3.1.3. Biologically active molecules – design, synthesis, extraction and study

Leading researcher: Prof. Dr. Eng. Dancho Lybenov Danalev, Prof. Dr. Eng. Peter Todorov Todorov

Theme: Peptides and hybride heterocycle-peptide molecules with potential applications in medicine; Preparation and purification of biologically active substances from medicinal and aromatic plants using membrane separation.

The scientific group includes several main areas of research, with specific research intentions for a period of 4 years /2023-2026/:

• Peptidomimetics and bioconjugates with potential application in medicine, especially for treatment of diseases such as cancer, chronic and acute pain, inflammation, bacterial infections:

– design, synthesis and study of biological activity in vitro and in vivo of newly synthesized peptides, their metal complexes with biogenic metals, heterocyclic compounds and hybrid heterocyclic-peptide molecules with anticancer, antimicrobial and some other important pharmacological activities by including unnatural amino acids in their structure in order to improve their pharmacodynamics, search for synergistic effect between the peptide fragment and the additional pharmacophore;

– Investigation of the redox behavior of newly synthesized N-modified hemorphin analogs in different electrolyte environments (pH 1.2–12.8) by applying voltammetric techniques. Investigation of different biological activities of the newly synthesized hemorphine analogues.

– synthesis and investigation of the properties of new amino acid biosurfactants as carriers of biologically active agents.

– research on expanding the possibilities for efficient utilization of waste products in the production of essential oils from aromatic plants and herbs using nanomembrane separation. Development of reverse osmosis and nanofiltration membranes with increased resistance to clogging by biologically active components of medicinal and aromatic plants. Development of a high intensity membrane module with improved performance.

• Preparation and purification of biologically active substances from medicinal and aromatic plants using membrane separation.

Publications:

1. Sirine Jaber, Veronica Nemska, Ivan Iliev, Elena Ivanova, Tsvetelina Foteva, Nelly Georgieva, Ivan Givechev, Dimiter Tanev, Emilia Naydenova, Dancho Danalev, Synthesis, antiproliferative and antimicrobial activities of (KLAKLAK)₂-NH₂ analogue containing nor-Leu and its conjugates with a second pharmacophore, Biotechnology & Biotechnological Equipment, 2023, 151-158, https://doi.org/10.1080/13102818.2022.2162965 (i.f. 1.7, Q4)
2. Dancho Danalev, Ivan Iliev, Stefan Dobrev, Silvia Angelova, Stoiko Petrin, Tatyana Dzimbova, Elena Ivanova, Dessislava Borisova, Emilia Naydenova, Synthesis, antiproliferative effect and in silico logP prediction of BIM-23052 analogs containing Tyr instead of Phe, Pharmaceutics, 2023, https://doi.org/10.3390/pharmaceutics15041123 (i.f. 5.5, Q1)
3. Boryana Borisova, Hristina Nocheva, Stéphane Gérard, Marie Cochard, Stefan Dobrev, Silvia Angelova, Stoyko Petrin, Dancho Danalev, Synthesis, In Silico LogP Study, and In Vivo Analgesic Activity of Analogs of Tetrapeptide FELL, Pharmaceuticals, 2023, 16(8), 1183; https://doi.org/10.3390/ph16081183 (i.f. 4.6, Q1)
4. Todorov, P.; Assenov, B.; Angelov, D.; Dzhambazova, E.; Pechlivanova, D. Behavioral Effects and Analgesic Profile of Hemoglobin-Derived Valorphin and Its Synthetic Analog in Rodents. Biomedicines 2023, 11, 2783. https://doi.org/10.3390/biomedicines11102783, (i.f. 4.1, Q1).
5. Todorov P, Georgieva S, Peneva P, Nikolov S, Rangelov M, Todorova N, Pechlivanova D, Tchekalarova J. Synthesis, molecular docking, electrochemical and fluorimetric analysis of new caffeic and cinnamic acid-conjugated hemorphin derivatives designed as potential anticonvulsant and antinociceptive agents. Bioorg Chem., 2024 Feb; 143:107063. https://doi.org/10.1016/j.bioorg.2023.107063 (i.f. 5.1, Q1)
6. Todorov P, Georgieva S, Tchekalarova J, Peneva P, Mateeva P, Assenov B, Dzhambazova E, Pechlivanova D. Synthesis, characterization and evaluation of anti-hyperalgesia, anticonvulsant and antioxidant activity of novel VV-hemorphin-5 analogs, Archiv der Pharmazie. 2023:e202300267. https://doi.org/10.1002/ardp.202300267 (i.f. 5.1, Q2)
7. Kameliya Anichina, Nikolai Georgiev, Nikolay Lumov, Dimitar Vuchev, Galya Popova-Daskalova, Georgi Momekov, Emiliya Cherneva, Rositsa Mihaylova, Anelia Mavrova, Stela Atanasova-Vladimirova, Iskra Piroeva, Denitsa Yancheva, Fused Triazino-benzimidazoles Bearing Heterocyclic Moiety: Synthesis, Structure Investigations, In silico and In vitro Biological activity, Molecules, 2023, 28, 5034, https://doi.org/10.3390/molecules28135034 (i.f. 4.6, Q2)
8. Boryana Borisova, Stanislava Vladimirova, Hristina Nocheva, Marie Laronze-Cochard, Stéphane Gérard, Stoyko Petrin, Dancho Danalev, Synthesis, Hydrolytic Stability and In Vivo Biological Study of Bioconjugates of the Tetrapeptides FELL Containing Pyrrole Moiety, Biomedicines, 2023, 11(12), 3265, https://doi.org/10.3390/biomedicines11123265 (i.f. 4.9, Q1)
9. K. Anichina, N. Georgiev, Synthesis of 2-Substituted Benzimidazole Derivatives as a Platform for Development of UV Filters and Radical Scavengers in Sunscreens, Organics, 2023, 4 (4), 524-538 https://doi.org/10.3390/org4040036 (i.f. 1.5, Q3).
10. P. Todorov, S. Georgieva, C. Trapella, K. Chakarov, J. Tchekalarova, D. Pechlivanova, D. Cheshmedzhieva, A. Fantinati, D. Illuminati, Synthesis, characterization, and biological study of new synthetic opioid hemorphin-4 peptides containing sterically restricted nonnatural amino acids, Arch. Pharm., 2024, e2400052. https://doi.org/10.1002/ardp.202400052 (i.f. 5.1, Q2)
11. Kameliya Anichina, Nikolay Kaloyanov, Diana Zasheva, Rusi Rusew, Rositsa Nikolova, Denitsa Yancheva, Ventsislav Bakov, Nikolai Georgiev, Self-Assembled Molecular Complexes of 1,10-Phenanthroline and 2-Aminobenzimidazoles: Synthesis, Structure Investigations, and Cytotoxic Properties, Molecules, 2024, 29, 583. https://doi.org/10.3390/molecules29030583 (i.f. 4.6, Q2)
12. Victoria Vitkova, Krassimira Antonova, Ognyan Petkov, Angelina Stoyanova-Ivanova, Sirine Jaber, Vladislava Ivanova, Emilia Naydenova, Dancho Danalev, Interaction of KLAKLAK-NH₂ and Analogs with Biomimetic Membrane Models, Pharmaceutics, 2024, 16, 340, https://doi.org/10.3390/pharmaceutics16030340 (i.f. 5.4, Q1)
13. Dimitrova, D.; Nemska, V.; Foteva, T.; Iliev, I.; Georgieva, N.; Danalev, D., Synthesis and Biological Studies of New Temporin A Analogs Containing Unnatural Amino Acids in Position 7, Pharmaceutics, 2024, 16, 716. https://doi.org/10.3390/pharmaceutics16060716 (i.f. 5.4, Q1)
14. Sirine Jaber, Yana Evstatieva, Veronica Nemska, Dilyana Nikolova, Emilia Naydenova, Nelly Georgieva, Dancho Danalev, Antimicrobial activity of (KLAKLAK)-NH₂ analogs against pathogenic microbial strains, Current Research in Biotechnology, 2024, 8, 100236 https://doi.org/10.1016/j.crbiot.2024.100236 (i.f. 4.0, Q2)
15. Boryana Borisova, Hristina Nocheva, Ivan Iliev, Marie Laronze-Cochard, Stéphane Gérard, Stoyko Petrin, Dancho Danalev, Synthesis and analgesic activity of new analogs of FELL tetrapeptide containing D-Phe in the first position, Current Research in Biotechnology, 2024, 8, 100249, https://doi.org/10.1016/j.crbiot.2024.100249 (i.f. 4.0, Q2)
16. Konstantinos Papadakis, Kadir Bezirci, Boryana Borisova, Stanislava Vladimirova, Dancho Danalev, Teodora Handjieva-Darlenska, Radka Tafradjiiska-Hadjiolova, Hristina Nocheva, Attenuation of 1-chloro-2,4-dinitrobenzene-induced inflammation in atopic dermatitis-like skin lesions in rat by a pyrrole containing FELL-NH₂ bioconjugate: cannabinoid receptor type 1 involvement, Pharmacia, 2024, 71: 1-10. https://doi.org/10.3897/pharmacia.71.e130213 (i.f. 1.0, Q4)
17. S. Georgieva, E. Stefanov, T. Radoykova, Direct ion chromatographic method for speciation micro analysis of arsenic forms in industrial samples with “rich” matrix composition, Journal of Chromatography A, 2024, 465421, https://doi.org/10.1016/j.chroma.2024.465421 (i.f. 3.8, Q1)
18. Hristina Zlatanova-Tenisheva, Stanislava Vladimirova, Pharmacological Evaluation of Novel Hydrazide and Hydrazone Derivatives: Anti-Inflammatory and Analgesic Potential in Preclinical Models, Molecules, 2025, 30, 1472. https://doi.org/10.3390/molecules30071472 (i.f. 5.0, Q2)
19. Dilyana Dimitrova, Veronica Nemska, Ivan Iliev, Stoyko Petrin, Nelly Georgieva, Dancho Danalev, New Temporin A Analogues Modified in Positions 1 and 10 – Synthesis and Biological Studies, Pharmaceutics 2025, 17, 396. https://doi.org/10.3390/Pharmaceutics17040396 (i.f. 5.8, Q1)
20. Y. Stoyanova, N. Lazarova-Zdravkova, D. Peshev, Is Membrane Filtration Applicable for the Recovery of Biologically Active Substances from Spent Lavender? Membranes. 2025, 15, 21. https://doi.org/10.3390/membranes15010021 (i.f. 3.3, Q2)
21. Karadashka, I.; Romanova, P.; Karadjova, V. Glass Transition Temperature and Mean Bond Energy of Chalcogenide Glasses in the As2Se3-GeTe-CdTe System. Inorganics 2025, 13, 160. https://doi.org/10.3390/inorganics13050160 (i.f. 3.0, Q2)
22. Kameliya Anichina, Galya Popova-Daskalova, Dimitar Vuchev, Maya Guncheva, Denitsa Yancheva, Nikolai Georgiev, Synthesis and In Vitro Biological Studies of Heterocyclic Benzimidazole Derivatives as Potential Therapeutics for Trichinellosis, Sci. 2025, 15, 6758. https://doi.org/10.3390/app15126758 (i.f. 2.5, Q1).
23. Kadir Bezirci, Boryana Borisova, Konstantinos Papadakis, Dancho Danalev, Hristina Nocheva, Drug Administration Before or After Exposure to Low Temperatures – Does It Matter for the Therapeutic Effect? Int. J. Mol. Sci., 2025, 26, 3883. https://doi.org/10.3390/ijms26083883 (i.f. 5.7, Q1)
24. Angelova, N., Iliev, I., Nemska, V., Dzimbova, T., Georgieva, N., Danalev, D., Naydenova, E., Design, Synthesis, and Biological Evaluation of New Analogs of Aurein 1.2 Containing Non-Proteinogenic Amino Acids, Molecules, 30(9), 2050 https://doi.org/10.3390/molecules30092050 (i.f. 5.0, Q2)
25. Neli Vilhelmova-Ilieva, Rayna Nenova, Ana Dobreva, Dimitar Peshev, Ivan Iliev, Anti-Herpes Simplex Virus Type 1 Activity of Rosa damascena Mill Essential Oil and Floral Water in Retinal Infection in Vitro, Int. J. Mol. Sci. 2025, 26, 7521. https://doi.org/10.3390/ijms26157521 (i.f. 5.7, Q1)
26. Simeon Stoyanov, Kameliya Anichina, Borislava Ivanova, Stela Georgieva, Neno Todorov, Bistra Stamboliyska and Denitsa Yancheva, Conversion of 1-alkylated 5(6)-nitro-1H-benzimidazoles into Radical Anions and Characterization of Their Bioreductive Potential, Journal of The Electrochemical Society, 172 (2025), 065501, https://doi.org/10.1149/1945-7111/ade1fc (i.f. 3.3, Q1)
27. B. Borisova, H. Nocheva, H. Zlatanova-Tenisheva, M. Laronze-Cochard, S. Gérard, D. Danalev, Synthesis and biological study of novel FELL analogs containing L- or D-Tyr instead of L-Phe in the N-terminus, Current Research in Biotechnology, 10, 2025, 100332, https://doi.org/10.1016/j.crbiot.2025.100332 (i.f. 4.5, Q2)
28. H. Zlatanova-Tenisheva, S. Vladimirova, Anti-Inflammatory and Immunomodulatory Effects of 2-(3-Acetyl-5-(4-Chlorophenyl)-2-Methyl-1H-Pyrrol-1-yl)-3-Phenylpropanoic Acid, Biomedicines, 2025, 13, 2003, https://doi.org/10.3390/biomedicines13082003 (i.f. 4.2, Q1)
29. Y. Stoyanova, N. Lazarova-Zdravkova, D. Peshev, Valorisation via nanofiltration of the antioxidant residual water from industrial hydrodistillation of rosa damascena mill. petals, J. Chem. Technol. Metall., 60(1), 2025, 3-10, https://doi.org/10.59957/jctm.v60.i1.2025.1 (SJR 0.196, Q3)
30. I. Uzunova-Raycheva, T. Nihtyanova, R. Raycheva, D. Danalev, P. Romanova, A. Belcheva-Krivorova, Infiltration level of CPP-ACFP (MI Varnish™), self-assembling peptide P11-4 (Curodont™ Repair), and newly synthesized fluorinated selfassembling peptides in artificial enamel initial carious lesions on smooth surfaces assessed by laser confocal microscopy – an in vitro study, Folia Med (Plovdiv), 2025;67(3):е151396, https://doi.org/10.3897/folmed.67.e151396 , (SJR 0.21, Q4)

31. Petar Todorov, Stela Georgieva, Diana Cheshmedzhieva, Borislav Assenov, Еlena Dzhambazova, Dimo Angelov, and Daniela Pechlivanova, Synthesis and analytical profile of new synthetic analogs of angiotensin 1‐7, the main balancing peptide of the renin–angiotensin system,  Archiv der Pharmazie 358, no. 3 (2025): e2500093; https://doi.org/10.1002/ardp.202500093

32. S. Georgieva, P. Todorov, P. Peneva, L.T.M. Hoa, Dual-Mode Chemosensing of iron ions by new Schiff Bases derived from cinnamyl 5,5′-dimethyl- and diphenylhydantoins, Results in Chemistry – under review (i.f. 4.2, Q2)
33. S. Georgieva, T. Radoykova, P. Todorov, Diana Cheshmedzhieva, Rositca Kukeva, Newly synthesized peptide-based chemosensor bearing azobenzene side chain as dual chemosensor for trace Au detection, Talanta, 2025 – under review (i.f. 3.7, Q1)
34. T. Radoykova, E. Stefanov, S. Nenkova, S. Georgieva, Antioxidant Activity of Phenolic Compounds Derived from Waste Hydrolyzed Lignocellulosic Material: A Comparative Evaluation Using Spectrophotometric and Electrochemical Methods, Cellulose, 2025 – under review (i.f. 5.6, Q1)
35. Ch. Chilev, Y. Stoyanova, N. Lazarova-Zdravkova, S. Petrin, D. Peshev, Experimental optimization of clove oil production, Journal of Essential Oil Research – under review (i.f. 2.1, Q2)
36. Vladimirova, S., Hristova, R., Iliev, I. Design, Synthesis and Biological Evaluation of Novel Methyl-Substituted Pyrrole Hydrazones as Selective Melanoma Agents, Current Research in Biotechnology, 2025 – under review (i.f. 4.0, Q2)