NEW SULFONAMIDO-BENZOXAZOLE DERIVATIVES AS ANTIMICROBIAL AGENTS: DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION

Öz

Objective: Many investigations are conducted in the battle against infectious diseases in order to develop new drug-active ingredient candidate compounds and to identify leading compounds. The goal of this study was to synthesis a total of seven compounds, six of which are novel, with the general structure 2-(4-tert-butylphenyl)-5-(4-substitutedphenylsulfonamido)benzoxazole, to elucidate their structures, and to test their antimicrobial activities using the microdilution method. Material and Method: The synthesis of the compounds was carried out in two stages. In the first stage, under PPA catalyst 2,4-diaminophenol and 4-tert-butylbenzoic acid were refluxed, and target compounds were produced in the second step by reacting 4-substitutedbenzenesulfonyl chloride with 5-Amino-2-(4-tert-butylphenyl)benzoxazole. The compounds' antimicrobial activity was determined by using Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and drug-resistant strains of these microorganisms in vitro antimicrobial activity studies. Furthermore, estimated ADME profiles were calculated using the SwissADME online software. Result and Discussion: The structures of the synthesized compounds were elucidated using 1H-NMR, 13C-NMR and Mass spectroscopy, and also their melting points were determined. The antimicrobial activities of the compounds ranged from 64 µg/ml to ˃512 µg/ml and were weaker than the reference drugs. The best antimicrobial activity was reported against an isolate of E. faecalis, with all compounds having MIC values of 64 µg/ml. The fact that six of the seven synthesized compounds are novel and that their antimicrobial activity will be tested for the first time will make a significant contribution to studies to develop new or alternative antimicrobial agents.

Anahtar Kelimeler

• ADME
• antimicrobial activity
• benzoxazole
• sulfonamide

ANTİMİKROBİYAL AJAN OLARAK YENİ SÜLFONAMIDO-BENZOKSAZOL TÜREVLERİ: TASARIM, SENTEZ VE BİYOLOJİK DEĞERLENDİRME

Öz

Amaç: Bulaşıcı hastalıklarla mücadelede yeni ilaç-etkin madde aday bileşikleri geliştirmek ve öncü bileşiklere ulaşmak için birçok araştırma yapılmaktadır. Bu çalışmanın amacı, genel yapısı 2-(4-tert-bütilfenil)-5-(4-sübstitüefenilsülfonamido)benzoksazol olan altısı yeni olmak üzere toplam yedi bileşiğin yapılarını aydınlatmak ve mikrodilüsyon yöntemini kullanarak antimikrobiyal aktivitelerini test etmektir. Gereç ve Yöntem: Bileşiklerin sentezi iki aşamada gerçekleştirilmiştir. İlk basamakta, PPA katalizörü altında 2,4-diaminofenol ve 4-tert-bütilbenzoik asit refluks edilmiş ve ikinci aşamada 4-sübstitüebenzensülfonil klorürün 5-Amino-2-(4-tert-bütilfenilbenzoksazol ile reaksiyona sokulmasıyla hedef bileşikler üretilmiştir. Bileşiklerin antimikrobiyal aktivitesi, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans ve bu mikroorganizmaların ilaca dirençli suşları kullanılarak in vitro antimikrobiyal aktivite çalışmaları ile belirlenmiştir. Ayrıca, SwissADME çevrimiçi yazılımı kullanılarak tahmini ADME profilleri hesaplanmıştır. Sonuç ve Tartışma: Sentezlenen bileşiklerin yapıları, 1H-NMR, 13C-NMR ve Kütle spektroskopisi kullanılarak aydınlatıldı ve ayrıca erime noktaları belirlenmiştir. Bileşiklerin antimikrobiyal aktiviteleri 64 µg/ml ila ˃512 µg/ml aralığındaydı ve referans ilaçlardan daha zayıftı. En iyi antimikrobiyal aktivite, tüm bileşiklerin 64 µg/ml MİK değerlerine sahip olduğu bir E. faecalis izolatına karşı rapor edilmiştir. Sentezlenen yedi bileşikten altısının yeni olması ve antibakteriyel aktivitelerinin ilk kez test edilecek olması, yeni veya alternatif antimikrobiyal ajanların geliştirilmesine yönelik çalışmalara önemli katkı sağlayacaktır.

Anahtar Kelimeler

• ADME
• antimikrobiyal aktivite
• benzoksazol
• sülfonamid

Kaynakça

1. 1. Peng, X.M., Cai, G.X., Zhou, C.H. (2013). Recent developments in azole compounds as antibacterial and antifungal agents. Current Topics in Medicinal Chemistry, 13(16), 1963-2010. [CrossRef]
2. 2. Takeuchi, O., Akira, S. (2010). Pattern recognition receptors and inflammation. Cell, 140(6), 805-820. [CrossRef]
3. 3. Arvanitis, M., Mylonakis, E. (2015). Fungal-bacterial interactions and their relevance in health. Cellular Microbiology, 17(10), 1442-1446. [CrossRef]
4. 4. Singh, N., Rogers, P., Atwood, C.W., Wagener, M.M., Yu, V.L. (2000). Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription. American Journal of Respiratory and Critical Care Medicine, 162(2), 505-511. [CrossRef]
5. 5. Zehra, A., Gulzar, M., Singh, R., Kaur, S., Gill, J. (2019). Prevalence, multidrug resistance and molecular typing of methicillin-resistant Staphylococcus aureus (MRSA) in retail meat from Punjab, India. Journal of global antimicrobial resistance, 16, 152-158. [CrossRef]
6. 6. Tfifha, M., Ferjani, A., Mallouli, M., Mlika, N., Abroug, S., Boukadida, J. (2018). Carriage of multidrug-resistant bacteria among pediatric patients before and during their hospitalization in a tertiary pediatric unit in Tunisia. Libyan Journal of Medicine, 13(1), 1419047. [CrossRef]
7. 7. Miyanaga, M., Nejima, R., Miyai, T., Miyata, K., Ohashi, Y., Inoue, Y., Toyokawa, M., Asari, S. (2009). Changes in drug susceptibility and the quinolone-resistance determining region of Staphylococcus epidermidis after administration of fluoroquinolones. Journal of Cataract Refractive Surgery, 35(11), 1970-1978. [CrossRef]
8. 8. Todd, B. (2017). Reconsidering antibiotic resistance. AJN The American Journal of Nursing, 117(12), 66-67. [CrossRef]

9. 9. Spellberg, B. (2016). The new antibiotic mantra-“shorter is better”. JAMA Internal Medicine, 176(9), 1254-1255. [CrossRef]
10. 10. Khan, Z., Ahmad, S., Benwan, K., Purohit, P., Al-Obaid, I., Bafna, R., Emara, M., Mokaddas, E., Abdullah, A.A., Al-Obaid, K. (2018). Invasive Candida auris infections in Kuwait hospitals: epidemiology, antifungal treatment and outcome. Infection, 46(5), 641-650. [CrossRef]
11. 11. Nweke, M.C., Okolo, C.A., Daous, Y., Esan, O.A. (2018). Challenges of human papillomavirus infection and associated diseases in low-resource countries. Archives of Pathology Laboratory Medicine, 142(6), 696-699. [CrossRef]
12. 12. Wang, X.L., Wan, K., Zhou, C.H. (2010). Synthesis of novel sulfanilamide-derived 1,2,3-triazoles and their evaluation for antibacterial and antifungal activities. European Journal of Medicinal Chemistry, 45(10), 4631-4639. [CrossRef]
13. 13. Khan, M.S., Alam, M., Tabassum, Z., Ahmad, A., Khan, A.U. (2010). Synthesis, antibacterial and antifungal activities of 6, 5 fused steroidal oxazoles in cholestane series. European Journal of Medicinal Chemistry, 45(3), 1094-1097. [CrossRef]
14. 14. Erol, M., Celik, I., Temiz-Arpaci, O., Kaynak-Onurdag, F., Okten, S. (2020). Design, synthesis, molecular docking, density functional theory and antimicrobial studies of some novel benzoxazole derivatives as structural bioisosteres of nucleotides. Journal of Biomolecular Structure and Dynamics, 39(9), 3080-3091. [CrossRef]
15. 15. Osmaniye, D., Çelikateş, B.K., Sağlık, B.N., Levent, S., Çevik, U.A., Çavuşoğlu, B.K., Ilgın, S., Özkay, Y., Kaplancıklı, Z.A. (2021). Synthesis of some new benzoxazole derivatives and investigation of their anticancer activities. European Journal of Medicinal Chemistry, 210, 112979. [CrossRef]
16. 16. Angajala, G., Subashini, R. (2020). Synthesis, molecular modeling, and pharmacological evaluation of new 2-substituted benzoxazole derivatives as potent anti-inflammatory agents. Structural Chemistry, 31(1), 263-273. [CrossRef]
17. 17. Yatam, S., Jadav, S.S., Gundla, R., Gundla, K.P., Reddy, G.M., Ahsan, M.J., Chimakurthy, J. (2018). Design, synthesis and biological evaluation of 2 (((5‐aryl‐1, 2, 4‐oxadiazol‐3‐yl) methyl) thio) benzo [d] oxazoles: new antiinflammatory and antioxidant agents. ChemistrySelect, 3(37), 10305-10310. [CrossRef]
18. 18. Celik, I., Erol, M., Temiz Arpaci, O., Sezer Senol, F., Erdogan Orhan, I. (2020). Evaluation of activity of some 2,5-disubstituted benzoxazole derivatives against acetylcholinesterase, butyrylcholinesterase and tyrosinase: ADME prediction, DFT and comparative molecular docking studies. Polycyclic Aromatic Compounds, 42(2), 412-423. [CrossRef]
19. 19. Song, M.X., Huang, Y., Wang, S., Wang, Z.T., Deng, X.Q. (2019). Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4‐triazolone moiety. Archiv der Pharmazie, 352(8), 1800313. [CrossRef]
20. 20. Temiz-Arpaci, O., Yildiz, I., Ozkan, S., Kaynak, F., Akı-Şener, E., Yalçın, İ. (2008). Synthesis and biological activity of some new benzoxazoles. European Journal of Medicinal Chemistry, 43(7), 1423-1431. [CrossRef]
21. 21. Erol, M., Celik, I., Uzunhisarcikli, E., Kuyucuklu, G. (2020). Synthesis, molecular docking, and dft studies of some new 2,5-disubstituted benzoxazoles as potential antimicrobial and cytotoxic agents. Polycyclic Aromatic Compounds, 42(4), 1679-1696. [CrossRef]
22. 22. Temiz-Arpaci, O., Doğanc, F., Sac, D., Sari, E., Kaynak-Onurdag, F., Okten, S. (2016). Synthesis and antimicrobial evaluation of some novel sulfonylamido-benzoxazoles. Acta Biologica Hungarica, 67(1), 75-84. [CrossRef]
23. 23. Washburn, A., Abdeen, S., Ovechkina, Y., Ray, A.M., Stevens, M., Chitre, S., Sivinski, J., Park, Y., Johnson, J., Hoang, Q.Q. (2019). Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections. Bioorganic Medicinal Chemistry Letters, 29(13), 1665-1672. [CrossRef]