Berberine, a naturally occurring compound, inhibits the growth of cancer cells in vitro at micromolar concentrations. Selective cytotoxicity was revealed for berberine derivatives and monoterpene aminoalcohols in the FCCT (fluorescent cells co-cultivation test) screening of almost a 100 recently synthesized compounds. C9-substituted berberines were found to be selective and cytotoxic in the nanomolar concentration range, and were investigated in detail. They exhibit some selectivity for A549 and MCF7 cancer cells in comparison to non-cancerous VA13 cells. Several berberine derivatives were synthesized, which allowed us to analyze their structure-activity relationships (SAR) and mechanism of action on the cells. Investigation of berberine's and its derivatives' action on the cells revealed some similarities with DNA intercalators. Compounds bearing charged groups, such as 1 and 2, have also been observed to disrupt the mitochondrial membrane potential. Compound 17a, lacking a charge on the nitrogen, retains the effects on the cells and the ability to intercalate DNA, but affects mitochondria only at high concentrations. The significant mechanism of action of the investigated berberine derivatives is intercalation into DNA.

Natural compounds are widely used in medical practice in their native form [...].

A large series of new chiral heterocyclic cineol-like methanopyrano[4,3-b]pyrans was prepared by reactions of the (+)- and (–)-isomers of 8-hydroxy-6-hydroxymethyllimonene, obtained from the corresponding α-pinenes with high optical purity, and aromatic aldehydes with OH and/or OMe substituents. The synthesized heterocycles were tested for analgesic activity in the in vivo tests. Some of cineol-like methanopyrano[4,3-b]pyrans synthesized from 4-methoxybenzaldehyde, 2,3,4-trimethoxybenzaldehyde and 2,4,5-trimethoxybenzaldehyde exhibit significant analgesic activity. Experiments in vivo with agonists and antagonists of several neurotransmitter systems helped to elucidate the probable mechanism of analgesic action mediated by these compounds. Thus, cannabinoid CB1 receptors do not appear to be involved in the development of the analgesic effect. Opioid and GABAA receptors of the central nervous system likely play a significant role in the analgesic activity of the tested cineol-like methanopyrano[4,3-b]pyrans. (3R,4aR,5R,8S,8aS)-5-(4-Methoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran likely mediates its analgesic effect through both muscarinic and adrenergic receptors of the central nervous system. Serotonin receptors may be involved into the mechanism of analgesic action of (3R,4aR,5R,8S,8aS)-5-(2,3,4-trimethoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran and (3R,4aR,5R,8S,8aS)-5-(2,4,5-trimethoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran.

Polyhydroxy containing compounds, in particular those derived from monoterpenoids, have attracted attention as biologically active compounds, but a key limitation in their synthesis is the need for regio- and stereoselective hydroxylation. Here, the synthesis of two dihydroxy derivatives and potential metabolites of the antiparkinsonian agent Prottremine, which is a monoterpenoid diol with a para-menthene scaffold, was carried out using an epoxy ester-orthoester rearrangement as the key step. The isomerization of epoxyacetate derivative of Prottremine to corresponding orthoester proceeded stereoselectively, as a result, two new stereoisomeric tetraols were obtained in yields of 22% and 3%. Using a similar approach directly and in combination with the Mitsunobu reaction, three stereoisomeric triols based on (-)-isopulegol and (+)-neoisopulegol were synthesized in yields ranging from 13% to 36%, thus demonstrating the potential to expand the approach to other compounds. Isomerization of the epoxyacetate derivative in the presence of superacids was accompanied by aromatization of cyclohexene ring with the formation of the dioxolane cation, which then, upon longer storage at room temperature, was completely converted into a mixture of protonated ketones, one of which was a dimeric form (dication).

Tuberculosis (TB) remains a global health issue exacerbated by spreading drug resistance and lengthy treatment regimens. Targeting bacterial DNA-repair pathways, particularly those counteracting host-generated genotoxic stress, represents a promising strategy to sensitize Mycobacterium tuberculosis to existing antibiotics. Through structure-based virtual screening of a compound library, we identified novel small-molecule inhibitors of M. tuberculosis uracil-DNA glycosylase (MtbUng), an enzyme essential for the repair of DNA damage inflicted by macrophage-produced reactive nitrogen species. Experimental validation revealed that four derivatives of usnic acid, a lichen-derived metabolite, significantly inhibited MtbUng activity, with the most potent compound, OL10-88-1, exhibiting IC50 26 ± 7 µM. Molecular docking suggests that OL10-88-1 inhibits MtbUng by occupying both the active site and the DNA-binding groove, thereby disrupting multiple steps of uracil recognition. The compounds also showed variable inhibitory activity against uracil-DNA glycosylases from Escherichia coli, humans, and vaccinia virus. Our findings establish that the compound could potentially be used in combination therapies to enhance the efficacy of current anti-TB drugs by exploiting the vulnerability of DNA-repair-deficient mycobacteria.

Schizophrenia is a severe, chronic mental disorder affecting near 1% of the global population, with about 60% of patients showing resistance to currently available antipsychotic drugs (APDs). The modern dopaminergic (DA) hypothesis of schizophrenia postulates that multiple pathogenic factors contribute to hyperdopaminergia in the striatum. Therefore, effective modulation of striatal DA remains a key strategy in the development of novel APDs. The striatum-enriched protein phosphatase (STEP) is selectively expressed in the dopaminergic neurons of the striatum together with D2 receptors - the main target of existing APDs. In this study, we investigated the APD-like effects of the STEP inhibitor TC-2153 in a genetic mouse model of schizophrenia (Disc1-L100P). We found that TC-2153 [10 mg/kg; i.p.] effectively reduced hyperactivity in Disc1-L100P mutant mice as assessed in the open field test. The STEP inhibitor also ameliorated disrupted latent inhibition (LI) in Disc1-L100P animals, but unexpectedly impaired LI in wild-type (WT) mice. In opposite, TC-2153 had no effect on deficient sensorimotor gating, measured by the pre-pulse inhibition (PPI) paradigm. Additionally, TC-2153 induced antidepressant-like effects in both WT and Disc1-L100P mutant mice, increasing their activity in the Forced Swim Test (FST). These new findings suggest that STEP inhibition produces APD-like effects in a genotype-specific manner while promoting antidepressant-related behavioural phenotypes regardless of genetic background. Overall, our preclinical results support STEP as a promising target for APD development and highlight a potential link between STEP and DISC1 molecular complex in the pathogenesis of schizophrenia – an avenue that warrants further investigation to better understand the molecular mechanisms underlying APD action.

Background: This study explored the biotransformation of (-)-isopulegol using immobilized cells of Rhodococcus rhodochrous IEGM 1362 to optimize the production of new bioactive compounds. Methods: An efficient biocatalyst based on R. rhodochrous IEGM 1362 cells immobilized in a macroporous polyvinyl alcohol (PVA) cryogel matrix was developed for the production of bioactive derivatives of (-)-isopulegol. The biological characteristics of the immobilized cells were investigated using scanning and transmission electron microscopy and energy-dispersive X-ray spectroscopy methods. Results: The use of the biocatalyst increased the overall yield of target products from 54% with free cells to 87% with immobilized cells in a single cycle. Major derivatives identified included (1R,2S,5R)-5-(hydroxymethyl)-2-(prop-1-en-2-yl)cyclohexanol and (1R,3R,4S)-3-hydroxy-4-(prop-1-en-2-yl)cyclohexanecarboxylic acid, both exhibiting potential pharmacological activity. The biocatalyst retained functional activity toward monoterpenoid over 13 exploitation cycles, meeting industrial biotechnology requirements. Immobilized cells were characterized by the absence of endogenous reserve inclusions (in particular lipids) and a high intracellular iron content. Conclusions: The developed immobilized biocatalyst is promising for scaling up the production of biologically active compounds.

Fatigue is a widespread issue that affects both mental and physical performance, yet effective treatments remain limited. This study focused on developing and evaluating new synthetic adaptogens—compounds designed to enhance endurance and reduce fatigue. We synthesized and tested derivatives of 3,7-diazabicyclo[3.3.1]nonanes (bispidine) and 1,3-diazaadamantanes, incorporating monoterpenoid fragments to improve their pharmacological properties. Using SwissADME and PreADMET tools, we predicted that most of these compounds would be well-absorbed in the gastrointestinal tract and capable of crossing the blood-brain barrier. Among them, compound 2, a 1,3-diazaadamantane derivative, stood out for its strong antifatigue effects at 10 mg/kg in swimming and running endurance tests in in vivo experiments with mice, even outperforming the reference drug bromantane. Acute toxicity tests showed that this compound has a high safety margin, with an LD50 value 237.5 times greater than its effective dose. Further analysis of structure-activity relationships revealed that monosubstituted 1,3-diazaadamantane derivatives had the most promising effects, suggesting that specific chemical modifications can enhance performance. These findings indicate that this new class of synthetic adaptogens could offer a safe and effective way to combat fatigue, making them strong candidates for further pharmacological research and potential therapeutic use.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose primary manifestation is motor dysfunction. Previous research showed that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremine) exhibits potent antiparkinsonian activity in animal models of PD, with an efficacy comparable to levodopa. Herein, we report the synthesis of a new Prottremine derivative, (1R,2R,6S)-3-methyl-6-(3-(4-phenylpiperidin-1-yl)prop-1-en-2-yl)cyclohex-3-ene-1,2-diol. The compound was fully characterized and its structure was confirmed through single-crystal X-ray diffraction analysis.

Cineole is a natural compound that is used in traditional medicine and pharmaceuticals. This work describes for the first time the selective catalytic synthesis of heterocyclic compounds with a cineole fragment by condensation of 8-hydroxy-6-hydroxymethyllimonene (alpha-pinene based platform molecules) with thiophene-2-carbaldehyde. Acid-modified halloysite nanotubes and commercial montmorillonites K-10 and K-30 were used as heterogeneous catalysts and compared with the traditional ones. The materials were characterized by SEM, EDX, N2 adsorption-desorption, MAS NMR, and FTIR with pyridine methods. Selectivity to the product with the 1,8cineole moiety increased slightly with increasing solids acidity, reaching 77 % on K-10, which was the same as in the presence of BF3 & sdot;Et2O. Over strong Br & oslash;nsted acid (Amberlyst-15), mainly intramolecular cyclization of the diol occurred. Formation of the product with the 1,4-cineole fragment was more pronounced at high initial reagents concentrations, or when water was added, since it is formed through another intermediate containing two hydroxy groups. The reaction mechanism and pathways are discussed using both experimental data and DFT calculations. The use of a catalytic system based on resistant to leaching montmorillonite K-10 in methylene chloride allowed generation of the products with a 1,8-cineole moiety with selectivity up to 96 % depending on the aldehyde.

Monoterpenes and their derivatives are important starting compounds in the design of new biologically active substances. In particular, cineole, isolated from eucalyptus essential oil, exhibits a wide range of biological activities. Here, the synthesis of new heterocyclic compounds containing a cineole fragment by the acid-catalyzed condensation of α-pinene-derived 8-hydroxy-6-hydroxymethyllimonene with monoterpene aldehydes was carried out for the first time. The reactions of 8-hydroxy-6-hydroxymethyllimonene with cuminaldehyde, perillylaldehyde, myrtenal, citral, and geranial were studied in the presence of heterogeneous K10 clay or Lewis acid BF3·Et2O. The main products of these reactions were compounds with the methanopyrano[4,3-b]pyran scaffold having a 1,8-cineole fragment. As a result of this work, five new compounds with the methanopyrano[4,3-b]pyran scaffold were synthesized. The use of BF3·Et2O led to an increase in the yields of target products, compared with the results obtained on K10 clay.

Monoterpenes and their derivatives are often considered as widespread and cheap raw materials for the transformation into the valuable chemicals using for the development of new drugs. In this study, a series of compounds with methanofuro[3,2-c]pyran and methanopyrano[4,3-b]pyran scaffolds were synthesized starting from (+)- and (- )-alpha-pinene-derived monoterpenoids and p-halogen substituted aromatic aldehydes. These compounds contain a fragment of 1,4- and 1,8-cineoles - monoterpenes exhibited a wide range of biological effects. Methanofuro[3,2-c]pyrans 18 with a fragment of 1,4-cineole were synthesized from 8-acetoxy-6-hydroxymethyllimonene in the presence of K10 dried at 105 degrees C in solvent-free conditions. Optimized conditions for the synthesis of the methanopyrano[4,3-b]pyrans 19 bearing the 1,8-cineol moiety were developed. It was shown that the 8hydroxy-6-hydroxymethyllimonene reactions with aldehydes proceed with high selectivity towards product 19 when catalyzed by K10 (dried at 200 degrees C) in methylene chloride. Cytotoxic activity of cineol-like compounds was studied against HeLa, MCF7 and A-172 cells. It was shown that cytotoxic activity of compounds 18b-d and 19bd is depended on both their (+)/(-) configuration and halogen atom presence in a particular structure. The most active compounds - methanopyrano[4,3-b]pyrans (+)-19c and (+)-19d with Cl and Br substituents exhibited high toxicity to cancerous cells, but were little toxic to Vero cells. Compounds (+)-19c and (+)-19d can exert cytostatic effects in HeLa cells or induce apoptotic cell death in MCF7 and A-172 cells.

Novel monoterpenoid derivatives of 7-hydroxycoumarine containing an isoxazole linker were synthesized, 2,3-dichloropropene having been the synthetic equivalent of propargyl chloride at the step of isoxazole moiety construction. The conjugates demonstrated promising inhibitory activity against TDP1, an important target for complex anticancer therapy, with IC50 values in the low micromolar or submicromolar concentration range. Me Me Me IC50([DP1) = 0.8 +/- 0.5 mu M O N O O O

Dialkyl malonates and dialkyl 1,3-dimethoxypropanes containing one or two natural pinane fragments were obtained for the first time and used as internal donors in the composition of titanium–magnesium catalysts (TMC) for propylene polymerization. It was found that diethyl 2-isobutyl-2-pinanylmalonate (DM) and 2-isobutyl-2-pinanyl-1,3-dimethoxypropane (DP) are anchored on the surface of magnesium chloride during the synthesis of titanium–magnesium catalysts TMC-DM and TMC-DP. Their content in the catalysts is 9.4 and 15.6 wt

Противовирусная активность монотерпен-арилкумариновых коньюгатов зависит от абсолютной конфигурации монотерпенового фрагмента, что, по-видимому, связано с различным расположением соединений в сайте связывания F-белка респираторно-синцитиального вируса, предполагаемой мишенью этих соединений. Методы молекулярной динамики и метадинамики позволили оценить разницу в природе взаимодействия стереоизомеров с ключевыми аминокислотными остатками сайта связывания и объяснить их различную противовирусную активность.

While synthesis of hydroxymethyl derivatives of common terpenes by a reaction with formaldehyde (FA) has been commercialized, no open data are available on the preparation of such alpha-pinene derivatives. Here, an approach for the renewable (-)-alpha-pinene catalytic utilization by its condensation with FA into a novel terpenoid 8-acetoxy-6-hydroxymethyllimonene is proposed. Both common homogeneous acids and aluminosilicates (halloysite nanotubes pretreated with H3PO4 and HCl, montmorillonite K-10, zeolite H -Beta -25) have been investigated. The solids were characterized by SEM, EDX, Al-27 and Si-29 MAS NMR, as well as FTIR with pyridine and N2 adsorption-desorption methods. Traditional Lewis and Bronsted acids (ZnCl2, FeCl3, H3PO4 etc.) catalyzed the desired condensation although selectivity did not exceed 24 % in the case of phosphoric acid due to the side reactions, including opening of the alpha-pinene cyclobutane ring, as well as skeletal rearrangements of its bicyclic structure. On aluminosilicates with a weak to moderate Lewis and Bronsted acidity (45-104 mu mol/g), the products of a direct substrate protonation (up to 52.8 %) were predominantly formed. In the presence of strongly acidic H -Beta -25 (301 mu mol/g) and phosphoric acid, selectivity to alpha-pinene addition products with formaldehyde (32.3-35.3 %) and substrate direct protonation (30.0-36.8 %) were comparable. However, with H3PO4 the content of borneol derivatives formed via the Wagner -Meerwein rearrangement was the smallest (13.5 %) giving subsequently the largest selectivity to the desired 8-acetoxy-6-hydroxymethyllimonene. Higher selectivity to the target product was observed at lower reaction temperature and a larger formaldehyde amount. The reaction mechanism has been proposed and elucidated using kinetic and quantum chemical approaches. The developed kinetic model adequately describes the experimental results. The DFT calculations showed that in the presence of H3PO4 there are no significant differences between the energy of the intermediates formed due to formaldehyde addition to alpha-pinene or its direct protonation. Synthesis of 8-acetoxy-6-hydroxymethyllimonene was performed on 22 g scale. This compound can be considered as a chiral platform for further utilization, including synthesis of heterocyclic compounds.

Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (−)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.

A new monoterpene–azole hybrid containing myrtenyl- bispidine moiety, 2-(2,4-difluorophenyl)-1-(7-{[(1R,5S)-6,6- dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl}-1,5-dimethyl- 3,7-diazabicyclo[3.3.1]non-3-yl)-3-(1H-1,2,4-triazol-1-yl)- propan-2-ol was prepared in six steps with 55% overall yield. The compound was tested against a number of Candida spp. fungi and found to be active against Candida albicans. Molecular docking suggested possible inhibition of lanosterol 14α-demethylase (CYP51), a membrane enzyme targeted by azole antifungals.

Topotecan administered intraperitoneally at single doses of 0.25, 0.5, and 1 mg/kg induced chromosomal aberrations in bone marrow cells of F1(CBA×C57BL/6) hybrid mice in a dose-dependent manner. A tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitor, an usnic acid derivative OL9-116 was inactive in a dose range of 20-240 mg/kg, but enhanced the cytogenetic effect of topotecan (0.25 mg/kg) at a dose of 40 mg/kg (per os). The TDP1 inhibitor, a coumarin derivative TX-2552 (at doses of 20, 40, 80, and 160 mg/kg per os), increased the level of aberrant metaphases induced by topotecan (0.25 mg/kg) by 2.1-2.6 times, but was inactive at a dose of 10 mg/kg. The results indicate that TDP1 inhibitors enhance the clastogenic activity of topotecan in mouse bone marrow cells in vivo and are characterized by different dose profiles of the co-mutagenic effects.

The antiviral activity of monoterpene-aryl coumarin conjugates depends on the absolute configuration of the monoterpene moiety, which seems to be due to different arrangements of compounds at the binding site of the F-protein of respiratory syncytial virus - the supposed target for these compounds. Molecular dynamics and metadynamics methods make it possible to estimate the difference in the nature of the interaction between stereoisomers and key amino acid residues of the binding site and to explain their different antiviral activity.