et al.  Synthesis of piplartine analogs and preliminary findings on structure–antimicrobial activity relationship , 2017, Medicinal Chemistry Research.

[17]  M. Malkowski,et al.  Crystal structure of rofecoxib bound to human cyclooxygenase-2. , 2016, Acta crystallographica. Section F, Structural biology communications.

[18]  Mihai V. Putz,et al.  Learning the Relationship between the Primary Structure of HIV Envelope Glycoproteins and Neutralization Activity of Particular Antibodies by Using Artificial Neural Networks , 2016, International journal of molecular sciences.

[19]  F. Al-Omran,et al.  Synthesis, Spectroscopy and X-Ray Characterization, of Novel Derivatives of Substituted 2-(Benzothiazol-2’-ylthio)acetohydrazide , 2016 .

[20]  J. Grúz,et al.  Design, Synthesis and Evaluation of Novel Phthalimide Derivatives as in Vitro Anti-Microbial, Anti-Oxidant and Anti-Inflammatory Agents , 2015, Molecules.

[21]  P. Yogeeswari,et al.  Development of 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives as novel enoyl-acyl carrier protein reductase (InhA) inhibitors for the treatment of tuberculosis. , 2014, European journal of medicinal chemistry.

[22]  D. Zicāne,et al.  Synthesis and Antioxidant Properties of Novel Quinazoline Derivatives , 2014 .

[23]  Guangfu Yang,et al.  Hexahydrophthalimide–benzothiazole hybrids as a new class of protoporphyrinogen oxidase inhibitors: synthesis, structure–activity relationship, and DFT calculations , 2014 .

[24]  C. Shi,et al.  Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma. , 2014, Acta biochimica et biophysica Sinica.

[25]  M. Chifiriuc,et al.  Synthesis and microbiological evaluation of several benzocaine derivatives , 2013 .

[26]  Salwa S. Abdelwahab,et al.  Synthesis and Spectral Characterization of Novel 2, 3-Disubstituted Quinazolin-4(3H) one Derivatives , 2012 .

[27]  P. Ioniță,et al.  Chemical and biological evaluation of some new antipyrine derivatives with particular properties. , 2012, Bioorganic chemistry.

[28]  Rizk E. Khidre,et al.  Synthesis and anti-microbial activity of some 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile derivatives. , 2011, European journal of medicinal chemistry.

[29]  Neeraj Kumar,et al.  Recent advances in the chemistry of phthalimide analogues and their therapeutic potential. , 2010, Mini reviews in medicinal chemistry.

[30]  Peicheng Zhang,et al.  Synthesis and antiviral activity of phthiobuzone analogues. , 2010, Chemical & pharmaceutical bulletin.

[31]  T. Bansode,et al.  Synthesis and antimicrobial activity of some new N-acyl substituted phenothiazines. , 2009, European journal of medicinal chemistry.

[32]  A. Chan,et al.  The preparation and in vitro antiproliferative activity of phthalimide based ketones on MDAMB-231 and SKHep-1 human carcinoma cell lines. , 2009, European journal of medicinal chemistry.

[33]  F. Pavan,et al.  Synthesis and in vitro anti Mycobacterium tuberculosis activity of a series of phthalimide derivatives. , 2009, Bioorganic & medicinal chemistry.

[34]  Garrett M Morris,et al.  Using AutoDock for Ligand‐Receptor Docking , 2008, Current protocols in bioinformatics.

[35]  Michael L. Wang,et al.  Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. , 2008, Blood.

[36]  Hiroko Sano,et al.  Angiogenesis inhibitors derived from thalidomide. , 2005, Bioorganic & medicinal chemistry letters.

[37]  L. M. Lima,et al.  Synthesis and anti-inflammatory activity of phthalimide derivatives, designed as new thalidomide analogues. , 2002, Bioorganic & medicinal chemistry.

[38]  Gregory L. Verdine,et al.  Structure of the NF-κB p50 homodimer bound to DNA , 1995, Nature.

[39]  OUP accepted manuscript , 2022, Nucleic Acids Research.

[40]  C. S. Karthik,et al.  Investigation of Antioxidant Properties of Phthalimide Derivatives , 2015 .

[41]  Shaker Awad Abdul Husseina,et al.  Synthesis, characterization and antimicrobial activity of new 2,5-disubstituted-1,3,4-thiadiazole derivatives , 2015 .

[42]  P. Schafer,et al.  Isosteric analogs of lenalidomide and pomalidomide: synthesis and biological activity. , 2013, Bioorganic & medicinal chemistry letters.

[43]  M. Suvaikin,et al.  Synthesis, characterization and antimicrobial activity of 2-(dimethylaminomethyl)isoindoline-1,3-dione and its cobalt(II) and nickel(II) complexes , 2012 .

[44]  K. Dguigui,et al.  3D-QSAR FOR α-GLUCOSIDASE INHIBITORY ACTIVITY OF N-(PHENOXYALKYL) PHTHALIMIDE DERIVATIVES , 2012 .

[45]  Andrea Mattevi,et al.  Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders , 2002, Nature Structural Biology.

[46]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..