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Considering the escalating global prevalence and the huge therapeutic demand for the treatment of hypertension, there is a persistent need to identify novel target sites for vasodilator action. This study aimed to investigate the role of TRPA1 channels in carvacrol-induced vasodilation and to design novel compounds based on carvacrol structure with improved activities. In an isolated tissue bath experiment, it was shown that 1 µM of the selective TRPA1 antagonist A967079 significantly (p < 0.001) reduced vasodilation induced by 3 mM of carvacrol. A reliable 3D-QSAR model with good statistical parameters was created (R2 = 0.83; Q2 = 0.59 and R 2 pred = 0.84) using 29 TRPA1 agonists. Obtained results from this model were used for the design of novel TRPA1 activators, and to predict their activity against TRPA1. Predicted pEC50 activities of these molecules range between 4.996 to 5.235 compared to experimental pEC50 of 4.77 for carvacrol. Molecular docking studies showed that designed molecules interact with similar amino acid residues of the TRPA1 channel as carvacrol, with eight compounds showing lower binding energies. In conclusion, carvacrol-induced vasodilation is partly mediated by the activation of TRPA1 channels. Combining different in silico approaches pointed out that the molecule D27 (2-[2-(hydroxymethyl)-4-methylphenyl]acetamide) is the best candidate for further synthesis and experimental evaluation in in vitro conditions.

Fourteen novel N-benzylpiperidine and N,N-diarylpiperazine conjugates were synthesized and pharmacologically evaluated as donepezil analogs, in a ligand-based drug design approach. All compounds possessed high to moderate in vitro inhibitory activity with IC50 in range 2.3–20 µM and selectivity towards acetylcholinesterase, while being inactive towards butyrylcholinesterase. Structure-activity relationship analysis revealed the influence of N,N-diarylpiperazine moiety and the linker connecting two pharmacophores on the inhibitory activity. Kinetic studies on the two most active compounds 7g and 8g (IC50 = 2.3 and 4 µM, respectively) revealed mixed type mode of inhibition, binding to both, free enzyme and enzyme-substrate complex. For further understanding of mechanism of action and binding orientations, molecular docking was performed for all compounds, while the ligand transport simulation and molecular dynamics simulations were performed for 7g and 8g. Computational results corroborated well with in vitro activities and kinetic studies.

Adrenergic receptors are among the most studied G protein-coupled receptors. Activation or blockade of these receptors is a major therapeutic approach for the treatment of numerous disorders such as cardiac hypertrophy, congestive heart failure, hypertension, angina pectoris, cardiac arrhythmias, depression, benign prostate hyperplasia, anaphylaxis, asthma, and hyperthyroidism. Among all nine cloned adrenoceptor subtypes and the subsequent development of animal models, a significant target for various neurological conditions treatment is alpha1-adrenergic receptors. 2-{[4-(2-Methoxyphenyl)piperazin-1-yl]alkyl}-1H-benzo[d]imidazoles, their 5 substituted derivatives, and structurally similar, arylpiperazine based alpha1-adrenergic receptors antagonists (trazodone, naftopidil, and urapidil) have been subjects of comparative analysis. Most of the novel compounds showed alpha1-adrenergic affinity in the range from 22 nM to 250 nM. The in silico docking and molecular dynamics simulations, binding data together with absorption, distribution, metabolism, and excretion (ADME) calculations identified the promising lead compounds. The results brought out the conclusions which allowed us to propose a rationale for the activity of these molecules and to highlight six compounds (2-5, 8, and 12) that exhibited an acceptable pharmacokinetic profile to the advanced investigation as the potential alpha1-adrenergic receptor antagonists.

Adrenergic receptors are among the most studied G protein-coupled receptors. Activation or blockade of these receptors is a major therapeutic approach for the treatment of numerous disorders such as cardiac hypertrophy, congestive heart failure, hypertension, angina pectoris, cardiac arrhythmias, depression, benign prostate hyperplasia, anaphylaxis, asthma, and hyperthyroidism. Among all nine cloned adrenoceptor subtypes and the subsequent development of animal models, a significant target for various neurological conditions treatment is alpha1-adrenergic receptors. 2-{[4-(2-Methoxyphenyl)piperazin-1-yl] alkyl}-1H-benzo[d]imidazoles, their 5 substituted derivatives, and structurally similar, arylpiperazine based alpha1-adrenergic receptors antagonists (trazodone, naftopidil, and urapidil) have been subjects of comparative analysis. Most of the novel compounds showed alpha1-adrenergic affinity in the range from 22 nM to 250 nM. The in silico docking and molecular dynamics simulations, binding data together with absorption, distribution, metabolism, and excretion (ADME) calculations identified the promising lead compounds. The results brought out the conclusions which allowed us to propose a rationale for the activity of these molecules and to highlight six compounds (2–5, 8, and 12) that exhibited an acceptable pharmacokinetic profile to the advanced investigation as the potential alpha1-adrenergic receptor antagonists.

Adrenergic receptors are among the most studied G protein-coupled receptors. Activation or blockade of these receptors is a major therapeutic approach for the treatment of numerous disorders such as cardiac hypertrophy, congestive heart failure, hypertension, angina pectoris, cardiac arrhythmias, depression, benign prostate hyperplasia, anaphylaxis, asthma, and hyperthyroidism. Among all nine cloned adrenoceptor subtypes and the subsequent development of animal models, a significant target for various neurological conditions treatment is alpha1-adrenergic receptors. 2-{[4-(2-Methoxyphenyl)piperazin-1-yl]alkyl}-1H-benzo[d]imidazoles, their 5 substituted derivatives, and structurally similar, arylpiperazine based alpha1-adrenergic receptors antagonists (trazodone, naftopidil, and urapidil) have been subjects of comparative analysis. Most of the novel compounds showed alpha1-adrenergic affinity in the range from 22 nM to 250 nM. The in silico docking and molecular dynamics simulations, binding data together with absorption, distribution, metabolism, and excretion (ADME) calculations identified the promising lead compounds. The results brought out the conclusions which allowed us to propose a rationale for the activity of these molecules and to highlight six compounds (2-5, 8, and 12) that exhibited an acceptable pharmacokinetic profile to the advanced investigation as the potential alpha1-adrenergic receptor antagonists.

Adrenergic receptors are among the most studied G protein-coupled receptors. Activation or blockade of these receptors is a major therapeutic approach for the treatment of numerous disorders such as cardiac hypertrophy, congestive heart failure, hypertension, angina pectoris, cardiac arrhythmias, depression, benign prostate hyperplasia, anaphylaxis, asthma, and hyperthyroidism. Among all nine cloned adrenoceptor subtypes and the subsequent development of animal models, a significant target for various neurological conditions treatment is alpha1-adrenergic receptors. 2-{[4-(2-Methoxyphenyl)piperazin-1-yl]alkyl}-1H-benzo[d]imidazoles, their 5 substituted derivatives, and structurally similar, arylpiperazine based alpha1-adrenergic receptors antagonists (trazodone, naftopidil, and urapidil) have been subjects of comparative analysis. Most of the novel compounds showed alpha1-adrenergic affinity in the range from 22 nM to 250 nM. The in silico docking and molecular dynamics simulations, binding data together with absorption, distribution, metabolism, and excretion (ADME) calculations identified the promising lead compounds. The results brought out the conclusions which allowed us to propose a rationale for the activity of these molecules and to highlight six compounds (2-5, 8, and 12) that exhibited an acceptable pharmacokinetic profile to the advanced investigation as the potential alpha1-adrenergic receptor antagonists.

У оквиру ове докторске дисертације извршена је хемијска и фармаколошка карактеризација етарских уља изолованих из две врсте рода Seseli: Seseli pallasii и Seseli gracile.У испитивању су коришћени биљни материјали S. pallasii (корен, ризом, херба и плод) и S. gracile (корен, херба, цваст и плод) прикупљени током шестогодишњег периода са природног станишта као и гајени (само S. gracile). Етарска уља су изолована дестилацијом воденом паром, након чега су хемијски анализирана методом гасне хроматографије уз масени (GC-MS) и пламено-јонизујући детектор (GC-FID). Резултати хемијске анализе су показали да у узорцима надземних органа обе испитиване врсте доминирају монотрепенска једињења, са најзаступљенијим компонентама α-пиненом (S. pallasii) и терпиноленом (S. gracile). У подземним органима обе врсте доминирају не-терпенска једињења: n-нонан и n-ундекан (S. pallasii), односно фалкаринол (S. gracile). Хемијске варијације у саставу етарских уља изолованих из различитих биљних делова су анализиране мултиваријантним статистичким методама (PCA и HCA). У оквиру фармаколошке карактеризације спроведена су in vitro испитивања антирадикалске (DPPH метода), антимикробне (микродилуциона метода), спазмолитичке (метода на изолованом илеуму пацова), вазорелаксантне (метода на изолованој мезентеричној артерији пацова), и ACE инхибиторне активности (колориметријска метода). Испитивању in vitro ACE инхибиторне активности, претходило је in silico испитивање, где је разматран и потенцијални утицај појединачних компоненти на инхибицију ACE.Тестирана етарска уља су показала добар спазмолитички и вазорелаксантни (S. pallasii) умерен антимикробни (S. pallasii) и антирадикалски ( S. gracile), а слаб ACE инхибиторни потенцијал., Chemical and pharmacological characterisation of essential oils isolated from two Seseli species: Seseli gracile and Seseli pallasii were explored in this doctoral dissertation.Samples of S. pallasii (root, rhizome, herb and fruit) and S. gracile (root, herb, inflorescence and fruit) collected from a natural habitat over a six-year period and cultivated plants (just for S. gracile) were used in this research. Essential oils were isolated from the plant material by hydro-distillation method, and were thereafter chemically analysed by gas chromatography method with mass (GC-MS) and flame-ionizing detector (GC-FID). The results of the chemical analysis suggest that essential oils isolated from aerial parts of both investigated species are dominated by monoterpenes with α-pinene (S. pallasii) and terpinolene (S. gracile) as the most abundant compounds. In essential oils from underground plant organs, non-terpenic compounds are predominantly present in both species: n-nonane and n-undecane (S. pallasii) and falcarinol (S. gracile). Chemical composition variations of essential oils isolated from different plant parts were statistically analyzed using multivariate statistical methods (PCA and HCA). Within the pharmacological characterization, in vitro studies of antiradical (DPPH test), antimicrobial (microdilution test), spasmolytic (isolated rat ileum method), vasorelaxant (isolated mesenteric artery method) and ACE inhibitor (colorimetric test) activities were conducted. In vitro test of ACE inhibitor activity was preceded by in silico test, where the individual compounds potential for ACE inhibition was analyzed.Tested essential oils exhibited good spasmolytic and vasorelaxant activity (S. pallasii), moderate antimicrobial (S. pallasii) and anti-DPPH (S. gracile) activity and low ACE inhibition potential.

5HT1A receptor targeting drugs have been used as the treatment for the many neuropsychiatric disorders, such as schizophrenia and depression. As a part of ongoing research, we designed series of new compounds that share arylpiperazine common structural motif with the 5HT1A receptor ligand aripiprazole. Receptor-ligand interactions were determined by the molecular docking simulations, revealing the positive impact of the phenyl substitution in the arylpiperazine part of the molecules. Nine selected compounds were synthesized in four reaction steps in high overall yields (59-73%). In vitro pharmacological evaluation of the synthesized compounds revealed three compounds (5b, 6b and 6c) with high 5HT1A binding affinity, comparable with aripiprazole (Ki 12.0, 4.8, 12.8, 5.6 nM, respectively). Compounds from b series, 5b and 6b, possess 2-methoxyphenyl substituents, while 6c possess 2,3-dichlorophenyl substituent in the arylpiperazine part of the molecule. The pharmacological results are therefore in accordance with the molecular docking simulations thus proving the rational design. Compounds 5c, 6b and 6c can be considered as the candidates for further evaluation as new, potential antidepressants.

5HT1A receptor targeting drugs have been used as the treatment for the many neuropsychiatric disorders, such as schizophrenia and depression. As a part of ongoing research, we designed series of new compounds that share arylpiperazine common structural motif with the 5HT1A receptor ligand aripiprazole. Receptor-ligand interactions were determined by the molecular docking simulations, revealing the positive impact of the phenyl substitution in the arylpiperazine part of the molecules. Nine selected compounds were synthesized in four reaction steps in high overall yields (59-73%). In vitro pharmacological evaluation of the synthesized compounds revealed three compounds (5b, 6b and 6c) with high 5HT1A binding affinity, comparable with aripiprazole (Ki 12.0, 4.8, 12.8, 5.6 nM, respectively). Compounds from b series, 5b and 6b, possess 2-methoxyphenyl substituents, while 6c possess 2,3-dichlorophenyl substituent in the arylpiperazine part of the molecule. The pharmacological results are therefore in accordance with the molecular docking simulations thus proving the rational design. Compounds 5c, 6b and 6c can be considered as the candidates for further evaluation as new, potential antidepressants.

The present paper describes environmental and seasonal-related chemical composition variations, vasorelaxant and angiotensin I-converting enzyme (ACE) activities of essential oil from aerial parts of Seseli pallasii BESSER. The composition was analyzed by GC and GC/MS. Monoterpenes were found to be the most abundant chemical class with alpha-pinene (42.7 - 48.2%) as the most prevalent component. Seseli pallasi essential oil relaxed isolated endothelium-intact mesenteric arteries rings precontracted with phenylephrine with IC50 = 3.10 nl/ml (IC50 = 2.70 mu g/ml). Also, S. pallasii essential oil was found to exhibit a dose-dependent ACE inhibitory activity with an IC50 value of 0.33 mg/ml. In silico evaluation of ACE inhibitory activity of the individual components showed that spathulenol exhibited the best binding affinity with ACE, and the lowest binding energy of -7.5 kcal/mol. The results suggested that combination of vasorelaxing and ACE inhibitory effects of the analyzed S. pallasii essential oil might have the potential therapeutic significance in hypertension.

У оквиру ове докторске дисертације извршена је хемијска и фармаколошка карактеризација етарских уља изолованих из две врсте рода Seseli: Seseli pallasii и Seseli gracile. У испитивању су коришћени биљни материјали S. pallasii (корен, ризом, херба и плод) и S. gracile (корен, херба, цваст и плод) прикупљени током шестогодишњег периода са природног станишта као и гајени (само S. gracile). Етарска уља су изолована дестилацијом воденом паром, након чега су хемијски анализирана методом гасне хроматографије уз масени (GC-MS) и пламено-јонизујући детектор (GC-FID). Резултати хемијске анализе су показали да у узорцима надземних органа обе испитиване врсте доминирају монотрепенска једињења, са најзаступљенијим компонентама α-пиненом (S. pallasii) и терпиноленом (S. gracile). У подземним органима обе врсте доминирају не-терпенска једињења: n-нонан и n-ундекан (S. pallasii), односно фалкаринол (S. gracile). Хемијске варијације у саставу етарских уља изолованих из различитих биљних делова су анализиране мултиваријантним статистичким методама (PCA и HCA). У оквиру фармаколошке карактеризације спроведена су in vitro испитивања антирадикалске (DPPH метода), антимикробне (микродилуциона метода), спазмолитичке (метода на изолованом илеуму пацова), вазорелаксантне (метода на изолованој мезентеричној артерији пацова), и ACE инхибиторне активности (колориметријска метода). Испитивању in vitro ACE инхибиторне активности, претходило је in silico испитивање, где је разматран и потенцијални утицај појединачних компоненти на инхибицију ACE. Тестирана етарска уља су показала добар спазмолитички и вазорелаксантни (S. pallasii) умерен антимикробни (S. pallasii) и антирадикалски ( S. gracile), а слаб ACE инхибиторни потенцијал., Chemical and pharmacological characterisation of essential oils isolated from two Seseli species: Seseli gracile and Seseli pallasii were explored in this doctoral dissertation. Samples of S. pallasii (root, rhizome, herb and fruit) and S. gracile (root, herb, inflorescence and fruit) collected from a natural habitat over a six-year period and cultivated plants (just for S. gracile) were used in this research. Essential oils were isolated from the plant material by hydro-distillation method, and were thereafter chemically analysed by gas chromatography method with mass (GC-MS) and flame-ionizing detector (GC-FID). The results of the chemical analysis suggest that essential oils isolated from aerial parts of both investigated species are dominated by monoterpenes with α-pinene (S. pallasii) and terpinolene (S. gracile) as the most abundant compounds. In essential oils from underground plant organs, non-terpenic compounds are predominantly present in both species: n-nonane and n-undecane (S. pallasii) and falcarinol (S. gracile). Chemical composition variations of essential oils isolated from different plant parts were statistically analyzed using multivariate statistical methods (PCA and HCA). Within the pharmacological characterization, in vitro studies of antiradical (DPPH test), antimicrobial (microdilution test), spasmolytic (isolated rat ileum method), vasorelaxant (isolated mesenteric artery method) and ACE inhibitor (colorimetric test) activities were conducted. In vitro test of ACE inhibitor activity was preceded by in silico test, where the individual compounds potential for ACE inhibition was analyzed. Tested essential oils exhibited good spasmolytic and vasorelaxant activity (S. pallasii), moderate antimicrobial (S. pallasii) and anti-DPPH (S. gracile) activity and low ACE inhibition potential.

The chemical composition of the essential oils of Seseli gracile Waldst. & Kit. from natural habitat (Derdap Gorge, Serbia) and from cultivated plants (Belgrade, Serbia) were characterized. The essential oils of the root, aerial parts, inflorescence and fruit were analyzed by GC/MS and GC/FID. Monoterpene hydrocarbons were the main compounds in the essential oil of aerial parts (45.2-93.0 %), inflorescences (84.1 and 90.0 %) and fruit (85.0 %). Polyacetylenes (38.8 and 87.6 %) were dominant in the essential oil of root. The cluster analysis revealed that there were significant differences in the chemical composition of the S. gracile oils at different phenological stages. On the other hand, essential oils from the aerial parts from natural and cultivated plants showed quite uniform qualitative composition. The aerial parts essential oil from natural habitat contained higher content of para-cymene (mean values 17.3 vs. 6.5 %) and lower amounts of terpinolene (mean values 23.1 vs. 49.9 %). Also polyacetylene falcarinol was present only in the aerial parts samples from natural habitat. The essential oil of inflorescences from natural habitat contained higher concentration of terpinolene, quite similar amount of para-cymene and lower content of a-pinene.