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2000
Volume 22, Issue 4
  • ISSN: 1570-1794
  • E-ISSN: 1875-6271

Abstract

Derivatives of pyrimidinone, dihydropyrimidinone, and 2,4-diaryl-substituted pyrimidines were synthesized by cyclocondensation of α-aminoamidines with various saturated carbonyl derivatives and their analogs. The therapeutic potential of the newly synthesized derivatives for cancer treatment was evaluated using molecular docking calculations. The molecular docking results indicate that some of the synthesized diaryl derivatives of pyrimidine exhibit high binding affinity towards PIK3γ.

Aims and Objectives

4,6-Diaryl-substituted pyrimidines have shown high inhibitory potency against phosphoinositide 3-kinases (PI3Ks), which are important targets in oncology. Inhibition of PI3Ks could potentially be a viable therapy for human cancers.

Materials and Methods

The synthesis of pyrimidinone and dihydropyrimidinone derivatives as well as a series of 2,4-diaryl-substituted pyrimidines were described. These compounds were synthesized by cyclocondensation of α-aminoamidines with various saturated carbonyl derivatives and their analogs.

Results

Derivatives of pyrimidinone, dihydropyrimidinone, and 2,4-diaryl-substituted pyrimidines were synthesized by combining α-aminoamidines with various saturated carbonyl derivatives and their analogs. By adjusting the large substituents in the 2-position, we gained the ability to modify the therapeutic properties of the resulting compounds. The potential of the newly synthesized derivatives for cancer treatment was assessed using molecular docking calculations. The results of the docking calculations suggest that some of the synthesized diaryl derivatives of pyrimidine have a strong binding affinity towards PIK3γ, making them promising candidates for the development of new anticancer medications.

Conclusion

We synthesized some pyrimidinones, dihydropyrimidinones, and 2,4-diaryl-substituted pyrimidines by combining α-aminoamidines with various saturated carbonyl derivatives and similar compounds. Molecular docking results suggest that certain diaryl derivatives of pyrimidine have a strong binding affinity for PIK3γ. Moreover, diphenyl derivatives of pyrimidine exhibited dual inhibitory activity against PI3K and tubulin, showing promise for the development of next-generation microtubule-targeting agents for use in combination therapies.

This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2024-12-05
2025-05-29
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References

  1. DomínguezM. VidalM. García-ArriagadaM. RezendeM. Ultrasound-promoted synthesis of 4-pyrimidinols and their tosyl derivatives.Synthesis201648234246425210.1055/s‑0035‑1562788
    [Google Scholar]
  2. ZhanJ.L. WuM.W. ChenF. HanB. Cu-catalyzed [3 + 3] annulation for the synthesis of pyrimidines via β-c(sp3)–h functionalization of saturated ketones.J. Org. Chem.20168123119941200010.1021/acs.joc.6b02181 27805404
    [Google Scholar]
  3. ChuX.Q. CaoW.B. XuX.P. JiS.J. Iron catalysis for modular pyrimidine synthesis through β-ammoniation/cyclization of saturated carbonyl compounds with amidines.J. Org. Chem.20178221145115410.1021/acs.joc.6b02767 28032761
    [Google Scholar]
  4. KolomoitsevO.O. GladkovE.S. KotlyarV.M. PedanP.I. OnipkoO.V. BuravovO.V. ChebanovV.A. Efficient synthesis of imidazole and pyrimidine derivatives.Chem. Heterocycl. Compd.202056101329133410.1007/s10593‑020‑02818‑x
    [Google Scholar]
  5. DesenkoS.M. GorobetsM.Y. LipsonV.V. SakhnoY.I. ChebanovV.A. Dihydroazolopyrimidines: Past, present and perspectives in synthesis, green chemistry and drug discovery.Chem. Rec.2024242e20230024410.1002/tcr.202300244 37668291
    [Google Scholar]
  6. SnizhkoA.D. KyrychenkoA.V. GladkovE.S. Synthesis of novel derivatives of 5,6,7,8-tetrahydro-quinazolines using of α-aminoamidines and in silico screening of their biological activity.Int. J. Mol. Sci.2022237378110.3390/ijms23073781 35409144
    [Google Scholar]
  7. HicksR.G. KoivistoB.D. LemaireM.T. Synthesis of multitopic verdazyl radical ligands. Paramagnetic supramolecular synthons.Org. Lett.20046121887189010.1021/ol049746i 15176775
    [Google Scholar]
  8. GayonE. SzymczykM. GérardH. VranckenE. CampagneJ.M. Stereoselective and catalytic access to β-enaminones: an entry to pyrimidines.J. Org. Chem.201277209205922010.1021/jo301675g 23006434
    [Google Scholar]
  9. RulevA.Y. RomanovA.R. PopovA.V. KondrashovE.V. ZinchenkoS.V. Reaction of bromoenones with amidines: A simple catalyst-free approach to trifluoromethylated pyrimidines.Synthesis202052101512152210.1055/s‑0040‑1707969
    [Google Scholar]
  10. Folmer-AndersenJ.F. Aït-HaddouH. LynchV.M. AnslynE.V. 2,6-di(pyrimidin-4-yl)pyridine ligands with nitrogen-containing auxiliaries: The formation of functionalized molecular clefts upon metal coordination.Inorg. Chem.200342268674868110.1021/ic034823b 14686844
    [Google Scholar]
  11. ShultzM.D. CheungA.K. KirbyC.A. FirestoneB. FanJ. ChenC.H.T. ChenZ. ChinD.N. DiPietroL. FazalA. FengY. FortinP.D. GouldT. LaguB. LeiH. LenoirF. MajumdarD. OchalaE. PalermoM.G. PhamL. PuM. SmithT. StamsT. TomlinsonR.C. TouréB.B. VisserM. WangR.M. WatersN.J. ShaoW. Identification of NVP-TNKS656: The use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor.J. Med. Chem.201356166495651110.1021/jm400807n 23844574
    [Google Scholar]
  12. KotlyarV.M. KolomoitsevO.O. TarasenkoD.O. BondarenkoY.H. BuravovO.V. KotlyarM.I. RoshalA.D. Prospective biologically active compounds based on 5-formylthiazole.Funct. Mater.202128230130710.15407/fm28.02.1
    [Google Scholar]
  13. JonesP.D. GlassT.E. Synthesis of pyrimidine based metal ligands.Tetrahedron Lett.200142122265226710.1016/S0040‑4039(01)00091‑0
    [Google Scholar]
  14. YangC. YuH. YangN. MengL. XuJ. ZhangR. XieY. DingJ. Synthesis of 4-(5-benzyl-2-phenylpyrimidin-4-yl)morpholines as novel PI3K inhibitors via acetates of baylis-hillman adducts and benzamidines.Lett. Org. Chem.20096213414010.2174/157017809787582816
    [Google Scholar]
  15. AdamsL.A. AggarwalV.K. BonnertR.V. BresselB. CoxR.J. ShepherdJ. de VicenteJ. WalterM. WhittinghamW.G. WinnC.L. Diastereoselective synthesis of cyclopropane amino acids using diazo compounds generated in situ.J. Org. Chem.200368249433944010.1021/jo035060c 14629169
    [Google Scholar]
  16. ChebanovV.A. DesenkoS.M. GurleyT.W. Azaheterocycles Based on α,β-Unsaturated Carbonyls.Berlin, HeidelbergSpringer-Verlag2008
    [Google Scholar]
  17. GoodsellD.S. MorrisG.M. OlsonA.J. Automated docking of flexible ligands: Applications of autodock.J. Mol. Recognit.19969115 8723313
    [Google Scholar]
  18. TrottO. OlsonA.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J. Comput. Chem.201031245546110.1002/jcc.21334 19499576
    [Google Scholar]
  19. MairaS.M. PecchiS. HuangA. BurgerM. KnappM. SterkerD. SchnellC. GuthyD. NagelT. WiesmannM. BrachmannS. FritschC. DorschM. ChèneP. ShoemakerK. De PoverA. MenezesD. Martiny-BaronG. FabbroD. WilsonC.J. SchlegelR. HofmannF. García-EcheverríaC. SellersW.R. VolivaC.F. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor.Mol. Cancer Ther.201211231732810.1158/1535‑7163.MCT‑11‑0474 22188813
    [Google Scholar]
  20. BohnackerT. ProtaA.E. BeaufilsF. BurkeJ.E. MeloneA. InglisA.J. RageotD. SeleA.M. CmiljanovicV. CmiljanovicN. BargstenK. AherA. AkhmanovaA. DíazJ.F. FabbroD. ZvelebilM. WilliamsR.L. SteinmetzM.O. WymannM.P. Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention.Nat. Commun.2017811468310.1038/ncomms14683 28276440
    [Google Scholar]
  21. HumphreyW. DalkeA. SchultenK. VMD: Visual molecular dynamics. J. Mol. Graph.,1996141333827-2810.1016/0263‑7855(96)00018‑58744570
    [Google Scholar]
  22. IvanovV. LohachovaK. KolesnikY. ZakharovA. YevsieievaL. KyrychenkoA. LangerT. KovalenkoS.M. KaluginO.N. Recent advances in computational drug discovery for therapy against coronavirus SARS-CoV-2. ScienceRise.Pharm. Sci.202364642410.15587/2519‑4852.2023.290318
    [Google Scholar]
  23. MarchenkoK.I. KyrychenkoA.V. KolosN.M. Synthesis and modification of 7-aroyl derivatives of 4,7-dihydro-[1,2,4]triazolo-[1,5-a]-pyrimidine as potent inhibitors of sirtuin-2.Funct. Mater.202431226026810.15407/fm31.02.260
    [Google Scholar]
  24. LipsonV.V. YaremenkoF.G. VakulaV.M. KovalenkoS.V. KyrychenkoA.V. DesenkoS.M. BoryskoP.O. ZozulyaS.O. Discovery of novel n-acylhydrazone derivatives as potent inhibitors of sirtuin-1.SynOpen20248210010810.1055/s‑0043‑1763747
    [Google Scholar]
  25. ZahrychukH.Y. GladkovE.S. KyrychenkoA.V. PoliovyiD.O. ZahrychukO.M. KucherT.V. LogoydaL.S. Structure-based rational design and virtual screening of valsartan drug analogs towards developing novel inhibitors of angiotensin ii type 1 receptor.Biointerface Res. Appl. Chem.202313544010.33263/BRIAC135.440
    [Google Scholar]
  26. LipsonV.V. YaremenkoF.G. VakulaV.M. KovalenkoS.V. KyrychenkoA.V. DesenkoS.M. MusatovV.I. BoryskoP.O. ZozulyaS.O. Imidazole derivatives as potent inhibitors of sirtuin-1.Functional Materials202330448649310.15407/fm30.04.486
    [Google Scholar]
  27. BurgerM.T. PecchiS. WagmanA. NiZ.J. KnappM. HendricksonT. AtallahG. PfisterK. ZhangY. BartulisS. FrazierK. NgS. SmithA. VerhagenJ. HaznedarJ. HuhK. IwanowiczE. XinX. MenezesD. MerrittH. LeeI. WiesmannM. KaufmanS. CrawfordK. ChinM. BussiereD. ShoemakerK. ZarorI. MairaS.M. VolivaC.F. Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer.ACS Med. Chem. Lett.201121077477910.1021/ml200156t 24900266
    [Google Scholar]
  28. ChengH. LiC. BaileyS. BaxiS.M. GouletL. GuoL. HoffmanJ. JiangY. JohnsonT.O. JohnsonT.W. KnightonD.R. LiJ. LiuK.K.C. LiuZ. MarxM.A. WallsM. WellsP.A. YinM.J. ZhuJ. ZientekM. Discovery of the highly potent PI3K/MTOR dual inhibitor PF-04979064 through structure-based drug design.ACS Med. Chem. Lett.201341919710.1021/ml300309h 24900568
    [Google Scholar]
  29. TangJ. LiuJ. HeX. FuS. WangK. LiC. LiY. ZhuY. GongP. ZhaoY. LiuY. HouY. Design and synthesis of 1,3,5-triazines or pyrimidines containing dithiocarbamate moiety as PI3Kα selective inhibitors.ACS Med. Chem. Lett.20231491266127410.1021/acsmedchemlett.3c00287 37736169
    [Google Scholar]
  30. ChengH. OrrS.T.M. BaileyS. BroounA. ChenP. DealJ.G. DengY.L. EdwardsM.P. GallegoG.M. GrodskyN. HuangB. JalaieM. KaiserS. KaniaR.S. KephartS.E. LafontaineJ. OrnelasM.A. PairishM. PlankenS. ShenH. SuttonS. ZehnderL. AlmadenC.D. BagrodiaS. FalkM.D. GukasyanH.J. HoC. KangX. KosaR.E. LiuL. SpilkerM.E. TimofeevskiS. VisswanathanR. WangZ. MengF. RenS. ShaoL. XuF. KathJ.C. Structure-based drug design and synthesis of PI3Kα-selective inhibitor (PF-06843195).J. Med. Chem.202164164466110.1021/acs.jmedchem.0c01652 33356246
    [Google Scholar]
  31. OcchiuzziM.A. LicoG. IoeleG. De LucaM. GarofaloA. GrandeF. Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents.Eur. J. Med. Chem.202324611497110.1016/j.ejmech.2022.114971 36462440
    [Google Scholar]
  32. AvendañoC. MenéndezJ.C. Anticancer drugs acting on signaling pathways, part 2: Inhibitors of serine-threonine kinases and miscellaneous signaling pathways. In: Medicinal Chemistry of Anticancer Drugs, 3rd ed; 565-635.Elsevier,202310.1016/B978‑0‑12‑818549‑0.00011‑X
    [Google Scholar]
  33. GarcesA.E. StocksM.J. Class 1 PI3K clinical candidates and recent inhibitor design strategies: A medicinal chemistry perspective.J. Med. Chem.201962104815485010.1021/acs.jmedchem.8b01492 30582807
    [Google Scholar]
  34. SunD. ZhaoY. ZhangS. ZhangL. LiuB. OuyangL. Dual-target kinase drug design: Current strategies and future directions in cancer therapy.Eur. J. Med. Chem.202018811202510.1016/j.ejmech.2019.112025 31931340
    [Google Scholar]
  35. VenkatesanA.M. DehnhardtC.M. Delos SantosE. ChenZ. Dos SantosO. Ayral-KaloustianS. KhafizovaG. BrooijmansN. MallonR. HollanderI. FeldbergL. LucasJ. YuK. GibbonsJ. AbrahamR.T. ChaudharyI. MansourT.S. Bis(morpholino-1,3,5-triazine) derivatives: Potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor.J. Med. Chem.20105362636264510.1021/jm901830p 20166697
    [Google Scholar]
  36. SoltanO.M. ShomanM.E. Abdel-AzizS.A. NarumiA. KonnoH. Abdel-AzizM. Molecular hybrids: A five-year survey on structures of multiple targeted hybrids of protein kinase inhibitors for cancer therapy.Eur. J. Med. Chem.202122511376810.1016/j.ejmech.2021.113768 34450497
    [Google Scholar]
  37. YangF.F. ZhaoT.T. MilanehS. ZhangC. XiangD.J. WangW.L. Small molecule targeted therapies for endometrial cancer: Progress, challenges, and opportunities.RSC Med. Chem.20241561828184810.1039/D4MD00089G 38911148
    [Google Scholar]
  38. TahaM.O. Al-Sha’erM.A. KhanfarM.A. Al-NadafA.H. Discovery of nanomolar phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using ligand-based modeling and virtual screening followed by in vitro analysis.Eur. J. Med. Chem.20148445446510.1016/j.ejmech.2014.07.056 25050878
    [Google Scholar]
  39. LiuP. ChengH. RobertsT.M. ZhaoJ.J. Targeting the phosphoinositide 3-kinase pathway in cancer.Nat. Rev. Drug Discov.20098862764410.1038/nrd2926 19644473
    [Google Scholar]
  40. DasmahapatraU. KumarC.K. DasS. SubramanianP.T. MuraliP. IsaacA.E. RamanathanK. MmB. ChandaK. In-silico molecular modelling, MM/GBSA binding free energy and molecular dynamics simulation study of novel pyrido fused imidazo[4,5-c]quinolines as potential anti-tumor agents.Front Chem.20221099136910.3389/fchem.2022.991369 36247684
    [Google Scholar]
  41. SalemM.E. SamirM. ElwahyA.H.M. FaragA.M. SelimA.M. AlsaeghA.A. SharakyM. BagatoN. RadwanI.T. Design, synthesis, docking study, cytotoxicity evaluation, and PI3K inhibitory activity of novel di-thiazoles, and bis(di-thiazoles).J. Mol. Struct.2024130113737910.1016/j.molstruc.2023.137379
    [Google Scholar]
  42. AfifiT.H. NaqviA. AlsehliM.H. SethD.S. El-GabyM.S.A. OkashaR.M. HagarM. Dft and in-silico investigations, along with in-vitro antitumor and antimicrobial assessments of pharmacological molecules.Curr. Org. Synth.202320552354510.2174/1570179419666220913141629 36100991
    [Google Scholar]
  43. JankuF. ChoongG.M. OpyrchalM. DowlatiA. HierroC. RodonJ. WickiA. ForsterM.D. BlagdenS.P. YinJ. ReidJ.M. MullerH. CmiljanovicN. CmiljanovicV. AdjeiA.A. A phase i study of the oral dual-acting pan-PI3K/MTOR inhibitor bimiralisib in patients with advanced solid tumors.Cancers (Basel)2024166113710.3390/cancers16061137 38539472
    [Google Scholar]
  44. LiuT. SongS. WangX. HaoJ. Small-molecule inhibitors of breast cancer-related targets: Potential therapeutic agents for breast cancer.Eur. J. Med. Chem.202121011295410.1016/j.ejmech.2020.112954 33158576
    [Google Scholar]
  45. SteinmetzM.O. ProtaA.E. Structure-based discovery and rational design of microtubule-targeting agents.Curr. Opin. Struct. Biol.20248710284510.1016/j.sbi.2024.102845 38805950
    [Google Scholar]
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