Browsing by Author "Iliev I."
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Item 2-Alkyl-Substituted-4-Amino-Thieno[2,3-d]Pyrimidines: Anti-Proliferative Properties to In Vitro Breast Cancer Models(2023-09-01) Iliev I.; Mavrova A.; Yancheva D.; Dimov S.; Staneva G.; Nesheva A.; Tsoneva I.; Nikolova B.Thienopyrimidines are structural analogs of quinazolines, and the creation of new 2-alkyl derivatives of ethyl 4-aminothienopyrimidine-6-carboxylates for the study of their anti-proliferative properties is of great pharmacological interest. Some 2-alkyl-4-amino-thieno[2,3-d]pyrimidines 2–5 were synthesized, and their cyto- and phototoxicity against BALB 3T3 cells were established by an in vitro 3T3 NRU test. The obtained results indicate that the tested compounds are not cytotoxic or phototoxic, and that they are appropriate to be studied for their anti-proliferative and anti-tumor properties. The anti-proliferative potential of the compounds was investigated on MCF-7 and MDA-MB-231 cancer cells, as well as a MCF-10A cell line (normal human mammary epithelial cells). The most toxic to MCF-7 was thienopyrimidine 3 with IC50 13.42 μg/mL (IC50 0.045 μM), followed by compound 4 (IC50 28.89 μg/mL or IC50 0.11 μM). The thienopyrimidine 4 revealed higher selectivity to MCF-7 and lower activity (IC50 367 μg/mL i.e., 1.4 μM) than compound 3 with MCF-10A cells. With respect to MDA-MB-231 cells, ester 2 manifested the highest effect with IC50 52.56 μg/mL (IC50 0.16 μM), and 2-ethyl derivative 4 revealed IC50 62.86 μg/mL (IC50 0.24 μM). It was estimated that the effect of the substances on the cell cycle progression was due to cell cycle arrest in the G2 stage for MDA-MB-231, while arrest in G1 was detected for the estrogen (ER)-positive MCF-7 cell line. The tested compound’s effects on the change of the zeta potential in the tumorigenic cells utilized in this study were determined. The calculation which we performed of the physicochemical properties and pharmacokinetic parameters influencing the biological activity suggested high intestinal absorption, as well as drug-likeness.Item COMPARATIVE ANALYSIS OF ANTIBACTERIAL ACTIVITY AND PHYSICOCHEMICAL PROPERTIES OF PEPPERMINT AND CORNMINT ESSENTIAL OILS AND THEIR MAIN COMPOUND MENTHOL(2023-01-01) Gandova V.; Fidan H.; Iliev I.; Lasheva V.; Stankov S.; Stoyanova A.; Yavorov N.The aim of the present paper was to study and present a comparative analysis of the antibacterial activity and physicochemical properties of commercial mint essential oils from two different species - peppermint (Mentha piperita Huds. (L.)) and cornmint (Mentha arvensis L.). Peppermint oils exhibited weak antibacterial activity, but were more pronounced against Gram-positive bacteria Staphylococcus aureus (1.3 - 2.0 mm) and Gram-negative bacteria Escherichia coli (1.2 - 1.9 mm) and Klebsiella sp. (2.6 mm). The essential oil of the species M. arvensis did not exhibit antimicrobial activity against the tested cultures. L-menthol, which is a commercial sample isolate, exhibited activity against all tested microorganisms, with the exception of Gram-positive bacteria Listeria monocytogenes and Bacillus cereus. The diameter of the inhibition zones was the largest against Gram-positive bacteria Bacillus subtilis (3.4 mm), and the smallest was against Gram-positive bacteria Staphylococcus aureus (1.6 mm) and Gram-negative bacteria Klebsiella sp. (1.4 mm). The surface tension, density and refractive index of different mint essential oils were determined experimentally. The surface energy and surface heat capacity were calculated based on the calculations of surface tension. All experiments and calculations were provided at a temperature range between 6℃ and 30℃. A dependence between surface tension and temperature was not observed.Item Design, Cytotoxicity and Antiproliferative Activity of 4-Amino-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylates against MFC-7 and MDA-MB-231 Breast Cancer Cell Lines(2022-05-01) Mavrova A.; Dimov S.; Sulikovska I.; Yancheva D.; Iliev I.; Tsoneva I.; Staneva G.; Nikolova B.Novel 4-amino-thieno[2,3-d]pyrimidine-6-carboxylates substituted at the second position were prepared by cyclocondensation of 2-amino-3-cyano-thiophene and aryl nitriles in an acidic medium. The design of the target compounds was based on structural optimization. The derivatives thus obtained were tested in vitro against human and mouse cell lines. The examination of the compound effects on BLAB 3T3 and MFC-10A cells showed that they are safe, making them suitable for subsequent experiments to establish their antitumor activity. The photoirritancy factor of the compounds was calculated. Using the MTT test, the antiproliferative activity to MCF-10A, MCF-7 and MDA-MB-231 cell lines was estimated. The best antiproliferative effect in respect to the MCF-7 cell line revealed compound 2 with IC50 4.3 ± 0.11 µg/mL (0.013 µM). The highest selective index with respect to MCF-7 cells was shown by compound 3 (SI = 19.3), and to MDA-MB-231 cells by compound 2 (SI = 3.7). Based on energy analysis, the most stable conformers were selected and optimized by means of density functional theory (DFT). Ligand efficiency, ligand lipophilicity efficiency and the physicochemical parameters of the target 4-amino-thienopyrimidines were determined. The data obtained indicated that the lead compound among the tested substances is compound 2.Item POLYPHENOLS OF GRAPE POMACE FROM LOCAL BULGARIAN VARIETY MAVRUD. ANTIOXIDANT AND ANTITUMOR EFFECT AGAINST BREAST CANCER(2022-01-01) Radoeva R.; Yankova I.; Enchev B.; Karsheva M.; Ivanova E.; Iliev I.Grape pomace is the main by-product of winemaking, a valuable source of polyphenols with antimicrobial, antioxidant and anti-cancer effect. Grape seeds and marcs extracts are of strategic importance for the development of new therapeutic approaches against certain cancer diseases, including breast cancer. In this study the antioxidant and antitumor potential of the polyphenolic fraction of grape pomace obtained from the vinification of the local Bulgarian grape variety Mavrud is reported. After Soxhlet extraction with 50 % water solution of ethanol, the total polyphenol content of the extracts by the Folin-Ciocalteu colorimetric method was determined. The obtained extracts were characterized by HPLC-DAD and their antioxidant activity was studied with DPPH assay. The cytotoxic effect was tested on 3T3 cell line, while MCF-7 and MDA-MB-231 breast cancer cell lines were selected to determine antitumor activity. The results showed higher total polyphenol content in the marc compared to the seed extracts and prevalence of gallic acid, catechin and epigallocatechin. A correlation between antioxidant activity and total polyphenol content was established. The studied extracts had a low cytotoxic effect, as the seed extracts showed a stronger antitumor activity compared to the extracts of marcs and potential for treatment of luminal breast cancer.Item Synthesis and Biological Studies of New Temporin A Analogs Containing Unnatural Amino Acids in Position 7(2024-06-01) Dimitrova D.; Nemska V.; Foteva T.; Iliev I.; Georgieva N.; Danalev D.(1) Background: Antimicrobial resistance is growing at an extreme pace and has proven to be an urgent topic, for research into alternative treatments. Such a prospective possibility is hidden in antimicrobial peptides because of their low to no toxicity, effectiveness at low concentrations, and most importantly their ability to be used for multiple treatments. This work was focused on the study of the effect of the modification in position 7 of Temporin A on its biological activity; (2) Methods: The targeted peptides were synthesized using Fmoc/Ot-Bu SPPS. The antibacterial activity of the analogs was determined using the broth microdilution method and disk-diffusion method. In vitro tests were performed to determine the cytotoxicity, phototoxicity, and antiproliferative activity of the peptide analogs on a panel of tumor and normal cell lines; (3) Results: All analogs except DTCit showed good antibacterial activity, with DTDab having the best activity according to the disk-diffusion method. However, DTCit had an acceptable cytotoxicity, combined with good selectivity against the test MCF-7 cell line; (4) Conclusions: The obtained results revealed the importance of the basicity and length of the side chain at position 7 in the Temporin A sequence for both tested activities.Item Synthesis and biological studies on (KLAKLAK)2-NH2 analog containing unnatural amino acid β-ala and conjugates with second pharmacophore(2021-12-01) Jaber S.; Nemska V.; Iliev I.; Ivanova E.; Foteva T.; Georgieva N.; Givechev I.; Naydenova E.; Karadjova V.; Danalev D.(1) Background: Peptides are good candidates for anticancer drugs due to their natural existence in the body and lack of secondary effects. (KLAKLAK)2 is an antimicrobial peptide that also shows good anticancer properties. (2) Methods: The Solid Phase Peptide Synthesis (Fmoc-strategy) was used for the synthesis of target molecules, analogs of (KLAKLAK)2-NH2. The purity of all compounds was monitored by HPLC, and their structures were proven using mass spectrometry. Cytotoxicity and antiproliferative effects were studied using 3T3 NRU and MTT tests, respectively. For determination of antimicrobial activity, the disc-diffusion method was used. Hydrolytic stability at three pH values, which mimic the physiological pH in the body, was investigated by means of the HPLC technique. (3) Results: A good selective index against MCF-7 tumor cell lines, combined with good cytotoxicity and antiproliferative properties, was revealed for conjugates NphtG-(KLAKLAK)2-NH2 and Caf-(KLAKLAK)2-NH2. The same compounds showed very good antifungal properties and complete hydrolytic stability for 72 h. The compound Caf-(KLβ-AKLβ-AK)2-NH2 containing β-Ala in its structures exhibited good antimicrobial activity against Escherichia coli K12 407 and Bacillus subtilis 3562, in combination with very good antiproliferative and cytotoxic properties, as well as hydrolytic stability. (4) Conclusions: The obtained results reveal that all synthesized conjugates could be useful for medical practice as anticancer or antimicrobial agents.Item Synthesis and investigation of the properties of hybrid materials for enzyme immobilization(2018-01-01) Yaneva S.; Semerdzhieva V.; Raykova R.; Marinkova D.; Chernev G.; Iliev I.; Yotova L.The chemical nature of carriers for enzyme immobilization plays an important role for retention of the enzyme activity and stability. Two new materials are synthesized for enzyme immobilization based on trimethoxy silane/cellulose acetate butyrate/poly (amido amine) dendrimers (TMOS/CAB/PAMAM) and methyltriethoxy silane/cellulose acetate propionate/ poly (amido amine) dendrimers (MTES/CAP/PAMAM). The synthesis is carried out via the sol-gel method, which allows the preparation of porous glasses through hydrolysis and poly-condensation at a low temperature using high purity initial materials. The PAMAM dendrimers are mono-dispersive, well defined and have a developed three dimensional structure of a high functional groups concentration. The obtained materials are used to investigate the properties of immobilized enzymes such as lipoxygenase and laccase. These enzymes are widely used in industry as bleaching agents. There is also data on application of laccase and lipoxygenase in preparation of biosensors for toxic pollutants determination. Biosensors with immobilized laccase are used to determine phenolic compounds, whereas immobilized lipoxygenase is applied to biosensors formulation for determining Aflatoxin B1 presence.Item Synthesis, antiproliferative and antimicrobial activities of (KLAKLAK)2-NH2 analogue containing nor-Leu and its conjugates with a second pharmacophore(2023-01-01) Jaber S.; Nemska V.; Iliev I.; Ivanova E.; Foteva T.; Georgieva N.; Givechev I.; Tanev D.; Naydenova E.; Danalev D.Peptides are a promising alternative of conventional medical drugs for the treatment of different diseases because they have no or have very few side effects owing to the natural mechanisms for their elimination. There are a lot of examples of drugs on the pharmaceutical market based on modified amino acids and peptides. Herein, we report the synthesis and studies on the antimicrobial peptide (KLAKLAK)2-NH2 where Leu is replaced by the unnatural amino acid nor-Leu. In addition, a second pharmacophore with well proven anticancer properties is introduced to the peptide moiety. All structures were synthesized by conventional solid phase peptide synthesis. The antiproliferative and antimicrobial activities were studied using MTT-dye reduction assay and disk-diffusion test, respectively. Biological activity assays showed that the introduction of nor-Leu in the primary structure of the parent compound does not lead to an increase in the antiproliferative activity. However, the combination with the second pharmacophore 1,8-naphtalimide in a hybrid structure 1,8-NphtG-(KNleAKNleAK)2-NH2 leads to a significant increase in the antiproliferative properties. The antimicrobial tests showed that all tested compounds exhibit antimicrobial activity. The peptide and the second pharmacophore had a synergistic effect. In combination with complete hydrolytic stability for 72 h in model systems, the compound 1,8-NphtG-(KNleAKNleAK)2-NH2 is the best candidate for a medical drug in the treatment of mammary gland type A adenocarcinoma (MCF-7) in combination with antimicrobial properties.Item Synthesis, Antiproliferative Effect and In Silico LogP Prediction of BIM-23052 Analogs Containing Tyr Instead of Phe(2023-04-01) Danalev D.; Iliev I.; Dobrev S.; Angelova S.; Petrin S.; Dzimbova T.; Ivanova E.; Borisova D.; Naydenova E.(1) Background: Hydrophobicity (or lipophilicity) is a limiting factor in the ability of molecules to pass through cell membranes and to perform their function. The ability to efficiently access cytosol is especially important when a synthetic compound has the potential to become a drug substance. D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2 (BIM-23052) is a linear analog of somatostatin with established in vitro GH-inhibitory activity in nanomolar (nm) concentrations and high affinity to different somatostatin receptors. (2) Methods: Series of analogs of BIM-23052 were synthesized where Phe residue(s) in the BIM-23052 molecule were replaced with Tyr using standard SPPS, Fmoc/t-Bu strategy. Analyses of target compounds were performed using HPLC/MS technique. Toxicity and antiproliferative activity were studied using in vitro NRU and MTT assays. The values of logP (partition coefficient in octanol/water) for BIM-23052 and its analogs were calculated. (3) Results: The obtained data show the best antiproliferative effect against studied cancer cells for compound D-Phe-Phe-Phe-D-Trp-Lys-Thr-Tyr7-Thr-NH2 (DD8), the most lipophilic compound according to the predicted logP values. (4) Conclusions: Multiple analyses of the obtained data reveal that compound D-Phe-Phe-Phe-D-Trp-Lys-Thr-Tyr7-Thr-NH2 (DD8) where one Phe is replaced by Tyr has the best combination of cytotoxicity, antiproliferative effect and hydrolytic stability.Item Synthesis, antitumor and antibacterial studies of new shortened analogues of (KLAKLAK)2-NH2 and their conjugates containing unnatural amino acids(2021-02-02) Jaber S.; Iliev I.; Angelova T.; Nemska V.; Sulikovska I.; Naydenova E.; Georgieva N.; Givechev I.; Grabchev I.; Danalev D.(1) Background: (KLAKLAK)2 is a representative of the antimicrobial peptide group which also shows good anticancer properties. (2) Methods: Herein, we report synthesis using SPPS and characterization by HPLC/MS of a series of shortened analogues of (KLAKLAK)2. They contain single sequence KLAKLAK as C-terminal amides. In addition, substitution of some natural amino acids with unnatural β-Ala and nor-Leu is realized. In addition, these structures are conjugated with second pharmacophore with well proven anticancer properties 1,8-naphthalimide or caffeic acid. Cytotoxicity, antiproliferative effect and antimicrobial activity of newly synthesized structures were studied. (3) Results: The obtained experimental results reveal significant selective index for substances with common chemical structure KLβAKLβAK-NH2. The antibacterial properties of newly synthesized analogues at two different concentrations 10 μM and 20 μM, were tested against Gram-negative microorganisms Escherichia coli K12 407. Only two of the studied compounds KLAKLAK-NH2 and the one conjugated with second pharmacophore 1,8-naphthalimide and unnatural amino acid nor-Leu showed moderate activity against tested strains at concentration of 20 μM. (4) Conclusions: The obtained results reveal that the introducing of 1,8-naphthalimideGlyand Caf- increase the cytotoxicity and antiproliferative activity of the peptides but not their selectivity. Only two compounds KLAKLAK-NH2 and 1,8-naphthalimideGKnLAKnLAK-NH2 show moderate activity against Escherichia coli K12 at low concentration of 20 μM.