The project is a multidisciplinary approach with some important interdisciplinary valences aiming to bring its contribution in the solving of generic problems identified within the framework of Research Domain No. 6. BIOTECHNOLOGIES, with specific fit in the Research direction 6.1 Biotechnologies: 6.1.1 Design and development of new drugs with maximal efficiency and minimal secondary effects.
The final aim of the SYNTHIAZO project is to develop new thiazole, bithiazole and thiazolidin-4-one compounds with controlled delivery and antioxidant/antiproliferative effects and/or specific antitumoral activity, and antimicrobial properties in order to respond at two recurring problems in clinical medicine:
In the challenging process of new drug discovery, the partners tasked themselves not only with solving a whole range of difficult scientific and technical problems but even dissemination of project’s without affecting the allocation of intellectual property rights. Therefore, partners will work together and the outcomes of the project will be promoted at national and EU level.
The Consortium consists of four participating entities: three from the academic area (a national R&D institute and two universities) and one from industry (a SME).
Grant holder (Coordinator - CO): The National Research and Development Institute for Cryogenics and Isotopic Technologies – ICSI Rm. Valcea
Department of Research and Development and Technology Transfer: http://www.icsi.ro
Partner 1 (P1): University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca
Pharmaceutical chemistry: http://www.umfcluj.ro
Partner 2 (P2): University of Bucharest
3Nano-SAE Research Center: http://www.3nanosae.org
Partner 3 (P3): SC BioLumiMedica SRL Bucharest: http://biolumimedica.ro
Undertaking the aim of the project, we have developed a set of clearly defined "SMART" (Specific, Measurable, Attainable, Realistic, Time-bound) objectives
Requested budget: 2.760.000,00 RON
Approved budget: 1.380.000,00 RON
Budget allocation by stages (in RON):
Project progress: public results & dissemination
One of the main objectives of organic and medicinal chemistry is the design, synthesis and production of molecules having value as human therapeutic agents.
Computer-aided drug design (CADD) techniques were used to start the researches in the process of drug discovery:
Generation of combinatorial library
Lipophilicity study on thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles:
Lipophilicity, as one of the most important physicochemical parameters of bioactive molecules, was investigated for twenty-two thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles. The determination was carried out by reversed-phase thin-layer chromatography, using a binary isopropanol-water mobile phase. Chromatographically obtained lipophilicity parameters were correlated with calculated log P and log D and with some biological parameters, determined in order to evaluate the anti-inflammatory and antioxidant potential of the investigated compounds, by using principal component analysis (PCA). The PCA grouped the compounds based on the nature of their substituents (X, R and Y), indicating that their nature, electronic effects and molar volumes influence the lipophilicity parameters and their anti-inflammatory and antioxidant effects. Also, the results of the PCA analysis applied on all the experimental and computed parameters show that the best anti-inflammatory and antioxidant compounds were correlated with medium values of the lipophilicity parameters. On the other hand, the knowledge of the grouping patterns of the tested variables allows the reduction of the number of parameters, determined in order to establish the biological activity.
For references, please check our paper: R. Tamaian, A. Mot, R. Silaghi-Dumitrescu, I. Ionut, A. Stana, O. Oniga, C. Nastasa, D. Benedec, B. Tiperciuc, 2015, Study of the Relationships between the Structure, Lipophilicity and Biological Activity of Some Thiazolyl-carbonyl-thiosemicarbazides and Thiazolyl-azoles. Molecules, 20:22188–22201, doi:10.3390/molecules201219841
Profiles of RM values at all mobile binary phase composition (% of organic modifier) for thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles
Biological evaluation and docking of chromenyl-derivatives:
Various thiosemicarbazones (TSCs) and their heterocyclic thiadiazolines (TDZ) possess important biological effects. In addition, chromenyl derivatives exhibit a wide range of pharmacological activities. Based on these findings and as a continuation of our research on nitrogen and sulfur containing compounds, we investigated a series of previously reported chromenyl-TSCs (1a-j) and chromenyl-TDZs (2a-j) for their in vitro antimicrobial activities against two bacterial and four fungal strains. MIC and MBC/MFC (µg/mL) values of these compounds were evaluated and compared to those of Spectinomycin, Moxifloxacin and Fluconazole, used as reference drugs. For a better understanding of the drug-receptor interactions, all the compounds were further subjected to molecular docking against four targets that were chosen based on the specific mechanism of action of the reference drugs used in the antimicrobial screening. All compounds tested showed equal or higher antibacterial/antifungal activities relative to the used reference drugs. In silico studies (docking) revealed that all the investigated compounds showed good binding energies towards four receptor protein targets and supported their antimicrobial properties.
For references, please check our paper: I. Ionuţ, D. C. Vodnar, I. Oniga, O. Oniga, B. Tiperciuc, R. Tamaian, 2016, Biological evaluation and molecular docking of some chromenyl-derivatives as potential antimicrobial agents. Pakistan Journal of Pharmaceutical Sciences, 29(1-Suppl):261–272, http://www.pjps.pk/?page_id=276&id=2181
Docking poses of compounds 1a-j and 2a-j against 30S ribosomal protein S12
Design, synthesis and antifungal activity evaluation of novel thiazolin-4-ones:
Twenty-three thiazolin-4-ones were synthesized starting from phenylthioamide or thiourea derivatives by condensation with alpha-monochloroacetic acid or ethyl alpha-bromoacetate, followed by substitution in position 5 with various arylidene moieties. All the synthesized compounds were physico-chemically characterized and the IR, 1H NMR, 13C NMR and MS data were consistent with the assigned structures. The synthesized thiazolin-4-one derivatives were tested for antifungal properties against several strains of Candida and all compounds exhibited efficient anti-Candida activity, two of them (9b and 10) being over 500-fold more active than fluconazole. Furthermore, the compounds’ lipophilicity was assessed and the compounds were subjected to in silico screening for prediction of their ADME-Tox properties. Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme. The results of the in vitro antifungal activity screening, docking study and ADME-Tox prediction revealed that the synthesized compounds are potential anti-Candida agents that might act by inhibiting the fungal lanosterol 14α-demethylase and can be further optimized and developed as lead compounds.
For references, please check our paper: A. Stana, D. C. Vodnar, R. Tamaian, A. Pîrnău, L. Vlase, I. Ionuţ, O. Oniga, B. Tiperciuc, 2017, Design, Synthesis and Antifungal Activity Evaluation of New Thiazolin-4-ones as Potential Lanosterol 14 α-Demethylase Inhibitors. International Journal of Molecular Sciences, 18(1):177, doi:10.3390/ijms18010177
Docking poses of thiazolin-4-ones in the active site of lanosterol-14α-demethylase
Patent application A/00766 from September 28th, 2017: Chitosan nanoparticles based bio-support for transport of active principles and process for obtaining thereof (authors: Cornelia Nichita, Ioan Daniel Stamatin, Radu Tamaian)
SEM images of chitosan nanoparticles
Dissemination via scientific manifestations:
Bucharest University Faculty of Physics 2017 Meeting, 23 – 24 June 2017 Bucharest, Romania: