Buga Aktekin, Mine; Oksuz, Zehra; Alagoz, Mehmet Abdullah; Uluca Han, Bahar; Algul, Oztekin

Aims: Antibiotic-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA), have renewed interest in antivirulence strategies. This study aimed to design, synthesize, and evaluate asymmetric di‑heterocyclic benzazole derivatives as antibiofilm agents targeting wall teichoic acid (WTA) biosynthesis. Materials and methods: Twenty‑one novel bis‑heterocyclic benzazole derivatives bearing an ethyl‑thio linker were synthesized and characterized. Antibacterial activity was determined by broth microdilution. Antibiofilm activity (inhibition and eradication) was assessed at sub‑minimal inhibitory concentrations (sub‑MICs) using crystal violet. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed against key WTA enzymes (TarGH, TarS, TarM, TarL, and TarJ). Results: Compounds 18, 21, 23, and 24 showed potent antibacterial activity against methicillin‑susceptible S. aureus (MSSA) and MRSA, with MIC values as low as 15.62 µg/mL. All selected compounds significantly inhibited biofilm at sub‑MIC levels. Compound 24 was most effective, with an MBIC50 of 3.90 µg/mL against MSSA and eradicated pre‑formed biofilms at 7.81 µg/mL. Docking and MD simulations revealed stable interactions of compounds 23 and 24 with TarGH and TarS, suggesting a WTA‑targeting mechanism. Conclusions: Di‑heterocyclic benzazole derivatives, especially compound 24, are promising scaffolds for antibiofilm agents against S. aureus. Our findings support further mechanistic and preclinical evaluation as potential antivirulence therapeutics.

Türkeş, Cüneyt; Yapar, Gönül; Duran, Hatice Esra; Lolak, Nebih; Akocak, Suleyman

Aims: To develop isovanillin-based bis-hydrazones as multitarget inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I/II (hCA I/II). Materials & methods: Twelve bis-hydrazones (4a–4l) were synthesized in two steps and evaluated by spectrophotometric enzyme assays, Lineweaver–Burk kinetics, molecular docking, MM-GBSA, molecular dynamics simulations, and in silico ADME/Tox profiling. Results: All compounds showed nanomolar inhibition. Compound 4d was the most potent AChE/BChE inhibitor (KI = 10.46 and 3.56 nM), while 4a and 4j led the hCA I/II panel (KI = 3.46 and 16.12 nM). Docking, MM-GBSA, and molecular dynamics supported dual-site cholinesterase engagement and non-zinc, peripherally anchored hCA inhibition. Conclusions: Isovanillin-based bis-hydrazones, particularly 4d, 4a, and 4j, represent promising multitarget leads for cholinergic and hCA-linked disorders.

Yucel, Mehmet Ali; Ozcelik, Ibrahim; Algul, Oztekin

Aim: Investigating molecules having toxicity and chemical similarity to find hit molecules. Methods: The machine learning (ML) model was developed to predict the arylhydrocarbon receptor activity of anti-Parkinson's and US FDA-approved drugs. The ML algorithm was a support vector machine, and the dataset was Tox21. Results: The ML model predicted apomorphine in anti-Parkinson's drugs and 73 molecules in FDA-approved drugs as active. The authors were curious if there is any molecule like apomorphine in these 73 molecules. A fingerprint similarity analysis of these molecules was conducted and found tetrahydrocannabinol (THC). Molecular docking studies of THC for dopamine receptor 1 (affinity = -8.2 kcal/mol) were performed. Conclusion: THC may affect dopamine receptors directly and could be useful for Parkinson's disease.

Kuzu, Burak; Hepokur, Ceylan; Turkmenoglu, Burcin; Burmaoglu, Serdar; Algul, Oztekin

Background: Phortress produces reactive electrophilic metabolites that form DNA adducts only in sensitive tumor cells. The authors converted the 2-phenylbenzothiazole nucleus in phortress to 2-aryl and -heteroaryl benzoxazole derivatives (11 new and 14 resynthesized). All synthesized compounds were studied for antitumor activity in various cancer cells. Materials & methods: Cytotoxicity, cell morphology, flow cytometry and cell-cycle analyses of compounds were performed and more active derivatives were tested in the MCF-7 cell line. Conclusion: Methyl 2-(thiophen-2-yl)benzo[d]oxazole-6-carboxylate (BK89) has a higher effect than fluorouracil to induce apoptotic cell death (apoptosis value of 49.44%). Cell-cycle analysis shows that the compounds BK89 and methyl 2-(furan-2-yl)benzo[d]oxazole-6-carboxylate (BK82) can be used as potential cell-cycle blockers by arresting MCF-7 cells in G0/G1 phase at rates of 63% and 85%, respectively. Plain language summary There is an urgent need to develop potent and selective anticancer agents. In this study, the design and applications of compounds sensitive to specific cancer cells and targeting cancer cells were investigated. The results show that the synthesized compounds can be antiproliferative drug candidates for breast cancer. These compounds may shed light on cancer treatment and cancer research.