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2000
Volume 32, Issue 31
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Introduction

More than 20 protozoan species of are responsible for causing Leishmaniasis, an infection spread by blood-feeding phlebotomine sandflies. A narrow pool of drugs is currently available rendering the current drug stratagem to treat this infection inadequate, development of novel, less toxic, and more effective regimens is thus a need of the hour.

Objective

and synthesis of benzo[d]imidazole carboxamides as agents to combat Leishmaniasis.

Methods

14 benzo[d]imidazole carboxamides were synthesized and gauged against promastigotes and intramacrophage amastigote forms. All the tested compounds exhibited significant anti-promastigote properties with IC well below 10 uM. Compounds , showing the highest anti-parasitic activity against promastigote forms (IC: 0.91-1.33 μM), were also found to be associated with better anti-leishmanial potential (IC: 0.78-1.67 μM) against the intramacrophage amastigotes comparable to Amphotericin-B (IC: 0.13 μM), a drug used for Leishmaniasis. Compound (), namely N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)benzo[d][1,3]-5-carboxamide-dioxole, was found to be most potent against amastigotes among all the tested compounds, and demonstrated better anti-leishmanial properties (IC: 0.78 μM) when compared to the standard. Compound was also assessed for its toxicity profile against THP-1 human monocytic cells. To establish the molecular target(s) molecular docking studies were performed against cysteine protease, a putative virulence factor of parasites, and nucleoside diphosphate kinase, an enzyme with a critical role in nucleotide recycling, also associated with resistance in strains. Compound showed better binding affinity than the standard to these targets; furthermore, the molecular dynamic simulation studies further affirmed the stability of compound , within the active site of the targets. cysteine protease inhibitory activity (IC: 8.53 μM) using Bz-Arg-AMC hydrochloride fluorogenic peptide substrate established the promising potential of as a cysteine protease inhibitor.

Results

Computational ADMET analysis indicated appropriate pharmacokinetic profile and physicochemical characteristics for all members of the synthesized library.

Conclusion

Both and studies indicate that the synthesized imidazole carboxamides can act as potent hits and that N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)benzo[d][1,3]-5-carboxamide-dioxole can be an effective hit molecule which can be further developed into potent lead molecule (s) to fight .

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References

  1. CavalliA. BolognesiM.L. Neglected tropical diseases: Multi-target-directed ligands in the search for novel lead candidates against Trypanosoma and Leishmania.J. Med. Chem.200952237339735910.1021/jm9004835 19606868
     [Google Scholar]
  2. J, B.; M, B.M.; Chanda, K. An overview on the therapeutics of neglected infectious diseases—Leishmaniasis and Chagas diseases.Front Chem.2021962228610.3389/fchem.2021.622286 33777895
     [Google Scholar]
  3. WamaiR.G. KahnJ. McGloinJ. ZiaggiG. Visceral leishmaniasis: A global overview.J. Glob. Health Sci.202021e310.35500/jghs.2020.2.e3
     [Google Scholar]
  4. AkerbergA. A systematic review of research on treatment & prevention of the neglected tropical disease Leishmaniasis.Masters thesis, Genetics2023
     [Google Scholar]
  5. Abadías-GranadoI. DiagoA. CerroP.A. Palma-RuizA.M. GilaberteY. Cutaneous and mucocutaneous leishmaniasis.Actas Dermosifiliogr.2021112760161810.1016/j.ad.2021.02.008
     [Google Scholar]
  6. Global leishmaniasis surveillance: 2021, assessing the impact of the COVID-19 pandemic.2022Available from: https://www.who.int/publications/i/item/who-wer9745-575-590
  7. KumarV. MandalR. DasS. KesariS. DineshD.S. PandeyK. DasV.R. TopnoR.K. SharmaM.P. DasguptaR.K. DasP. Kala-azar elimination in a highly-endemic district of Bihar, India: A success story.PLoS Negl. Trop. Dis.2020145e000825410.1371/journal.pntd.0008254 32365060
     [Google Scholar]
  8. MoiranoG. ZanetS. GiorgiE. BattistiE. FalzoiS. AcquaottaF. FratianniS. RichiardiL. FerroglioE. MauleM. Integrating environmental, entomological, animal, and human data to model the Leishmania infantum transmission risk in a newly endemic area in Northern Italy.One Health20201010015910.1016/j.onehlt.2020.100159 33117874
     [Google Scholar]
  9. Camargo JúniorR. N. C. Sarmento GomesJ. S. Corrêa CarvalhoM. C. ChalkidisH. da SilvaWC. Sousa da SilvaJ. Silva de CastroSR. Lima NetoRC. MoutinhoVHP. Visceral Leishmaniasis associated with HIV coinfection in Pará, Brazil. HIV AIDS (Auckl)20231524725510.2147/HIV.S400189
     [Google Scholar]
  10. Graepp-FontouraI. BarbosaD.S. FontouraV.M. GuerraR.N.M. MeloS.A. FernandesM.N.F. CostaP.S.S. MacielS.M. GoiabeiraY.A. SantosF.S. Santos-NetoM. Hunaldo dos SantosL. SerraM.A.A.O. Abreu-SilvaA.L. Visceral leishmaniasis and HIV coinfection in Brazil: epidemiological profile and spatial patterns.Trans. R. Soc. Trop. Med. Hyg.2023117426027010.1093/trstmh/trac093 36219448
     [Google Scholar]
  11. KaurR. KumarR. ChaudharyV. DeviV. DhirD. KumariS. YanadaiahP. PandeyK. MurtiK. PalB. Prevalence of HIV infection among visceral leishmaniasis patients in India: A systematic review and meta-analysis.Clin. Epidemiol. Glob. Health20242510150410.1016/j.cegh.2023.101504
     [Google Scholar]
  12. SerafimT.D. Coutinho-AbreuI.V. DeyR. KissingerR. ValenzuelaJ.G. OliveiraF. KamhawiS. Leishmaniasis: The act of transmission.Trends Parasitol.2021371197698710.1016/j.pt.2021.07.003 34389215
     [Google Scholar]
  13. KumordziY.P. Investigation into the migration of leishmania within phlebotomine sand flies.PhD thesis, Lancaster University, 2019 https://eprints.lancs.ac.uk/id/eprint/136649/1/2019kumordzimres.pdf
    [Google Scholar]
  14. PradhanS. SchwartzR.A. PatilA. GrabbeS. GoldustM. Treatment options for leishmaniasis.Clin. Exp. Dermatol.202247351652110.1111/ced.14919 34480806
     [Google Scholar]
  15. MannS. FrascaK. ScherrerS. Henao-MartínezA.F. NewmanS. RamananP. SuarezJ.A. A review of Leishmaniasis: Current knowledge and future directions.Curr. Trop. Med. Rep.20218212113210.1007/s40475‑021‑00232‑7 33747716
     [Google Scholar]
  16. SasidharanS. SaudagarP. Leishmaniasis: Where are we and where are we heading?Parasitol. Res.202112051541155410.1007/s00436‑021‑07139‑2 33825036
     [Google Scholar]
  17. RoattB.M. de Oliveira CardosoJ.M. De BritoR.C.F. Coura-VitalW. de Oliveira Aguiar-SoaresR.D. ReisA.B. Recent advances and new strategies on leishmaniasis treatment.Appl. Microbiol. Biotechnol.2020104218965897710.1007/s00253‑020‑10856‑w 32875362
     [Google Scholar]
  18. MohammedR. FikreH. SchusterA. MekonnenT. van GriensvenJ. DiroE. Multiple relapses of visceral Leishmaniasis in HIV co-infected patients: A case series from Ethiopia.Curr. Ther. Res. Clin. Exp.20209210058310.1016/j.curtheres.2020.100583 32382359
     [Google Scholar]
  19. BurkiT. Guidelines for visceral leishmaniasis and HIV co-infection.Lancet Infect. Dis.20222281124112510.1016/S1473‑3099(22)00461‑3 35870462
     [Google Scholar]
  20. J S, D.; Gupta, A.K.; Veeri, R.B.; Garapati, P.; Kumar, R.; Dhingra, S.; Murti, K.; Ravichandiran, V.; Pandey, K. Knowledge, attitude and practices towards visceral leishmaniasis among HIV patients: A cross-sectional study from Bihar, India.PLoS One2021168e025623910.1371/journal.pone.0256239 34404087
     [Google Scholar]
  21. KassardjianA.A. YimK.M. RabiS. LiangT.Z. KimG.H. OchoaM.T. SattahM.V. AhronowitzI.Z. Diffuse cutaneous leishmaniasis and HIV co-infection: A case report and review of the literature.J. Cutan. Pathol.202148680280610.1111/cup.13993 33611800
     [Google Scholar]
  22. SampaioR.N.R. Pharmacotherapy in leishmaniasis: Old, new treatments, their impacts and expert opinion.Expert Opin. Pharmacother.202324215315810.1080/14656566.2022.2157208 36503319
     [Google Scholar]
  23. MathisonB.A. BradleyB.T. Review of the clinical presentation, pathology, diagnosis, and treatment of Leishmaniasis.Lab. Med.202354436337110.1093/labmed/lmac134 36468667
     [Google Scholar]
  24. van GriensvenJ. DorloT.P.C. DiroE. CostaC. BurzaS. The status of combination therapy for visceral Leishmaniasis: An updated review.Lancet Infect. Dis.2023 37640031
     [Google Scholar]
  25. GopuB. KourP. PandianR. SinghK. Insights into the drug screening approaches in leishmaniasis.Int. Immunopharmacol.202311410959110.1016/j.intimp.2022.109591 36700771
     [Google Scholar]
  26. BhattacharyaA. CorbeilA. do Monte-NetoR.L. Fernandez-PradaC. Of drugs and trypanosomatids: New tools and knowledge to reduce bottlenecks in drug discovery.Genes (Basel)202011772210.3390/genes11070722 32610603
     [Google Scholar]
  27. CohenA. AzasN. Challenges and tools for in vitro leishmania exploratory screening in the drug development process: An updated review.Pathogens20211012160810.3390/pathogens10121608 34959563
     [Google Scholar]
  28. ZulfiqarB. ShelperT.B. AveryV.M. Leishmaniasis drug discovery: Recent progress and challenges in assay development.Drug Discov. Today201722101516153110.1016/j.drudis.2017.06.004 28647378
     [Google Scholar]
  29. MahorH. MukherjeeA. SarkarA. SahaB. Anti-leishmanial therapy: Caught between drugs and immune targets.Exp. Parasitol.202324510844110.1016/j.exppara.2022.108441 36572088
     [Google Scholar]
  30. SreedharanV. RaoK.V.B. Protease inhibitors as a potential agent against visceral Leishmaniasis: A review to inspire future study.Braz. J. Infect. Dis.202327110273910.1016/j.bjid.2022.102739 36603827
     [Google Scholar]
  31. AndradeM.M.S. MartinsL.C. MarquesG.V.L. SilvaC.A. FariaG. CaldasS. dos SantosJ.S.C. LeclercqS.Y. MaltarolloV.G. FerreiraR.S. OliveiraR.B. Synthesis of quinoline derivatives as potential cysteine protease inhibitors.Future Med. Chem.202012757158110.4155/fmc‑2019‑0201 32116030
     [Google Scholar]
  32. SelzerP.M. ChenX. ChanV.J. ChengM. KenyonG.L. KuntzI.D. SakanariJ.A. CohenF.E. McKerrowJ.H. Leishmania major: Molecular modeling of cysteine proteases and prediction of new nonpeptide inhibitors.Exp. Parasitol.199787321222110.1006/expr.1997.4220 9371086
     [Google Scholar]
  33. JudiceW.A.S. FerrazL.S. LopesR.M. ViannaL.S. SiqueiraF.S. Di IorioJ.F. DalzotoL.A.M. TrujilhoM.N.R. SantosT.R. MachadoM.F.M. RodriguesT. Cysteine proteases as potential targets for anti-trypanosomatid drug discovery.Bioorg. Med. Chem.20214611636510.1016/j.bmc.2021.116365 34419821
     [Google Scholar]
  34. McKerrowJ. EngelJ.C. CaffreyC.R. Cysteine protease inhibitors as chemotherapy for parasitic infections.Bioorg. Med. Chem.19997463964410.1016/S0968‑0896(99)00008‑5 10353643
     [Google Scholar]
  35. ManoharR. KutumbaraoN.H.V. Krishna NagampalliR.S. VelmuruganD. GunasekaranK. Structural insights and binding of a natural ligand, succinic acid with serine and cysteine proteases.Biochem. Biophys. Res. Commun.2018495167968510.1016/j.bbrc.2017.11.033 29127014
     [Google Scholar]
  36. SelzerP.M. PingelS. HsiehI. UgeleB. ChanV.J. EngelJ.C. BogyoM. RussellD.G. SakanariJ.A. McKerrowJ.H. Cysteine protease inhibitors as chemotherapy: Lessons from a parasite target.Proc. Natl. Acad. Sci. USA19999620110151102210.1073/pnas.96.20.11015 10500116
     [Google Scholar]
  37. DasP. AlamM.N. PaikD. KarmakarK. DeT. ChakrabortiT. Protease inhibitors in potential drug development for Leishmaniasis.Indian J. Biochem. Biophys.2013505363376 24772958
     [Google Scholar]
  38. de AlmeidaL. AlvesK.F. Maciel-RezendeC.M. JesusL.O.P. PiresF.R. JuniorC.V. IzidoroM.A. JúdiceW.A.S. dos SantosM.H. MarquesM.J. Benzophenone derivatives as cysteine protease inhibitors and biological activity against Leishmania(L.) amazonensis amastigotes.Biomed. Pharmacother.201575939910.1016/j.biopha.2015.08.030 26463637
     [Google Scholar]
  39. CostaC.A. LopesR.M. FerrazL.S. EstevesG.N.N. Di IorioJ.F. SouzaA.A. de OliveiraI.M. ManarinF. JudiceW.A.S. StefaniH.A. RodriguesT. Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential.Bioorg. Med. Chem.2020281111551110.1016/j.bmc.2020.115511 32336669
     [Google Scholar]
  40. FerreiraR.S. SimeonovA. JadhavA. EidamO. MottB.T. KeiserM.J. McKerrowJ.H. MaloneyD.J. IrwinJ.J. ShoichetB.K. Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.J. Med. Chem.201053134891490510.1021/jm100488w 20540517
     [Google Scholar]
  41. FolquittoL.R.S. NogueiraP.F. EspuriP.F. GontijoV.S. de SouzaT.B. MarquesM.J. CarvalhoD.T. JúdiceW.A.S. DiasD.F. Synthesis, protease inhibition, and antileishmanial activity of new benzoxazoles derived from acetophenone or benzophenone and synthetic precursors.Med. Chem. Res.20172661149115910.1007/s00044‑017‑1824‑y
     [Google Scholar]
  42. PimentelI.A.S. PaladiC.S. KatzS. JúdiceW.A.S. CunhaR.L.O.R. BarbiériC.L. In vitro and in vivo activity of an organic tellurium compound on Leishmania (Leishmania) chagasi.PLoS One2012711e4878010.1371/journal.pone.0048780 23144968
     [Google Scholar]
  43. PavlosD. MavromoustakosT. Advances of medicinal chemistry against kinetoplastid protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) infections: Drug design, synthesis and pharmacology.Pharmakeftiki2022334254271
     [Google Scholar]
  44. ParksR.E.Jr BrownP.R. ChengY.C. AgarwalK.C. KongC.M. AgarwalR.P. ParksC.C. Purine metabolism in primitive erythrocytes.Comp. Biochem. Physiol. B197345235536410.1016/0305‑0491(73)90070‑9 4351428
     [Google Scholar]
  45. LascuI. GoninP. The catalytic mechanism of nucleoside diphosphate kinases.J. Bioenerg. Biomembr.200032323724610.1023/A:1005532912212 11768307
     [Google Scholar]
  46. PaulM.L.S. KaurA. GeeteA. SobhiaM.E. Essential gene identification and drug target prioritization in Leishmania species.Mol. Biosyst.20141051184119510.1039/C3MB70440H 24643243
     [Google Scholar]
  47. ChakrabartyA.M. Nucleoside diphosphate kinase: Role in bacterial growth, virulence, cell signalling and polysaccharide synthesis.Mol. Microbiol.199828587588210.1046/j.1365‑2958.1998.00846.x 9663675
     [Google Scholar]
  48. PostelE.H. Multiple biochemical activities of NM23/NDP kinase in gene regulation.J. Bioenerg. Biomembr.2003351314010.1023/A:1023485505621 12848339
     [Google Scholar]
  49. LandfearS.M. UllmanB. CarterN.S. SanchezM.A. Nucleoside and nucleobase transporters in parasitic protozoa.Eukaryot. Cell20043224525410.1128/EC.3.2.245‑254.2004 15075255
     [Google Scholar]
  50. KolliB.K. KostalJ. ZaborinaO. ChakrabartyA.M. ChangK.P. Leishmania-released nucleoside diphosphate kinase prevents ATP-mediated cytolysis of macrophages.Mol. Biochem. Parasitol.2008158216317510.1016/j.molbiopara.2007.12.010 18242727
     [Google Scholar]
  51. MirandaM.R. SayéM. ReigadaC. GalceranF. RengifoM. MacielB.J. DigirolamoF.A. PereiraC.A. Revisiting trypanosomatid nucleoside diphosphate kinases.Mem. Inst. Oswaldo Cruz2021116e21033910.1590/0074‑02760210339 35170678
     [Google Scholar]
  52. IstanbulluH. BayraktarG. Toward new antileishmanial compounds: Molecular targets for Leishmaniasis treatment. In: Leishmaniasis - General Aspects of a Stigmatized Disease;202110.5772/intechopen.101132
     [Google Scholar]
  53. VargasJ. LópezA. VargasA. FidalgoL. FroeyenM. In vitro evaluation and molecular docking studies of aryl-substituted imidazoles against leishmania amazonensis.Int. J. Trop. Dis2021450
     [Google Scholar]
  54. TonelliM. GabrieleE. PiazzaF. BasilicoN. ParapiniS. TassoB. LoddoR. SparatoreF. SparatoreA. Benzimidazole derivatives endowed with potent antileishmanial activity.J. Enzyme Inhib. Med. Chem.201833121022610.1080/14756366.2017.1410480 29233048
     [Google Scholar]
  55. Sánchez-SalgadoJ.C. Bilbao-RamosP. Dea-AyuelaM.A. Hernández-LuisF. Bolás-FernándezF. Medina-FrancoJ.L. Rojas-AguirreY. Systematic search for benzimidazole compounds and derivatives with antileishmanial effects.Mol. Divers.201822477979010.1007/s11030‑018‑9830‑7 29748853
     [Google Scholar]
  56. ShaukatA. MirzaH.M. AnsariA.H. YasinzaiM. ZaidiS.Z. DilshadS. AnsariF.L. Benzimidazole derivatives: Synthesis, leishmanicidal effectiveness, and molecular docking studies.Med. Chem. Res.20132283606362010.1007/s00044‑012‑0375‑5
     [Google Scholar]
  57. Mendez-CuestaA. Herrera-RuedaMA. Hidalgo-FigueroaS. TlahuextH. Moo-PucR. Chale-DzulJB. Chan-BacabM. Ortega-MoralesBO. Hernandez-NunezE. Mendez-LucioO. Medina-FrancoJL. Navarrete-VazquezG. Synthesis, screening and in silico simulations of anti-parasitic propamidine/benzimidazole derivatives.Med Chem201713213714810.2174/1573406412666160811112408
     [Google Scholar]
  58. EserM. Çavuşİ. In vitro and in silico evaluations of the antileishmanial activities of new benzimidazole-triazole derivatives.Vet. Sci.2023101164810.3390/vetsci10110648 37999471
     [Google Scholar]
  59. SharmaS. Anjaneyulu YakkalaP. BegM.A. TanwarS. LatiefI. KhanA. SharmaK. ur Rehman, S.; Selvapandiyan, A.; Shafi, S. 5‐Arylidene‐2,4‐thiazolidine-] diones as cysteine protease inhibitors against Leishmania donovani.ChemistrySelect2023829e20230241510.1002/slct.202302415
     [Google Scholar]
  60. IlaghiM. SharifiI. SharififarF. SharifiF. OliaeeR.T. BabaeiZ. MeimamandiM.S. KeyhaniA. BamorovatM. The potential role and apoptotic profile of three medicinal plant extracts on Leishmania tropica by MTT assay, macrophage model and flow cytometry analysis.Parasite Epidemiol. Control202112e0020110.1016/j.parepi.2021.e00201 33511293
     [Google Scholar]
  61. Valdés-TresancoM.S. Valdés-TresancoM.E. ValienteP.A. MorenoE. AMDock: A versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4.Biol. Direct20201511210.1186/s13062‑020‑00267‑2 32938494
     [Google Scholar]
  62. GuptaO. PradhanT. BhatiaR. MongaV. Recent advancements in anti-leishmanial research: Synthetic strategies and structural activity relationships.Eur. J. Med. Chem.202122311360610.1016/j.ejmech.2021.113606 34171661
     [Google Scholar]
  63. Nieto-MenesesR. CastilloR. Hernández-CamposA. Maldonado-RangelA. Matius-RuizJ.B. Trejo-SotoP.J. Nogueda-TorresB. Dea-AyuelaM.A. Bolás-FernándezF. Méndez-CuestaC. Yépez-MuliaL. In vitro activity of new N-benzyl-1H-benzimidazol-2-amine derivatives against cutaneous, mucocutaneous and visceral Leishmania species.Exp. Parasitol.2018184828910.1016/j.exppara.2017.11.009 29191699
     [Google Scholar]
  64. DukhyilA. A. A. Targeting trypanothione reductase of leishmanial major to fight against cutaneous Leishmaniasis.Infect. Disord. Drug Targets201919438839310.2174/187152651866618050214184
     [Google Scholar]
  65. Silva de Jesus PassaesA.C. Arantes DantasJ. Landim LopesF. Pereira SangiD. Girão AlbuquerqueM. Vataru NakamuraC. YonedaJ. Quinoxalines against Leishmania amazonensis: SAR study, proposition of a new derivative, QSAR prediction, synthesis, and biological evaluation.Sci. Rep.20231311813610.1038/s41598‑023‑45436‑1 37875605
     [Google Scholar]
  66. RiyadiP.H. SariI.D. KurniasihR.A. AgustiniT.W. SwastawatiF. HerawatiV.E. TanodW.A. SwissADME predictions of pharmacokinetics and drug-likeness properties of small molecules present in Spirulina platensis.IOP Conf. Ser. Earth Environ. Sci.2021890101202110.1088/1755‑1315/890/1/012021
     [Google Scholar]
  67. ChoA. LeeN. PhanT-N. KimS. LeeH. LeeH. ShumD. NoJ.H. High-throughput drug screening using leishmania amastigotes and promastigotes for potential therapeutics against Leishmaniasis.Infect. Chemother.202254
     [Google Scholar]
  68. GouveiaA.L.A. SantosF.A.B. AlvesL.C. Cruz-FilhoI.J. SilvaP.R. JacobI.T.T. SoaresJ.C.S. SantosD.K.D.N. SouzaT.R.C.L. OliveiraJ.F. LimaM.C.A. Thiazolidine derivatives: In vitro toxicity assessment against promastigote and amastigote forms of Leishmania infantum and ultrastructural study.Exp. Parasitol.2022236-23710825310.1016/j.exppara.2022.108253 35381223
     [Google Scholar]
  69. Van Der SpoelD. LindahlE. HessB. GroenhofG. MarkA.E. BerendsenH.J.C. GROMACS: Fast, flexible, and free.J. Comput. Chem.200526161701171810.1002/jcc.20291 16211538
     [Google Scholar]
  70. BhowmikS. SamratS.M. AkhterM.S. A Computational molecular docking studies on the tryparedoxin peroxidase of Leishmania donovani responsible for visceral leishmaniasis in human.Lett. Drug Des. Discov.202118771072210.2174/1570180817999200730171556
     [Google Scholar]
  71. SchulerL.D. DauraX. van GunsterenW.F. An improved GROMOS96 force field for aliphatic hydrocarbons in the condensed phase.J. Comput. Chem.200122111205121810.1002/jcc.1078
     [Google Scholar]
  72. HessB. BekkerH. BerendsenH.J.C. FraaijeJ.G.E.M. LINCS: A linear constraint solver for molecular simulations.J. Comput. Chem.1997181214631472
     [Google Scholar]
  73. EssmannU. PereraL. BerkowitzM.L. DardenT. LeeH. PedersenL.G. A smooth particle mesh Ewald method.J. Chem. Phys.1995103198577859310.1063/1.470117
     [Google Scholar]
  74. MartoňákR. LaioA. ParrinelloM. Predicting crystal structures: The Parrinello-Rahman method revisited.Phys. Rev. Lett.200390707550310.1103/PhysRevLett.90.075503 12633242
     [Google Scholar]
  75. VangoneA. SchaarschmidtJ. KoukosP. GengC. CitroN. TrelletM.E. XueL.C. BonvinA.M.J.J. Large-scale prediction of binding affinity in protein–small ligand complexes: The PRODIGY-LIG web server.Bioinformatics20193591585158710.1093/bioinformatics/bty816 31051038
     [Google Scholar]
  76. AzzamK. A. L. SwissADME and pkCSM webservers predictors: An integrated online platform for accurate and comprehensive predictions for in silico ADME/T properties of artemisinin and its derivatives.20223252142110.31643/2023/6445.13
     [Google Scholar]
  77. SimsekA. PehlivanogluS. Aydin AcarC. Anti-proliferative and apoptotic effects of green synthesized silver nanoparticles using Lavandula angustifolia on human glioblastoma cells.3 Biotech202111837410.1007/s13205‑021‑02923‑4
     [Google Scholar]
  78. LourençoE.M.G. Di IórioJ.F. da SilvaF. FialhoF.L.B. MonteiroM.M. BeatrizA. PerdomoR.T. BarbosaE.G. OsesJ.P. de ArrudaC.C.P. de Souza JúdiceW.A. RafiqueJ. de LimaD.P. Flavonoid derivatives as new potent inhibitors of cysteine proteases: An important step toward the design of new compounds for the treatment of Leishmaniasis.Microorganisms202311122510.3390/microorganisms11010225 36677517
     [Google Scholar]
  79. TantrayM.A. KhanI. HamidH. AlamM.S. DhulapA. KalamA. Synthesis of benzimidazole-linked-1,3,4-oxadiazole carboxamides as GSK-3β inhibitors with in vivo antidepressant activity.Bioorg. Chem.20187739340110.1016/j.bioorg.2018.01.040 29421716
     [Google Scholar]
  80. Al AzzamK.M. NegimE-S. Aboul-EneinH.Y. ADME studies of TUG-770 (a GPR-40 inhibitor agonist) for the treatment of type 2 Diabetes using SwissADME predictor: In silico study.J. Appl. Pharm. Sci.2022124159169
     [Google Scholar]
  81. CarterN.S. RagerN. UllmanB. Purine and pyrimidine transport and metabolism.In: Molecular and Medical Parasitology;200319722310.1016/B978‑012473346‑6/50012‑0
     [Google Scholar]
  82. DhingraN. KapoorK. SharmaS. AmetaK.L. Exploring the structural insights of trisubstituted isoxazoles against protozoal agents using QSAR and molecular docking model.Res. Sq202210.21203/rs.3.rs‑1716908/v1
     [Google Scholar]
  83. DainaA. ZoeteV. A BOILED‐Egg to predict gastrointestinal absorption and brain penetration of small molecules.ChemMedChem201611111117112110.1002/cmdc.201600182 27218427
     [Google Scholar]
  84. Silva, BRMGD.; Bezerra Júnior, NDS.; Oliveira, JF.; Duarte, DMFA.; Marques, DSC.; Nogueira, F.; Lima, MCA.; Cruz Filho, IJD. In silico ADMET prediction, evaluation of cytotoxicity in mouse splenocytes and preliminary evaluation of in vitro antimalarial activity of 4-(4-chlorophenyl) thiazole compounds. An Acad Bras Cienc202395e2023056610.1590/0001‑3765202320230566
     [Google Scholar]
  85. DulsatJ. López-NietoB. Estrada-TejedorR. BorrellJ.I. Evaluation of free online ADMET tools for academic or small biotech environments.Molecules202328277610.3390/molecules28020776 36677832
     [Google Scholar]
  86. KatsunoK. BurrowsJ.N. DuncanK. van HuijsduijnenR.H. KanekoT. KitaK. MowbrayC.E. SchmatzD. WarnerP. SlingsbyB.T. Hit and lead criteria in drug discovery for infectious diseases of the developing world.Nat. Rev. Drug Discov.2015141175175810.1038/nrd4683 26435527
     [Google Scholar]
  87. KushawahaP.K. Pati TripathiC.D. DubeA. Leishmania donovani secretory protein nucleoside diphosphate kinase B localizes in its nucleus and prevents ATP mediated cytolysis of macrophages.Microb. Pathog.202216610545710.1016/j.micpath.2022.105457 35219843
     [Google Scholar]
  88. FigueredoA.S. AssençoJ.N.F. Da CostaA.A.C. LópezR.E.S. Da SilvaM.C.P. Protease inhibitor activity of plant natural products as leishmanicine agents.Braz. J. Dev.202284236082363210.34117/bjdv8n4‑059
     [Google Scholar]
  89. SoniM. PratapJ.V. Development of novel anti-leishmanials: The case for structure-based approaches.Pathogens202211895010.3390/pathogens11080950 36015070
     [Google Scholar]
  90. SouzaT.A.C.B. TrindadeD.M. TonoliC.C.C. SantosC.R. WardR.J. ArniR.K. OliveiraA.H.C. MurakamiM.T. Molecular adaptability of nucleoside diphosphate kinase B from trypanosomatid parasites: Stability, oligomerization and structural determinants of nucleotide binding.Mol. Biosyst.2011772189219510.1039/c0mb00307g 21528129
     [Google Scholar]
  91. RibeiroJ.F.R. CianniL. LiC. WarwickT.G. de VitaD. RosiniF. dos Reis RochoF. MartinsF.C.P. KennyP.W. LameiraJ. LeitãoA. EmsleyJ. MontanariC.A. Crystal structure of Leishmania mexicana cysteine protease B in complex with a high-affinity azadipeptide nitrile inhibitor.Bioorg. Med. Chem.2020282211574310.1016/j.bmc.2020.115743 33038787
     [Google Scholar]
  92. ClementinoL.C. FernandesG.F.S. ProkopczykI.M. LaurindoW.C. ToyamaD. MottaB.P. BavieraA.M. Henrique-SilvaF. SantosJ.L. GraminhaM.A.S. Design, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activity.PLoS One20211611e025900810.1371/journal.pone.0259008 34723989
     [Google Scholar]
  93. KaushikD. GranatoJ.T. MacedoG.C. DibP.R.B. PiplaniS. FungJ. da SilvaA.D. CoimbraE.S. PetrovskyN. SalunkeD.B. Toll-like receptor-7/8 agonist kill Leishmania amazonensis by acting as pro-oxidant and pro-inflammatory agent.J. Pharm. Pharmacol.20217391180119010.1093/jpp/rgab063 33940589
     [Google Scholar]
  94. Challapa-MamaniM.R. Tomás-AlvaradoE. Espinoza-BaigorriaA. León-FigueroaD.A. SahR. Rodriguez-MoralesA.J. BarbozaJ.J. Molecular docking and molecular dynamics simulations in related to Leishmania donovani: An update and literature review.Trop. Med. Infect. Dis.202381045710.3390/tropicalmed8100457 37888585
     [Google Scholar]
  95. Salo-AhenO.M.H. AlankoI. BhadaneR. BonvinA.M.J.J. HonoratoR.V. HossainS. JufferA.H. KabedevA. Lahtela-KakkonenM. LarsenA.S. LescrinierE. MarimuthuP. MirzaM.U. MustafaG. Nunes-AlvesA. PantsarT. SaadabadiA. SingaraveluK. VanmeertM. Molecular dynamics simulations in drug discovery and pharmaceutical development.Processes (Basel)2020917110.3390/pr9010071
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673310232240910062647
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Design and Synthesis of Benzimidazole Carboxamide Cysteine Protease Inhibitors as Promising Anti-leishmanial Agents
Curr. Med. Chem. 32, 6900 (2025); https://doi.org/10.2174/0109298673310232240910062647
/content/journals/cmc/10.2174/0109298673310232240910062647
/content/journals/cmc/10.2174/0109298673310232240910062647
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  • Article Type:     Research Article
Keyword(s): anti-leishmanial; Benzimidazole; cysteine protease; inhibitors; Leishmania donovani; molecular dynamics simulation

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