Öz
Giriş: Bu çalışma, N-metoksietil (9) ve N-benzil (10) parçalarını içeren iki yeni nitroheteroaril-1,3,4-tiyadiazol türevinin Aspergillus fumigatus’a karşı antifungal aktivitesini ve sitotoksisitesini, özellikle de hücresel düzeydeki etki mekanizmalarına odaklanarak değerlendirmeyi amaçlamıştır.
Gereç ve Yöntem: Mantar büyüme hızı mikrobiyoassay tekniği ile değerlendirildi. Hücre zarının ergosterol içeriği belirlendi ve mantar bölmelerinin morfolojik değişiklikleri elektron mikroskobu ile değerlendirildi. Vero ve Hep2 hücre hatlarına karşı sitotoksisite, hücre kültürü tekniği ile belirlendi.
Bulgular: Elde edilen verilere dayanarak, bileşik 9 25-800 μM konsantrasyonlarda %31,90-100 inhibisyon gösterirken, bileşik 10 daha yüksek konsantrasyonlarda (25-3200 µm) %24,26-100 inhibisyon gösterdi. Bileşik 9 ve 10’un minimum fungusit konsantrasyonları sırasıyla 500 ve 8000 μM; IC50 değerleri ise 43,39 ve 1008.67 μM idi. Ergosterol içeriği, her iki bileşikten de anlamlı şekilde etkilenmedi. Elektron mikroskopisi; A. fumigatus hyphae’nin deformasyonunu, hif içeriklerinin tükenmesini ve her iki bileşiğe maruz kalan mantarda hücre zarı ve zarlı organellerin yok oluşunu gösterdi. Bileşikler 9 ve 10, in vitro olarak Vero ve Hep2 hücre hatlarına karşı belirgin bir sitotoksisiteye sahip değildi.
Sonuç: Birlikte ele alındığında, sonuçlarımız her iki bileşiğin, özellikle bileşik 9’un, yaşamı tehdit eden invaziv aspergillozun ana etiyolojik ajanı olan A. fumigatus’a karşı antifungal ilaçlar geliştirmek için potansiyel adaylar olarak kabul edilebileceğini göstermiştir.
Anahtar Kelimeler: Tiyadiazol, Aspergillus fumigatus, ergosterol, antifungal aktivite, elektron mikroskobu, sitotoksisite
Kaynakça
Tian J, Ban X, Zeng H, He J, Chen Y, Wang Y. The mechanism of antifungal action of essential oil from dill (Anethum graveolens L.) on Aspergillus flavus. PLoS One. 2012;7:e30147.
Lamoth F. Aspergillus fumigatus-Related Species in Clinical Practice. Front Microbiol. 2016;7:683.
Taccone FS, Van den Abeele AM, Bulpa P, Misset B, Meersseman W, Cardoso T, Paiva JA, Blasco-Navalpotro M, De Laere E, Dimopoulos G, Rello J, Vogelaers D, Blot SI; AspICU Study Investigators. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care. 2015;19:7.
Dagenais TR, Keller NP. Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis. Clin Microbiol Rev. 2009;22:447-65.
What is Aspergillus and aspergillosis? Accessed Aug 25, 2018. Available at: https://www.aspergillus.org.uk/what-is-asp?tid=4349
Rosowski EE, Raffa N, Knox BP, Golenberg N, Keller NP, Huttenlocher A. Macrophages inhibit Aspergillus fumigatus germination and neutrophil-mediated fungal killing. PLoS Pathog. 2018;14:e1007229.
Workum JD, de Jong SW, Gresnigt MS, Becker KL, Pickkers P, van de Veerdonk FL, Heijdra YF, Kolwijck E. Microbiological and immunological characteristics of a lethal pulmonary Aspergillus niger infection in a non-neutropenic patient. Med Mycol Case Rep. 2018;21:4-7.
van Paassen J, Russcher A, In ‘t Veld-van Wingerden AW, Verweij PE, Kuijper EJ. Emerging aspergillosis by azole-resistant Aspergillus fumigatus at an intensive care unit in the Netherlands, 2010 to 2013. Euro Surveill. 2016;21.
Sofan MA, Said SB, Kandeel SH. Antimicrobial activity of newly synthesized thiadiazoles, 5-benzyl-2h- tetrazole and their nucleosides. Der Pharma Chemica. 2012;4:1064-73.
Fisher MC, Hawkins NJ, Sanglard D, Gurr SJ. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science. 2018;360:739-42.
Holmes AR, Cardno TS, Strouse JJ, Ivnitski-Steele I, Keniya MV, Lackovic K, Monk BC, Sklar LA, Cannon RD. Targeting efflux pumps to overcome antifungal drug resistance. Future Med Chem. 2016;8:1485-501.
Srivastava S, Prasad RK, Saini R. Thiadiazole: A Brief Review. World J Pharm Pharm Sci. 2014;3:1198-1212. Available from: https://www.wjpps.com/Wjpps_controller/abstract_id/2021
Khalilullah H, Khan MU, Mahmood D, Akhtar J, Elhassan GO. 1,3,4-Thiadiazole: A biologically active scaffold. Int J Pharm Pharm Sci. 2014;6:8-15.
Kasımoğulları R, Bülbül M, Arslan BS, Gökçe B. Synthesis, characterization and antiglaucoma activity of some novel pyrazole derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide. Eur J Med Chem. 2010;45:4769-73.
Sandeep Reddy K, Purohit M, Pujar G. Synthesis and pharmacological activity of some novel bis-heterocycles encompassing pyrrole. Inter J Pharm Pharm Sci. 2012;4:153-7.
Mohammadhosseini N, Saniee P, Ghamaripour A, Aryapour H, Afshar F, Edraki N, Siavoshi F, Foroumadi A, Shafiee A. Synthesis and biological evaluation of novel benzyl piperazine derivatives of 5-(5-nitroaryl)-1,3,4-thiadiazoles as Anti-Helicobacter pylori agents. Daru. 2013;21:66.
Ragab FA, Heiba HI, El-Gazzar MG, Abou-Seri SM, El-Sabbagh WA, El-Hazek RM. Anti-inflammatory, analgesic and COX-2 inhibitory activity of novel thiadiazoles in irradiated rats. J Photochem Photobiol B. 2017;166:285-300.
Anusha S, Cp B, Mohan CD, Mathai J, Rangappa S, Mohan S, Chandra, Paricharak S, Mervin L, Fuchs JE, M M, Bender A, Basappa, Rangappa KS. A Nano-MgO and Ionic Liquid-Catalyzed ‘Green’ Synthesis Protocol for the Development of Adamantyl-Imidazolo-Thiadiazoles as Anti-Tuberculosis Agents Targeting Sterol 14α-Demethylase (CYP51). PLoS One. 2015;10:e0139798.
Tahghighi A, Babalouei F. Thiadiazoles: the appropriate pharmacological scaffolds with leishmanicidal and antimalarial activities: a review. Iran J Basic Med Sci. 2017;20:613-22.
Tahghighi A, Emami S, Razmi S, Rezazade Marznaki F, Kabudanian Ardestani S, Dastmalchi S, Kobarfard F, Shafiee A, Foroumadi A. New 5-(nitroheteroaryl)-1,3,4-thiadiazols containing acyclic amines at C-2: synthesis and SAR study for their antileishmanial activity. J Enzyme Inhib Med Chem. 2013;28:843-52.
Tahghighi A, Razmi S, Mahdavi M, Foroumadi P, Ardestani SK, Emami S, Kobarfard F, Dastmalchi S, Shafiee A, Foroumadi A. Synthesis and anti-leishmanial activity of 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-amines containing N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl] moieties. Eur J Med Chem. 2012;50:124-8.
Tahghighi A, Foroumadi A, Kabudanian-Ardestani S, Mahdian SMA. Synthesis and Comparison of in vitro Leishmanicidal Activity of 5-(Nitroheteroaryl)-1,3,4-Thiadiazols Containing Cyclic Amine of Piperidin-4-ol at C-2 with Acyclic Amine Analogues against Iranian Strain of Leishmania major (MRHO/IR/75/ER). J Arthropod Borne Dis. 2017;11:95-104.
Tolouee M, Alinezhad S, Saberi R, Eslamifar A, Zad SJ, Jaimand K, Taeb J, Rezaee MB, Kawachi M, Shams-Ghahfarokhi M, Razzaghi-Abyaneh M. Effect of Matricaria chamomilla L. flower essential oil on the growth and ultrastructure of Aspergillus niger van Tieghem. Int J Food Microbiol. 2010;139:127-33.
Soares BV, Morais SM, dos Santos Fontenelle RO, Queiroz VA, Vila-Nova NS, Pereira CM, Brito ES, Neto MA, Brito EH, Cavalcante CS, Castelo-Branco DS, Rocha MF. Antifungal activity, toxicity and chemical composition of the essential oil of Coriandrum sativum L. fruits. Molecules. 2012;17:8439-48.
CLSI M38-A2. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi; Approved Standard-Second Edition.
Borba-Santos LP, Visbal G, Gagini T, Rodrigues AM, de Camargo ZP, Lopes-Bezerra LM, Ishida K, de Souza W, Rozental S. Δ(24)-Sterol Methyltransferase Plays an Important Role in the Growth and Development of Sporothrix schenckii and Sporothrix brasiliensis. Front Microbiol. 2016;7:311.
Kunzler A, Neuenfeldt PD, das Neves AM, Pereira CM, Marques GH, Nascente PS, Fernandes MH, Hübner SO, Cunico W. Synthesis, antifungal and cytotoxic activities of 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidinones. Eur J Med Chem. 2013;64:74-80.
Khan MS, Ahmad I, Cameotra SS. Phenyl aldehyde and propanoids exert multiple sites of action towards cell membrane and cell wall targeting ergosterol in Candida albicans. AMB Express. 2013;3:54.
Cardoso NN, Alviano CS, Blank AF, Romanos MT, Fonseca BB, Rozental S, Rodrigues IA, Alviano DS. Synergism Effect of the Essential Oil from Ocimum basilicum var. Maria Bonita and Its Major Components with Fluconazole and Its Influence on Ergosterol Biosynthesis. Evid Based Complement Alternat Med. 2016;2016:5647182.
Senthilraja P, Kathiresan K. In vitro cytotoxicity MTT assay in Vero, HepG2 and MCF -7 cell lines study of Marine Yeast. J Appl Pharm Sci. 2015;5:80-4.
Foroumadi A, Daneshtalab M, Shafiee A. Synthesis and in vitro antifungal activity of 2-aryl-5-phenylsulfonyl-1,3,4-thiadiazole derivatives. Arzneimittelforschung. 1999;49:1035-8.
Aouad MR, Messali M, Rezki N, Ali AA, Lesimple A. Synthesis and characterization of some novel 1,2,4-triazoles, 1,3,4-thiadiazoles and Schiff bases incorporating imidazole moiety as potential antimicrobial agents. Acta Pharm. 2015;65:117-32.
Raj M, Patel HV, Raj L, Patel R. Synthesis and biological evaluation of some new 1,3,4-thiadiazole derivatives for their antimicrobial activities. Int J Pharm Chem Biol Sci. 2013;3:814-9.
Andrade Neto JBD, Silva CRD, Campos RDS, Nascimento FBSAD, Freitas DD, Josino MAA, Andrade LNDD, Gonçalves TB, Mesquita JRLD, Magalhaes HIF, Rodrigues FAR, Gaspar DM, Moraes Filho MOD, Lobo MDP, Moreno FBMM, Grangeiro TB, Gomes AOCV, Nascente LDC, Romeiro LAS, Cavalcanti BC, Nobre Junior HV. Effects of Piperonal Nitro Derivatives on Candida species: antifungal activity against fluconazole-resistant strains is associated with oxidative DNA damage. Inter J Curr Microbiol Appl Sci. 2015:4:777-92.
