Alex Zlatkov

Medical University of Sofia · Department of Pharmaceutical Chemistry

A series of ten new hydrazide–hydrazone derivatives bearing a pyrrole ring were synthesized and structurally elucidated through appropriate spectral characteristics. The target hydrazones were assessed for radical scavenging activity through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) test...

Molecular docking is an essential structure-based technique that is frequently used for virtual screenings. In most cases, the precision of search algorithms of the modern docking programs is satisfactory. However, the scoring algorithms' accuracy is not sufficient to completely distinguish true positives from inactive solutions. Therefore, initial...

With the significant growth of patients suffering from neurodegenerative diseases (NDs), novel classes of compounds targeting monoamine oxidase type B (MAO-B) are promptly emerging as distinguished structures for the treatment of the latter. As a promising function of computer-aided drug design (CADD), structure-based virtual screening (SBVS) is be...

An in silico consensus molecular docking approach and in vitro evaluations were adopted in the present study to explore a dataset of FDA-approved drugs as novel multitarget MAO-B/AChE agents in the treatment of Alzheimer’s disease (AD). GOLD 5.3 and Glide were employed in the virtual assessments and consensus superimpositions of the obtained poses...

In this study, one novel N-pyrrolyl carboxylic acid (3), the corresponding N-pyrrolyl hydrazide (5), and four new hydrazide-hydrazones (5a-d) bearing electron donating moieties were designed, synthesized, and fully elucidated by 1H NMR, FT-IR, and HRMS. The hydrazide-hydrazones were produced in five steps, which were optimized by applying microwave...

In December 2019, the World Health Organization was informed of an outbreak of pneumonia of unknown etiology in Wuhan, Hubei Province, China. On January 7, 2020, a new type of coronavirus was isolated, with the WHO later officially calling it “COVID-19” and the International Committee on Taxonomy of Viruses naming the virus “SARS-CoV-2”. On January...

The current study is focused on investigation and quantitation of seven commercially available on the Bulgarian market food supplements, containing multivitamin mixtures of water-soluble and fat-soluble vitamins. In addition, a second fermentation brewer’s yeast is also analyzed. The analytical procedures are performed on a RP-HPLC/DAD using Purosp...

Background In the current Alzheimer’s disease therapy as the preferred treatment are applied acetylcholinesterase inhibitors. Aiming to identify the active pharmacophores necessary for increased acetylcholinesterase inhibitory activity, some docking studies have been applied. Methods In silico docking evaluation of the binding modes, identificatio...

The neurotoxic, neuroprotective and MAO-B inhibitory effects of series N′-substituted 3-(1,3,7-trimethyl-xanthin-8-ylthio)propanehydrazides are evaluated. The results indicate compounds N′-(2,3-dimethoxybenzylidene)-3-(1,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylthio)propanehydrazide (6k) and N′-(2-hydroxybenzylidene)-3-(1,3,7-trimeth...

Background A new strain of a novel disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been recently declared a pandemic by the World Health Organization (WHO). The virus is resulting in significant mortality and morbidity across the planet therefore novel treatments are urgently required. Recently deposited crystallo...

This study is focused on determination of the most appropriate synthetic approach for obtaining series of theophylline-7-acetyl semi- and thiosemicarbazide hybrids by using the molecular hybridization strategy with and without a catalyst. The target derivatives were further investigated for their in vitro neurotoxic and neuroprotective effects on c...

Background The significant increase of patients suffering from different types of cancer, guides scientists to take prompt measures in the development of novel and effective antiproliferative agents, where the intercalation of heterocyclic fragment in the designed molecules has proven to be a useful practice. Objective The newly synthesized compou...

Background Tuberculosis is considered as a global health problem, hence the screening and synthesis of novel tuberculostatic drugs is a necessity. Molecular docking could drastically reduce the time of hit identification, however initial validation is required to reduce the false-positive results. Objective Assessment of several searching and scor...

Alzheimer's disease (AD) is the most widespread neurodegenerative disorder with a significant impact on health systems. Considering the lack of efficient treatment, compounds with multi-target activities are usually designed as promising options to fill the evident gap. In this study, two novel N-pyrrolyl carboxylic acids (4a and 5a) and eight corr...

New series of 3-(1,3,7-trimethyl-xanthin-8-ylthio)propanehydrazide derivatives were designed and synthesized. The targed compounds were obtained in yields of 54 to 100% and their structures were elucidated by FTIR, ¹ H NMR, ¹³ C NMR, MS and microanalyses. The tested compounds were subjected to in silico prediction of sites of metabolism (SOMs). The...

Molecular docking is one of the most utilized in silico techniques, which drastically reduces the cost and the time needed for the design of novel drugs. Recently, the tremendous growth of resolved crystallographic MAO-B structures, together with the rapidly rising computing power, has resulted in accelerated and moderately correct docking studies....

With the significant increase of patients suffering from different types of cancer, it is evident that prompt measures in the development of novel and effective agents need to be taken. Pyrrole moiety has been found in various active compounds with anti-inflammatory, antiseptic, antibacterial, lipid-lowering and anticancer properties. Recent advanc...

Molecular docking is emerging as a frequently applied structure-based virtual technique in the drug design processes. The method could significantly reduce the time required for the development of novel and effective molecules compared to high-throughput screening. However, a major drawback of the docking simulations is the high number of false-pos...

Virtual screening is emerging as a highly applied technique for the search of hits since it significantly reduces the time required for the establishment of novel, effective compounds compared to high-throughput screening. Implementing correlation coefficients to determine if a molecular docking study is robust and reliable has been established as...

Objective: The recent growth of highly resoluted crystallographic structures, together with the continuous improvements of the computing power, has established molecular docking as a leading drug design technique. However, the problems concerning the receptor flexibility and the lowered ability of docking software to correctly score the occurred in...

Molecular docking is one of the most utilized in silico techniques, which drastically reduces the cost and the time needed for the design of novel drugs. Recently, the tremendous growth of resolved crystallographic MAO-B structures, together with the rapidly rising computing power, has resulted in accelerated and moderately correct docking studies....

Recently, the application of molecular docking is drastically increasing due to the rapid growth of resolved crystallographic receptors with co-crystallized ligands. However, the inability of docking softwares to correctly score the occurred interactions between ligands and receptors is still a relevant issue. This study examined the Pearson’s corr...

The broad pharmacological effects of 5-membered nitrogen containing heterocycles require rapid and environmental friendly methods for their synthesis. Microwave irradiation has been heavily applied in the field of organic synthesis since its introduction. The beneficial reduction of reaction time from hours or even days to minutes is one of many ad...

The effects of new derivatives of caffeine-8-thioglycolic acid (100 µM) on isolated rat brain synaptosomes, human neuroblastoma cell line SH-SY5Y and human recombinant MAOB enzyme (hMAOB) (1 µM) were evaluated. Most of the compounds, administered alone, didn’t show statistically significant neurotoxic effects on SH-SY5Y, when compared to the contro...

In this work series new theobromine derivatives containing an arylpiperazine moiety at N 1 with established antioxidant and antiproliferative activities were evaluated for their hepatotoxic effects on cellular and sub-cellular level. On isolated rat hepatocytes, 3c and 4c expressed lowest toxicity, while 3f and 4f showed highest toxicity. The same...

New series of caffeine-8-(2-thio)-propanoic hydrazid-hydrazone derivatives were designed and synthesized. The targed compounds were obtained in yields of 51 to 96% and their structures were elucidated by FTIR, ¹ H NMR, ¹³ C NMR, MS and microanalyses. All of the compounds were found to be “drug-like” as they fulfill the criteria of drug-likeness, wh...

Objective: The syntheses and biological activities of 8-thiosubstituted-1,3,7- trimethylxanthine derivatives bearing an aromatic hydrazide-hydrazone fragment in the side chain at C8 are described. Methods: The chemical structures of the synthesized compounds 6a-m were confirmed based on their MS, FTIR, 1H NMR and 13C NMR analyses. Results: The...

A reversed phase enantio selective high performance liquid chromatographic method was developed for enantiomeric separation of 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purine-7(6H)-yl)-N'-(3-fluorobenzylidene)-propanehydrazide isomers. The enantiomers of 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purine-7(6H)-yl)-N'-(3-fluorobenzylidene)propanehydra-...

This studyinvestigates the effects of newly synthetized derivatives of caffeine-8 thioglycolic acid on isolated rat liver microsomes. The microsomeswere received by multiple centrifugation. The production of malondialdehyde (MDA) was exam as a marker of lipid peroxidation. The effects were compared to those of caffeine. From all exam compounds, onl...

Background: Cancer is one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases in 2012, with most of the clinically used drugs being ineffective. Methylxanthines have raised more interest in research on modifying their structure because of their diverse biological activity. In addition, the piperazine...

Acetylcholinesterase (AChE) is a good target in the design of new drugs for the treatment of Alzheimer’s disease. The currently known drugs -donepezil, galantamine and rivastignime- act as moderate AChE inhibitors. In the present study, we docked a newly synthesized arylpiperazine derivative 1-(3-(4-benzylpiperazin-1-yl)propyl)-3,7-dimethyl-1H-puri...

Aiming to obtain preliminary information on the toxicity, stability and pharmacokinetic behavior of a group of 12 methylxanthines, containing an arylpiperazine moiety at N1, we applied three virtual methods for prediction. The online hazard-screening tool-PBT profiler was used for toxicity evaluation. The pharmacokinetic behavior and drug like prop...

The synthesis of new oxazole derivatives was carried out under Davidson synthesis conditions from O-acylacyloins with an 8-thiosubstituted 1,3,7-trimethylxanthine skeleton and ammonium acetate in a 1:10 ratio in glacial acetic acid media. The starting O-acylacyloins were obtained as products from the interaction of the sodium salt of 2-(1,3,7-trime...

Parkinson's disease (PD) is a neurodegenerative and debilitating disease that affects 1% of elderly population. Patient's motor disability results in an extreme difficulty to deal with daily activities. Conventional treatment is limited to dopamine replacement therapy, which fails to delay disease's progression and is often associated with a number...

The study investigates the stability of novel aroylhydrazones containing susceptible to hydrolysis hydrazone group at conditions close to physiological. Two methoxy-derived hydrazones (3-methoxysalicylaldehyde benzoylhydrazone – 3M and 4-methoxysalicylaldehyde benzoylhydrazone – 4M) were dissolved in different buffer solutions (pH 2.0, 7.4 and 9.0)...

This study evaluates a series of caffeine-8-thioglycolic acid amides that were synthesized in the study, for signs of possible degradation. The chemical stability of the test compounds was examined under different conditions of pH and temperature over time. A modified reversed phase-high-performance liquid chromatography method was applied to deter...

The synthesis of methylxanthine derivatives could provide a sound approach to developing new analogues with similar or novel pharmacological profiles. The synthesis of six new compounds: two derivatives of 8-substituted-1,3,7-trimethylxanthine and four derivatives of 1-propyl-3,7-dimethylxanthine containing a cyclohexyl fragment, are presented. The...

The effects of new derivatives of caffeine-8-thioglycolic acid with proven antihypoxic activity were investigated in this study. The compounds were eval- uated for possible cytotoxic effects on isolated rat hepatocytes, isolated by two-stepped, collagenase perfusion. As biomarkers of cytotoxicity we measured cell viability by trypan blue exclusion,...

This paper proposes a simple and selective UHPLC method for determination of degradation products of a model pyrrole based compound, containing susceptible to hydrolysis ester group. The chromatographic separation was achieved on BDSHYPERSILC18 (150 mm × 4.6 mm, 3.5 μm) column thermostated at 30°C under gradient elution by a binary mixture of potas...

A new series of N-substituted 1-benzyltheobromine-8-thioacetamides were designed and synthesized. Their anti-proliferative activity against human chronic myelocytic leukemia cell K562, human T-cell leukemia cell SKW-3 and human acute myeloid leukemia HL-60 was evaluated. For the tested compounds a concentration-dependent cytotoxic activity was obse...

Resveratrol, an antioxidant found in red wine and certain foods, has been touted as a natural way to slow aging and fight cancer, obesity, heart disease, and diabetes. It also could be accounted as an agent, which has effects to reduced risk of inflammation and blood clotting. In addition there are some studies showing that resveratrol may actually...

Oxygen is one of the most important and indispensable elements, since life molecules on Earth can, under certain situations, produce from it constantly in the human body toxic molecules, called free radicals and/or other reactive oxygen species (ROS). ROS play a dual role in biological systems, since they can be either harmful or beneficial to livi...

Abstract. A fast, simple and fully automated RP-HPLC analytical method with UV detection for determination of indomethacin substance and its degradation product 4-chlorobenzoic acid was modified and validated. The analysis was performed at isocratic conditions, applying a mobile phase of acetonitrile and 0.5% ortophosphoric acid (50:50, v/v) at flo...

Four new 7,8-disubstituted theophylline derivartives were synthesized. Their purity was elucidated with melting points and TLC characteristics. The structure of the obtained compounds was proven by IR, 1H NMR and 13C NMR spectral data. The cytotoxicity, the in vitro effects on sub-cellular and cellular level and the antiproliferative activity of th...

Unlike antibiotics which mean “to destroy life,” probiotics literally means “life giving”. Probiotics are friendly bacteria. When consumed, probiotics confer beneficial effects to the host. It influences the homeostasis and controls various gastrointestinal disorders. Probiotic ingestion can be a preventive approach for maintaining the balance of t...

A series of monoterpenic ester derivatives of theophylline 7-acetic acid with a chosen monoter-pene alcohol were synthesized, according to two synthetic pathways. The structure of the new products was elucidated with TLC characteristics, IR and 1 H-NMR spectra. By evaluation of some electro-optical param-eters of the studied compounds was establish...

Piperazine nucleus is one of the most important heterocyclic systems exhibiting remarkable pharmacological activities. Thus, in the current study six new aryl/aralkyl substituted piperazine derivatives, containing methylxanthine moiety were synthesized and their structures were confirmed by IR and (1)H NMR analysis. All compounds were in vitro scre...

Using the web-based tool PharmMapper, based on the reverse pharmacophore approach, we aligned 7 newly synthesized pipreazine amide derivatives to 2241 human protein targets, from which the top 300 targets were analyzed. By the flexible alignment of these structures the calculated and recorded pharmacophores were obtained and the candidate targets w...

The synthesis of methylxanthine derivatives could be a good approach to develop new analogues with similar or novel pharmacological profiles including antiproliferative activity. The synthesis of four derivatives of 1,3,7-trimethylxanthine with substituents containing allantoin and saccharine in the side chain on 8th position in the xanthine ring w...

Correlations between experimental chemical shifts and GIAO-calculated isotropic shielding constants of hydrogen and carbon atoms were obtained for a series of imidazole derivatives with antiproloferative activity, in order to assess the performance of NMR spectral calculations, using both HF and DFT-B3LYP level of theory with different basis sets....

Five-stage synthetic scheme for obtaining of N-substituted 1-benzyltheobromine-8-thioglicolacetamides was described. The intermediate compound 1-benzyl-8-bromotheobromine was synthesized using aliquat 336 as phase transfer catalyst in very good yield. Five amide derivatives of 1-benzyltheobromine-8-thioglicolyc acid were obtained in yields of 61 to...

Novel computational strategies are continuously being demanded by the pharmaceutical industry to assist, improve and speed up the drug discovery process. In this scenario chemoinformatics provide reliable mathematical tools to derive quantitative structure–activity relationships (QSARs), able to describe the correlation between molecular descriptor...

Nine biologically active theophylline derivatives were investigated using quantum chemical methods (density functional theory level). All calculations were performed at B3LYP/6-31G** level of theory. The electrostatic potential charges, highest occupied molecular orbital (HOMO)/lowest unoccupied molecular orbital (LUMO) gap, dipole moment, vibratio...

Disorders of the central nervous system currently affect over 1.5 billion people worldwide and account for about a third of the global disease burden. The prevalence in recent years and the variety of mood disorders stimulate the development of new agents for their treatment. 1-Arylpiperazines are well known 5-HT receptor ligands with 5-HT1A and/or...

Analytical tests for identification, purity and assay of active molecule citalopram – racemic mixture and enantiomer in substance as well as in drug preparations were developed. The methods were optimized on the base of validation procedures in accordance with European Pharmacopoeia, EMA and ICH. Tests are HPLC with using of chiral chromatography c...

A direct molecular structure implementation of the gauge-including atomic orbital (GIAO) method for calculation of nuclear magnetic shielding tensors at density functional (B3LYP) level of theory with 6-31G(d,p) and 6-311+G(2d,p) basis sets is presented. The influence of the choice of the basis set on the 1H chemical shift for six 8-substituted 1,3...

Modified and optimized methods for synthesis of 8-bromocaffeine, caffeine-8-thioglycolic acid and its ester derivatives were developed. The modification of 8-bromocaffeine synthesis included a change in the brominating agent, which resulted in cost reduction. Some investigations were performed on the influence of the catalyst type and concentration...

In this study, high performance liquid chromatographic method have been developed and validated for the simultaneous determination of Paracetamol and Ibuprofen in combined pharmaceutical formulations. The chromatography was carried out on a C18 (250 mm x 4.6 mm, 10 μm) column with methanol and 0.05 M sodium dihydrogen phosphate (65:35 v/v) as mobil...

A validated method for the determination of validol in tablet dosage forms using gas chromatography with flame-ionization detection and n-octanol as the internal standard is developed. Validol represents a 25-30% solution of menthol in the menthyl ester of isovaleric acid. The separation of both compounds was achieved on a HP-FFAP (nitroterephthali...

This paper describes development and validation of a high-performance liquid chromatographic analytical procedure for simultaneously determination of paracetamol and caffeine in a tablet formulation. The separation was achieved on a C18 column at a flow rate of 1.5 ml/min with UV detection at 220 nm. The mobile phase was composed of 1mM phosphate b...

A reversed-phase high performance liquid chromatographic (RP-HPLC) method with UV detection was proposed for separation of indomethacin and its impurities from tablet dosage forms. The best separation was achieved on a LiChrosorb C18, 250 mm x 4.6 mm, 5 μm column at a detector wavelength of 240 nm. The utilization of mixture of 40 volumes 0.5 % v/v...