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Invasive fungal infections (IFIs) are increasing as major infectious diseases around the world, and the limited efficacy of existing medications has resulted in substantial morbidity and death in patients due to the lack of effective antifungal agents and serious drug resistance. In this study, a series of benzimidazole-1,2,4-triazole derivatives (6a-6l) were synthesized and characterized by 1H NMR, 13C NMR, and HR-MS spectral analysis. All the target compounds were screened for their in vitro antifungal activity against four fungal strains, namely, C. albicans, C. glabrata, C. krusei, and C. parapsilopsis. The synthesized compounds exhibited significant antifungal potential, especially against C. glabrata. Three compounds (6b, 6i, and 6j) showed higher antifungal activity with their MIC values (0.97 mu g/mL) compared with voriconazole and fluconazole. Molecular docking provided a possible binding mode of compounds 6b, 6i, and 6j in the 14 alpha-demethylase active site. Our studies suggested that the benzimidazole-1,2,4-triazole derivatives can be used as a new fungicidal lead targeting 14 alpha-demethylase for further structural optimization. In addition, their effects on the L929 cell line were also investigated to evaluate the cytotoxic effects of the compounds. SEM analyses were performed to examine the effects of compounds 6a, 6i, and 6j on C. glabrata cells under in vivo experimental conditions.

In this study, new benzimidazole-triazole derivatives were synthesized in two steps. First, 4-benzaldehyde derivatives are synthesized by reacting 1,2,4-triazole ring and 4-fluorobenzaldehyde. In the last step, the benzimidazole ring was obtained with o-phenylenediamine derivatives under microwave radiation. The structures of synthesized compounds were confirmed by 1H-NMR, 13C-NMR, infrared spectroscopy, mass spectroscopy, and elemental analysis. Antimicrobial activity of synthesized compounds is associated with six different types of bacteria (Escherichia coli ATCC 35218, E.coli ATCC 25922, Klebsiella pneumoniae NCTC 9633, Pseudomonas aeruginosa ATCC 27853, Salmonella typhimurium ATCC 13311, Staphylococcus aureus ATCC 25923), and four different Candida (C. albicans ATCC 24433, C. glabrata ATCC 90030, C. krusei ATCC 6258, C. parapsilosis ATCC 22019). Synthesized compounds showed weak antibacterial activity. However, 3a, 3b, and 3c compounds against C. albicans of the Candida species were found to show promising activity. Given the effect of substituents on antifungal activity, it is seen that the compounds 3a, 3b, and 3c carry chlorine, methyl, and fluoro substituents on the benzimidazole ring attract attention with higher activities. Molecular docking studies of 3a, 3b, and 3c were performed Schrödinger Glide XP against Candidas’ sterol 14-alpha demethylase (CYP51), and estimated ADME calculations were analyzed.

Nine new thiazole derivatives were synthesized considering 6-acetyl penicillanic acid (6-APA) and investigated for their antimicrobial activity. Ethyl 2-(2-mercaptoacetamido)-4-methylthiazole-5-carboxylate derivatives (3a–3i) were gained with a two-step synthetic method using conventional Hantzsch thiazole synthesis. The structural elucidation of the compounds was performed by 1H-NMR, 13C-NMR spectral data and HRMS. All compounds were tested on eleven bacteria and sixteen fungi species and minimum inhibitory concentration (MIC) was determined for each. Compounds 3d (4-methyl-2-(2-((5-methyl-1,3,4-thiadiazol-2-yl), 3f (4-methyl-2-(2-((5-nitro-1H-benzimidazol-2-yl) and 3g (4-methyl-2-(2-((5-methyl-4H-1,2,4-triazol-3-yl) bearing thiazole, 5-nitrobenzimidazole and triazole rings respectively exhibited high antimicrobial activity against most of the strains. In silico physicochemical properties were calculated for the compounds and it was detected that they comply with the rules of drug availability.

Enfeksiyon, bir organizmada patojen mikroorganizmaların neden olduğu birtakım istenmeyen etkilerin görülmesine denir. Özellikle de bakteri ve mantar kaynaklı enfeksiyonlar sıklıkla görülmektedir. Bu rahatsızlıkların tedavisinde kullanılan birçok antimikrobiyal ajan vardır. Ancak, günümüzde bu ajanların etkileri giderek azalmaktadır, bu duruma sebep olan ve dünya sağlığını tehdit eden en büyük problem antimikrobiyal ilaçlara karşı gelişen farklı fenotipteki dirençlerdir. Kinolin ve tiyazol, antimikrobiyal etkinlik açısından kendilerini kanıtlamış birer halka sistemleri olup klinikte kullanımı olan birçok antimikrobiyal ajanın yapısında bulunmaktadır. Araştırmalar, her iki halkanın da DNA giraz enziminin çalışmasını engelleyerek patojen mikroorganizmada birtakım bozukluklara sebep olduğunu ve bu sayede antimikrobiyal etki oluşturduğunu göstermektedir. Bu çalışmada, yeni antimikrobiyal ajan geliştirmek amacıyla bazı yeni kinolin-tiyazol türevleri sentezlenmiştir. Türev elde etmek için tiyazol halkası, hidrazin köprüsüyle kinolin halkasına birleştirilerek yeni moleküllerin sentezi yapılmıştır. Bileşiklerin yapıları IR, 1H-NMR, 13C-NMR ve yüksek çözünürlüklü kütle spektroskopisi ile aydınlatılmıştır. Bileşiklerin antimikrobiyal aktiviteleri ikisi gram negatif, dördü gram pozitif bakteri ile dört Candida türü üzerinde test edilmiştir. Bileşikler 4g ve 4m, E. coli ve S. aureus bakterileri üzerinde yüksek antimikrobiyal aktivite göstermiştir. DNA giraz inhibisyon çalışmasıyla da etki yolağı aydınlatılmıştır. Aynı zamanda 4b, 4e, 4f, 4h, 4j ve 4m bileşikleri 0,06 µg/mL'den daha düşük konsantrasyonlarda antikandidal aktivite gösterdikleri tespit edilmiştir. Genel olarak en aktif bileşik 4m olarak belirlenmiştir.Anahtar Sözcükler: Kinolin, Tiyazol, Antimikrobiyal aktivite, DNA giraz, Bakteriyeltopoizomeraz, Moleküler modelleme Infection is the occurrence of several undesirable effects which caused by pathogenic microorganisms in an organism. Especially bacterial and fungal infections are common. There are many antimicrobial agents used in the treatment of these infections. But today, the effects of these agents are gradually decreasing, and the biggest problem that causes this condition and threatens the world health is the development the different types of resistance to antimicrobial drugs. Quinoline and thiazole have proved their efficiency against microbial infections and were found in the structure of many antimicrobial agents that have been used clinically. Previous studies showed that both rings inhibit the DNA gyrase enzyme and thus they produce the antimicrobial effect. In this study, novel quinoline-thiazole derivatives were synthesized to develop new antimicrobial agents. The thiazole and quinoline rings were combined with the hydrazine bridge to obtain new molecules. The structures of the compounds were illuminated by IR, 1H-NMR, 13C-NMR and high-resolution mass spectroscopy (HRMS). The antimicrobial activities of the compounds were tested against four Candida spp., two gram negative and four gram positive bacteria species. Compounds 4g and 4m showed high antimicrobial activity against E. coli and S. aureus. The pathway of action was also demonstrated by the DNA gyrase inhibition study. At the same time, compounds 4b, 4e, 4f, 4h, 4j and 4m showed anticandidal activity at concentration lower than 0,06 µg /mL. In general, the most active compound was determined as 4m.Keywords: Quinoline, Antimicrobial activity, Thiazole, DNA gyrase, Bacterialtopoisomerase, Molecular modelling 165