Abstract
Acanthamoeba castellanii is a free-living amoeba which can cause a blinding keratitis and fatal granulomatous amoebic encephalitis. The treatment of Acanthamoeba infections is challenging due to formation of cyst. Quinazolinones are medicinally important scaffold against parasitic diseases. A library of nineteen new 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one derivatives was synthesized to evaluate their antiamoebic activity against Acanthamoeba castellanii. One-pot synthesis of 3-aryl-6,7-dimethoxyquinazolin-4(3H)-ones (1–19) was achieved by reaction of 2-amino-4,5-dimethoxybenzoic acid, trimethoxymethane, and different substituted anilines. These compounds were purified and characterized by standard chromatographic and spectroscopic techniques. Antiacanthamoebic activity of these compounds was determined by amoebicidal, encystation, excystation and host cell cytopathogenicity in vitro assays at concentrations of 50 and 100 μg/mL. The IC50 was found to be between 100 and 50 μg/mL for all the compounds except compound 5 which did not exhibit amoebicidal effects at these concentrations. Furthermore, lactate dehydrogenase assay was also performed to evaluate the in vitro cytotoxicity of these compounds against human keratinocyte (HaCaT) cells. The results revealed that eighteen out of nineteen derivatives of quinazolinones significantly decreased the viability of A. castellanii. Furthermore, eighteen out of nineteen tested compounds inhibited the encystation and excystation, as well as significantly reduced the A. castellanii–mediated cytopathogenicity against human cells. Interestingly, while tested against human normal cell line HaCaT keratinocytes, all compounds did not exhibit any overt cytotoxicity. Furthermore, a detailed structure-activity relationship is also studied to optimize the most potent hit from these synthetic compounds. This report presents several potential lead compounds belonging to 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one derivatives for drug discovery against infections caused by Acanthamoeba castellanii.
Similar content being viewed by others
References
Abjani F, Khan NA, Yousuf FA, Siddiqui R (2016) Targeting cyst wall is an effective strategy in improving the efficacy of marketed contact lens disinfecting solutions against Acanthamoeba castellanii cysts. Cont Lens Anter Eye 39:239–243. https://doi.org/10.1016/j.clae.2015.11.004
Alho MA, Marrero-Ponce Y, Barigye SJ, Meneses-Marcel A, Tugores YM, Montero-Torres A et al (2014) Antiprotozoan lead discovery by aligning dry and wet screening: prediction, synthesis, and biological assay of novel quinoxalinones. Bioorg Med Chem 22:1568–1585. https://doi.org/10.1016/j.bmc.2014.01.036
Anwar A, Siddiqui R, Shah MR, Khan NA (2018a) Gold nanoparticle conjugated cinnamic acid exhibit antiacanthamoebic and antibacterial properties. Antimicrob Agents Chemother 62:e00630–e00618. https://doi.org/10.1128/AAC.00630-18
Anwar A, Siddiqui R, Hussain MA, Ahmed D, Shah MR, Khan NA (2018b) Silver nanoparticle conjugation affects antiacanthamoebic activities of amphotericin B, nystatin, and fluconazole. Parasitol Res 117:265–271. https://doi.org/10.1007/s00436-017-5701-x
Anwar A, Rajendran K, Siddiqui R, Raza Shah M, Khan NA (2019a) Clinically approved drugs against CNS diseases as potential therapeutic agents to target brain-eating amoebae. ACS Chem Neurosci 10:658–666. https://doi.org/10.1021/acschemneuro.8b00484
Anwar A, Shahbaz MS, Saad SM, Khan KM, Siddiqui R, Khan NA (2019b) Novel antiacanthamoebic compounds belonging to quinazolinones. Eur J Med Chem 182:111575. https://doi.org/10.1016/j.ejmech.2019.111575
Aqeel Y, Iqbal J, Siddiqui R, Gilani AH, Khan NA (2012) Anti-Acanthamoebic properties of resveratrol and demethoxycurcumin. Exp Parasitol 132:519–523. https://doi.org/10.1016/j.exppara.2012.09.007
Debnath A, Tunac JB, Galindo-Gómez S, Silva-Olivares A, Shibayama M, McKerrow JH (2012) Corifungin, a new drug lead against Naegleria, identified from a high-throughput screen. Antimicrob Agents Chemother 56:5450–5457. https://doi.org/10.1128/AAC.00643-12
Dudley R, Jarroll EL, Khan NA (2009) Carbohydrate analysis of Acanthamoeba castellanii. Exp Parasitol 122:338–343. https://doi.org/10.1016/j.exppara.2009.04.009
García-Davis S, Sifaoui I, Reyes-Batlle M, Viveros-Valdez E, Piñero J, Lorenzo-Morales J, Fernández J, Díaz-Marrero A (2018) Anti-Acanthamoeba activity of brominated sesquiterpenes from Laurencia johnstonii. Marine Drugs 16:443. https://doi.org/10.3390/md16110443
Giri RS, Thaker HM, Giordano T, Williams J, Rogers D, Sudersanam V, Vasu KK (2009) Design, synthesis and characterization of novel 2-(2, 4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives as inhibitors of NF-κB and AP-1 mediated transcription activation and as potential anti-inflammatory agents. Eur J Med Chem 44:2184–2189. https://doi.org/10.1016/j.ejmech.2008.10.031
Gupta V, Kashaw SK, Jatav V, Mishra P (2008) Synthesis and antimicrobial activity of some new 3–[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-styrylquinazoline-4 (3H)-ones. Med Chem Res 17:205–211. https://doi.org/10.1007/s00044-007-9054-3
Hadda TB, Kerbal A, Bennani B, Al Houari G, Daoudi M, Leite AC, Masand VH, Jawarkar RD, Charrouf Z (2013) Molecular drug design, synthesis and pharmacophore site identification of spiroheterocyclic compounds: Trypanosoma crusi inhibiting studies. Med Chem Res 22:57–69. https://doi.org/10.1007/s00044-012-0010-5
Jatav V, Mishra P, Kashaw S, Stables JP (2008) CNS depressant and anticonvulsant activities of some novel 3-[5-substituted 1, 3, 4-thiadiazole-2-yl]-2-styryl quinazoline-4 (3H)-ones. Eur J Med Chem 43:1945–1954. https://doi.org/10.1016/j.ejmech.2007.12.003
Jeyamogan S, Khan NA, Anwar A, Shah MR, Siddiqui R (2018) Cytotoxic effects of benzodioxane, naphthalene diimide, porphyrin and acetamol derivatives on HeLa cells. SAGE Open Med 6:2050312118781962. https://doi.org/10.1177/2050312118781962
Khan NA (2006) Acanthamoeba: biology and increasing importance in human health. FEMS Microbiol Rev 30:564–595. https://doi.org/10.1111/j.1574-6976.2006.00023.x
Khan NA, Anwar A, Siddiqui R (2017) Future priorities in tackling infections due to brain-eating amoebae. ACS Chem Neurosci 8:2355. https://doi.org/10.1021/acschemneuro.7b00343
Kumar KS, Ganguly S, Veerasamy R, De Clercq E (2010) Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4 (3H)-ones. Eur J Med Chem 45:5474–5479. https://doi.org/10.1016/j.ejmech.2010.07.058
Lorenzo-Morales J, Khan NA, Walochnik J (2015) An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment. Parasite 22:10. https://doi.org/10.1051/parasite/2015010
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, AlMazroa MA et al (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. The Lancet 380:2095–2128. https://doi.org/10.1016/S0140-6736(12)61728-0
Marciano-Cabral F, Cabral G (2003) Acanthamoeba spp. as agents of disease in humans. Clin Microbiol Rev 16:273–307. https://doi.org/10.1128/cmr.16.2.273-307.2003
Masood MM, Irfan M, Khan P, Alajmi MF, Hussain A, Garrison J, Rehman MT, Abid M (2018) 1, 2, 3-Triazole–quinazolin-4 (3H)-one conjugates: evolution of ergosterol inhibitor as anticandidal agent. RSC Adv 8:39611–39625. https://doi.org/10.1039/C8RA08426B
Mhaske SB, Argade NM (2006) The chemistry of recently isolated naturally occurring quinazolinone alkaloids. Tetrahedron 62:9787–9826. https://doi.org/10.1016/j.tet.2006.07.098
Moore MB, McCulley JP, Newton C, Cobo LM, Foulks GN, O'Day DM, Johns KJ, Driebe WT, Wilson LA, Epstein RJ, Doughman DJ (1987) Acanthamoeba keratitis: a growing problem in soft and hard contact lens wearers. Ophthalmology 94:1654-1661. https://doi.org/10.1016/S0161-6420(87)33238-5
Ofir-Birin Y, Regev-Rudzki N (2019) Extracellular vesicles in parasite survival. Science 363:817–818. https://doi.org/10.1126/science.aau4666
Patel TS, Vanparia SF, Gandhi SA, Patel UH, Dixit RB, Chudasama CJ, Dixit BC (2015) Novel stereoselective 2,3-disubstituted quinazoline-4 (3H)-one derivatives derived from glycine as a potent antimalarial lead. New J Chem 39:8638–8649. https://doi.org/10.1039/C5NJ01408E
Rice CA, Colon BL, Alp M, Göker H, Boykin DW, Kyle DE (2015) Bis-benzimidazole hits against Naegleria fowleri discovered with new high throughput screens. Antimicrob Agents Chemother 59:2037–2044. https://doi.org/10.1128/AAC.05122-14
Rifkin JL (2002) Quantitative analysis of the behavior of Dictyostelium discoideum amoebae: stringency of pteridine reception. Cell Motil Cytoskel 51:39–48. https://doi.org/10.1002/cm.10012
Saad SM, Ghouri N, Perveen S, Khan KM, Choudhary MI (2016) 4-Arylamino-6-nitroquinazolines: synthesis and their activities against neglected disease leishmaniasis. Eur J Med Chem 108:13–20. https://doi.org/10.1016/j.ejmech.2015.11.016
Saccoliti F, Madia VN, Tudino V, De Leo A, Pescatori L, Messore A, De Vita D, Scipione L, Brun R, Kaiser M, Mäser P et al (2019) Design, synthesis, and biological evaluation of new 1-(Aryl-1 H-pyrrolyl)(phenyl) methyl-1 H-imidazole derivatives as antiprotozoal agents. J Med Chem 62:1330–1347. https://doi.org/10.1021/acs.jmedchem.8b01464
Seal DV (2003) Acanthamoeba keratitis update-incidence, molecular epidemiology and new drugs for treatment. Eye 17:893–905. https://doi.org/10.1038/sj.eye.6700563
Siddiqui R, Aqeel Y, Khan NA (2016) The development of drugs against Acanthamoeba infections. Antimicrob Agents Chemother 60:6441–6450. https://doi.org/10.1128/AAC.00686-16
Sissons J, Kim KS, Stins M, Jayasekera S, Alsam S, Khan NA (2005) Acanthamoeba castellanii induces host cell death via a phosphatidylinositol 3-kinase-dependent mechanism. Infect Immun 73:2704–2708. https://doi.org/10.1128/IAI.73.5.2704-2708.2005
Sissons J, Alsam S, Stins M, Rivas AO, Morales JL, Faull J, Khan NA (2006) Use of in vitro assays to determine effects of human serum on biological characteristics of Acanthamoeba castellanii. J Clin Microbiol 44:2595–2600. https://doi.org/10.1128/JCM.00144-06
Taha M, Ismail NH, Ali M, Rashid U, Imran S, Uddin N, Khan KM (2017) Molecular hybridization conceded exceptionally potent quinolinyloxadiazole hybrids through phenyl linked thiosemicarbazide antileishmanial scaffolds: in silico validation and SAR studies. Bioorg Chem 71:192–200. https://doi.org/10.1016/j.bioorg.2017.02.005
Tariq S, Avecilla F, Sharma GP, Mondal N, Azam A (2018) Design, synthesis and biological evaluation of quinazolin-4 (3H)-one Schiff base conjugates as potential antiamoebic agents. J Saud Chem Soc 22:306–315. https://doi.org/10.1016/j.jscs.2016.05.006
Terrazas LI, Satoskar AR, Morales-Montor J (2010) Immunology and cell biology of parasitic diseases. J Biomed Biotechnol 2010:419849–419845. https://doi.org/10.1155/2010/419849
Thomson S, Rice CA, Zhang T, Edrada-Ebel R, Henriquez FL, Roberts CW (2017) Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba. Sci Rep 7:8247. https://doi.org/10.1038/s41598-017-07495-z
Tiwary BK, Pradhan K, Nanda AK, Chakraborty R (2015) Implication of quinazoline-4 (3H)-ones in medicinal chemistry: a brief review. J Chem Biol Ther 1:1000104. https://doi.org/10.4172/2572-0406.1000104
Urbina JA, Lira R, Visbal G, Bartrolí J (2000) In vitro antiproliferative effects and mechanism of action of the new triazole derivative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi. Antimicrob Agents Chemother 44:2498–2502. https://doi.org/10.1128/aac.44.9.2498-2502.2000Visvesvara
Visvesvara GS, Moura H, Schuster FL (2007) Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immun Med Microbiol 50:1–26. https://doi.org/10.1111/j.1574-695X.2007.00232.x
Wang X, Li P, Li Z, Yin J, He M, Xue W, Chen Z, Song B (2013) Synthesis and bioactivity evaluation of novel arylimines containing a 3-aminoethyl-2-[(p-trifluoromethoxy) anilino]-4 (3H)-quinazolinone moiety. J Agric Food Chem 61:9575–9582. https://doi.org/10.1021/jf403193q
Wu D, Feng M, Wang ZX, Qiao K, Tachibana H, Cheng XJ (2018a) Molecular and biochemical characterization of key enzymes in the cysteine and serine metabolic pathways of Acanthamoeba castellanii. Parasit Vectors 11:604. https://doi.org/10.1186/s13071-018-3188-7
Wu D, Qiao K, Feng M, Fu Y, Cai J, Deng Y, Tachibana H, Cheng X (2018b) Apoptosis of Acanthamoeba castellanii trophozoites induced by oleic acid. J Eukaryot Microbiol 65:191–199. https://doi.org/10.1111/jeu.12454
Yan JW, Li YP, Ye WJ, Chen SB, Hou JQ, Tan JH, Ou TM, Li D, Gu LQ, Huang ZS (2012) Design, synthesis and evaluation of isaindigotone derivatives as dual inhibitors for acetylcholinesterase and amyloid beta aggregation. Bioorg Med Chem 20:2527–2534. https://doi.org/10.1016/j.bmc.2012.02.061
Funding
This work is supported by the Sunway University, Malaysia (University Research Award INT-2019-03), and the Pakistan Academy of Sciences for providing financial support Project No. (5-9/PAS/440).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing interests.
Ethical approval
Not required.
Additional information
Section Editor: Julia Walochnik
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 1110 kb)
Rights and permissions
About this article
Cite this article
Shahbaz, M.S., Anwar, A., Saad, S.M. et al. Antiamoebic activity of 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one library against Acanthamoeba castellanii. Parasitol Res 119, 2327–2335 (2020). https://doi.org/10.1007/s00436-020-06710-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-020-06710-7