Search

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC50 in the submicromolar range from 0.56 ± 0.01 µM to 0.74 ± 0.02 µM. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO• radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R2 = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological β-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer’s disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer’s disease.

Considering the constantly evolving type 2 diabetes mellitus epidemic and the lack of a safe and effective drug therapy, it is of high importance to search for new hypoglycemic drugs. One of this search’s directions is the chemical modification of some known natural metabolites, which potentially possess the necessary pharmacological properties. These criteria are met by usnic acid, which is produced by lichens and exhibit different biological properties, including hypoglycemic. However, this effect becomes noticeable only at relatively high doses, something that may lead to some adverse effects. The chemical modification of its molecule is able to enhance the safety profile and its hypoglycemic properties. With this in view in the present work several usnic acid derivatives were synthesized. As a result of the experiment using the alloxan-induced diabetes mellitus in mice, it was shown that a derivative of usnic acid, containing a 4-trifluoromethylphenyl fragment, exhibits a pronounced hypoglycemic effect, which was observed at a lower dose as compared to usnic acid itself in a similar experimental model.

Parkinson’s disease is the second most common neurodegenerative disease. Unfortunately, there is still no definitive disease-modifying therapy. In our work, the antiparkinsonian potential of trans-epoxide (1S,2S,3R,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo [4.1.0]heptan-2,3-diol (E-diol) was analyzed in a rotenone-induced neurotoxicity model using in vitro, in vivo and ex vivo approaches. It was conducted as part of the study of the mitoprotective properties of the compound. E-diol has been shown to have cytoprotective properties in the SH-SY5Y cell line exposed to rotenone, which is associated with its ability to prevent the loss of mitochondrial membrane potential and restore the oxygen consumption rate after inhibition of the complex I function. Under the conditions of rotenone modeling of Parkinson’s disease in vivo, treatment with E-diol led to the leveling of both motor and non-motor disorders. The post-mortem analysis of brain samples from these animals demonstrated the ability of E-diol to prevent the loss of dopaminergic neurons. Moreover, that substance restored functioning of the mitochondrial respiratory chain complexes and significantly reduced the production of reactive oxygen species, preventing oxidative damage. Thus, E-diol can be considered as a new potential agent for the treatment of Parkinson’s disease.

A new compounds containing 1,7,7-trimethylbicyclo[2.2.1]heptane fragment has been found to exhibit potent inhibitory activity against the influenza A(H1N1) virus. The most potent antiviral compound 10a is a quaternary ammonium salt based on (-)-borneol, with a therapeutic index of more than 500. Mechanism-of-action studies for compound 10a were performed. The compound appeared the most effective when added at the early stages of viral life cycle. In direct hemagglutinin inhibition tests the agent, 10a, was shown to decrease the activity of hemagglutinin of influenza virus A/Puerto Rico/8/34. According to the results of molecular modelling, the lead-compound, 10a, can attach at the binding sites of the stem part of the HA. These results prove that monoterpenoids with 1,7,7-trimethylbicyclo[2.2.1]heptane fragment are prospective natural compounds for the development of antiviral agents.

It has been found that usnic acid carbonyl groups can be hydrogenated by the action of H2/Pd(C). Thus, two new dibenzofuran derivatives were synthesized.

New heterocyclic derivatives of usnic acid have been obtained by the reaction of bromousnic acid with CS2-based nucleophiles. A series of compounds with dithiolane, 1,3,4-thiadiazine, and thiophene fragments was synthesized.

A series of bornyl derivatives of p-(benzyloxy)phenylpropionic acid were prepared, and their hypoglycemic activities were examined by an oral glucose tolerance test in mice. The results of this test revealed two compounds, 1 and 3, that can reduce the blood level of glucose similarly to reference compound vildagliptin. Both compounds were tested in an experiment on mice with metabolic disorders: the C57BL/6Ay strain. Along with hypoglycemic properties, the two compounds showed different abilities to correct lipid metabolism disorders. In silico prediction revealed that the studied substances are most likely bifunctional multitarget hypoglycemic compounds whose mechanism of action is based on a pronounced reduction in insulin resistance and a strong incretin-mimetic effect. The difference in the size of effects of these compounds on biochemical parameters of blood in the experiment on C57BL/6Ay mice was in good agreement with the computational prediction of the priority ranking of biological targets for these compounds. These results indicate that bornyl derivatives of p-(benzyloxy)phenylpropionic acid have a good potential as new agents for diabetes mellitus treatment due to their hypoglycemic and lipid-normalizing properties.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that plays a key role in repairing damage caused by various antitumor drugs. It is a promising target in medicinal chemistry for the creation of cancer adjuvant therapy. Inhibition of this enzyme together with the use of anticancer chemotherapy enhances the effect of the latter. The natural mutant of TDP1, TDP1(H493R), causes severe neurodegenerative disease spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1). Inhibition of TDP1(H493R) appears to be useful in containment the progression of the disease. A library of compounds was synthesized starting from dehydroabietylamine including heterocyclic pharmacophore groups in the core. To obtain the desired products, the starting dehydroabietylamine was introduced sequentially in reaction with isothiocyanate and ethyl bromoacetate. Different classes of heterocyclic derivatives-2-iminothiazolidin-4-ons and 2-thioxoimidazolidin-4-ones-were obtained depending on the addition order of reagents. 2-Iminothiazolidin-4-thiones were obtained from 2-iminothiazolidin-4-ones under the action of the Lawesson's reagent. Effective TDP1 inhibitors were found among the obtained compounds that work in submicromolar concentrations. The inhibitor of TDP1(H493R) was also detected.

The structure, stability, and reactivity of the host-guest complexes between a set of carotenoids and the triterpene glycoside, beta-glycyrrhizic acid (GA), were investigated by different physicochemical techniques: high-performance liquid chromatography, optical absorption, and fluorescence spectroscopy. It has been demonstrated recently that the molecular complexes of GA with a number of drugs are characterized by reduced toxicity and increased therapeutic activity of these drugs. In the present work it was found that carotenoids form 1:2 complexes with GA in aqueous solutions as well as in polar organic solvents, methanol, acetonitrile, and dimethylsulfoxide. We assume that the structure of the complex is a cycliclike dimer of GA encapsulating a carotenoid molecule. The stability constants in all solvents are near 10(4) M(-1). In addition, GA forms inclusion complexes with carotenoid radical cations, which results in their stabilization. Complex formation (a) decreases the rate of electron transfer from carotenoids to electron acceptors (Fe3+ or quinone) and (b) considerably increases the lifetime of the carotenoid-quinone charge-transfer complex and the yield of the major product (a carotenoid-quinone adduct). A thermodynamic study shows that hydrophobic interactions are the main driving force of the carotenoid-GA complex formation. These results are important for understanding both the nature of GA complexes and the influence of GA on the therapeutic activity of some drugs. Furthermore, carotenoid-GA complexes could be used for the design of artificial light-harvesting, photoredox, and catalytic systems.

Chemistry and Pharmacology of Naturally Occurring Bioactive Compounds Goutam Brahmachari Impact of Solid-Supported Cyclization-Elimination Strategies toward the Development of Natural Product Inspired Molecules in Drug Discovery Research Dhananjay Kumar, Bhuwan B. Mishra, Divya Kushwaha, and Vinod K. Tiwari Synthesis and Biological Studies of Novel ss-Lactams Bimal K. Banik Applications of Isatin Chemistry in Organic Synthesis and Medicinal Chemistry Girija S. Singh and Zelalem Y. Desta Role of Organic Carbamates in Anticancer Drug Design Devdutt Chaturvedi Rational Design of New Molecules of Biological Significance from Phenolic Constituents of Some Tropical Plants as Renewable Materials Vladimir V. Kouznetsov, Diego R. Merchan Arenas, Fernando A. Rojas Ruiz, and Leonor Y. Vargas Mendez Synthesis and Biological Activity of Promising Azole Marine Products: Largazole and Neopeltolide Danilo Davyt and Gloria Serra Omega-3 (omega-3) Polyunsaturated Fatty Acids Philip C. Calder Structure and Biological Activity of Natural Melanin Pigments Krystyna Stepien, Anna Dzierzega-Lecznar, Irena Tam, and Slawomir Kurkiewicz Recent Acquisitions on Naturally Occurring Oxyprenylated Secondary Plant Metabolites Francesco Epifano and Salvatore Genovese Role of Curcumin in Ameliorating Neuroinflammation and Neurodegeneration Associated with Alzheimer's Disease Sumit Sarkar, Balmiki Ray, Jay Sharma, Larry Schmued, and Debomoy K. Lahiri Plant Metabolites Marina P. Polovinka and Nariman F. Salakhutdinov X-Ray Structural Behavior of Some Significant Bioactive Steroids and Their Chemistry in the Crystal Packing and Related Matters Vivek K. Gupta Three-Dimensional Structure of Xanthones Luis Gales and Ana M. Damas Gambogic Acid Goutam Brahmachari Neuroplasticity as a New Approach to the Pathophysiology of Depression and the Role of Antidepressants in Inhibiting Brain Stress-Induced Changes Gianluca Serafini, Maurizio Pompili, and Paolo Girardi Statins Vincent Gullo and Arnold L. Demain Molecular Aspects of Fungal Bioactive Polyketides Ira Bhatnagar and Se-Kwon Kim Marine Microalgal Metabolites S.W.A. Himaya and Se-Kwon Kim Rosmarinic Acid Juan C. Luis, Maria Y. Gonzalez-Padron, Raquel M. Perez, Ignacio F. Viera, and Francisco V. Gonzalez Enhancement of Natural Antioxidants in Plants by Biosynthetic Pathway Modulation Kanakapura K. Namitha and Pradeep S. Negi Plant as Biofactories of Pharmaceuticals and Nutraceuticals Dandara R. Muniz, Raquel de Oliveira Faria, Vagner Augusto Benedito, Angelo de Fatima, and Luzia Valentina Modolo