Resveratrol and Extra Virgin Olive Oil: Protective Agents Against Age-Related Disease.

Resveratrol and extra virgin olive oil are both recognized for their potential protective effects against age-related diseases. This overview highlights their mechanisms of action, health benefits, and the scientific evidence supporting their roles in promoting longevity and cognitive health. A literature search was conducted.

Directed Design, Screening and Antiglycation Activity for 3-Substituted Thiazolium Derivatives, New Analogs of Alagebrium.

Preliminary ab initio calculations led to the synthesis of novel substituted thiazolium salts, analogs of Alagebrium, which were further explored in vitro for their potential as inhibitors of the glycation reaction utilizing three distinct assays: inhibition of fluorescent AGEs formation, anticrosslinking, and deglycation. Despite the unidirectionality of the assays, distinct differences were observed in the mechanisms of interference and activity manifestation by the compounds. The gathered data permitted the formation of hypotheses about the molecular fragments of the studied antiglycators that are of utmost significance in each assay, thereby guiding future design endeavors.

A Novel Dipterocarpol Derivative That Targets Alpha-Glucosidase and NLRP3 Inflammasome Activity for Treatment of Diabetes Mellitus.

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, chronic inflammation, impaired insulin secretion, and/or peripheral insulin resistance. Current α-glucosidase inhibitors approved for clinical use exhibit limited efficacy compared to other glucose-lowering agents. In this study, a series of mono- and bis-benzylidene derivatives were synthesized via aldol condensation of 3-oxo-dammarane triterpenoids with terephthalic aldehyde.

Preclinical Evaluation of Soluble Epoxide Hydrolase Inhibitor AMHDU against Neuropathic Pain.

Inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic strategy for treating neuropathic pain. These inhibitors effectively reduce diabetic neuropathic pain and inflammation induced by Freund's adjuvant which makes them a suitable alternative to traditional opioids. This study showcased the notable analgesic effects of compound (1,1'-(hexane-1,6-diyl)bis(3-((adamantan-1-yl)methyl)urea)) in both inflammatory and diabetic neuropathy models.

Derivatization of Abietane Acids by Peptide-like Substituents Leads to Submicromolar Cytotoxicity at NCI-60 Panel.

Natural compounds, including diterpenoids, play a critical role in various biological processes and are recognized as valuable components in cancer treatment. Isocyanides multicomponent reactions (IsMCRs) are one of the effective methods to obtain adducts at the carboxyl group with a peptide-like substituent. In this study, dehydroabietic acid and levopimaric acid diene adducts as the starting scaffolds were modified by the multicomponent Passerini (P-3CR) and Ugi (U-4CR) reactions to afford α-acyloxycarboxamides and α-acylaminocarboxamides.

New Organometallic Ru(II) Compounds with Lonidamine Motif as Antitumor Agents.

The combination of one molecule of organic and metal-based fragments that exhibit antitumor activity is a modern approach in the search for new promising drugs. In this work, biologically active ligands based on lonidamine (a selective inhibitor of aerobic glycolysis used in clinical practice) were introduced into the structure of an antitumor organometallic ruthenium scaffold. Resistant to ligand exchange reactions, compounds were prepared by replacing labile ligands with stable ones.

3-Arylidene-2-oxindoles as GSK3β inhibitors and anti-thrombotic agents.

Development of novel agents that prevent thrombotic events is an urgent task considering increasing incidence of cardiovascular diseases and coagulopathies that accompany cancer and COVID-19. Enzymatic assay identified novel GSK3β inhibitors in a series of 3-arylidene-2-oxindole derivatives. Considering the putative role of GSK3β in platelet activation, the most active compounds were evaluated for antiplatelet activity and antithrombotic activity.

Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury.

The problem of lung damage originating from excessive inflammation and cytokine release during various types of infections remains relevant and stimulates the search for highly effective and safe drugs. The biological activity of the latter may be associated with the regulation of hyperactivation of certain immune cells and enzymes. Here, we propose the design and synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5-]pyrimidines as promising double-acting pharmacophores inhibiting IL-6 and NO.

6-(Tetrazol-5-yl)-7-aminoazolo[1,5-]pyrimidines as Novel Potent CK2 Inhibitors.

In this work, we describe the design, synthesis, and structure-activity relationship of 6-(tetrazol-5-yl)-7-aminoazolo[1,5-a]pyrimidines as inhibitors of Casein kinase 2 (CK2). At first, we optimized the reaction conditions for the azide-nitrile cycloaddition in the series of 6-cyano-7-aminoazolopyridimines and sodium azide. The regioselectivity of this process has been shown, as the cyano group of the pyrimidine cycle was converted to tetrazole while the nitrile of the azole fragment did not react.

Discovery and evaluation of biphenyl derivatives of 2-iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity.

This work describes the synthesis of series hydrobromides of N-(4-biphenyl)methyl-N'-dialkylaminoethyl-2-iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi-privileged structures. Compound 7a proved to activate AMP-activated kinase (AMPK) and simultaneously inhibit protein tyrosine phosphatase 1B (PTP1B) with similar potency. This renders it an interesting prototype of potential antidiabetic agents with a dual-target mechanism of action.

Guanidine Derivatives of Quinazoline-2,4(1,3)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents.

Quinazolines are a rich source of bioactive compounds. Previously, we showed NHE-1 inhibitory, anti-inflammatory, antiplatelet, intraocular pressure lowering, and antiglycating activity for a series of quinazoline-2,4(1,3)-diones and quinazoline-4(3)-one guanidine derivatives. In the present work, novel N1,N3-bis-substituted quinazoline-2,4(1,3)-dione derivatives bearing two guanidine moieties were synthesized and pharmacologically profiled.

Anti-Inflammatory Activity of Soluble Epoxide Hydrolase Inhibitors Based on Selenoureas Bearing an Adamantane Moiety.

The inhibitory potency of the series of inhibitors of the soluble epoxide hydrolase (sEH) based on the selenourea moiety and containing adamantane and aromatic lipophilic groups ranges from 34.3 nM to 1.2 μM.

CK2 Inhibition and Antitumor Activity of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines.

Today, cancer is one of the most widespread and dangerous human diseases with a high mortality rate. Nevertheless, the search and application of new low-toxic and effective drugs, combined with the timely diagnosis of diseases, makes it possible to cure most types of tumors at an early stage. In this work, the range of new polysubstituted 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines was extended.

Selective synthesis of A-ring -arylidene derivatives from β-sitosterol and their activity.

A series of 24-ethylcholest-4-ene-3,6-dione 2-arylidene-derivatives has been synthesized by a Claisen-Schmidt reaction from a natural phytosterol β-sitosterol with yields of 80-85%. The structure of the obtained compounds was confirmed by NMR spectroscopy, including two-dimensional correlation experiments. The synthesized compounds were evaluated for their cytotoxicity and α-glucosidase inhibitory activity.

Discovery of Nitro-azolo[1,5-]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury.

Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion.

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues.

This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments.

Development of New Antimicrobial Oleanonic Acid Polyamine Conjugates.

A series of oleanolic acid derivatives holding oxo- or 3--polyamino-3-deoxy-substituents at C3 as well as carboxamide function at C17 with different long chain polyamines have been synthesized and evaluated for antimicrobial activities. Almost all series presented good to moderate activity against Gram-positive , and bacteria with minimum inhibitory concentration (MIC) values from 3.125 to 200 µg/mL.

Ru(III) Complexes with Lonidamine-Modified Ligands.

A series of bifunctional Ru(III) complexes with lonidamine-modified ligands (lonidamine is a selective inhibitor of aerobic glycolysis in cancer cells) was described. Redox properties of Ru(III) complexes were characterized by cyclic voltammetry. An easy reduction suggested a perspective for these agents as their whole mechanism of action seems to be based on activation by metal atom reduction.

Synthesis and multifaceted pharmacological activity of novel quinazoline NHE-1 inhibitors.

The Na/H exchanger isoform 1 (NHE-1) attracts ongoing attention as a validated drug target for the management of cardiovascular and ocular diseases owing to cytoprotective, anti-ischemic and anti-inflammatory properties of NHE-1 inhibitors. Herein we report novel NHE-1 inhibitors realized via functionalization of N-alkyl quinazoline-2,4(1H,3H)-dione and quinazoline-4(3H)-one with N-acylguanidine or 3-acyl(5-amino-1,2,4-triazole) side chain. Lead compounds show activity in a nanomolar range.

Towards multi-target antidiabetic agents: In vitro and in vivo evaluation of 3,5-disubstituted indolin-2-one derivatives as novel α-glucosidase inhibitors.

Type 2 diabetes mellitus is a chronic progressive disease that usually requires polypharmacological treatment approaches. Previously we have described a series of 2-oxindole derivatives as GSK3β inhibitors with in vivo antihyperglycemic activity. α-Glucosidase is another antidiabetic target that prevents postprandial hyperglycemia and corresponding hyperinsulinemic response.

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis.

A series of A-ring modified oleanolic and ursolic acid derivatives including C28 amides (3-oxo-C2-nicotinoylidene/furfurylidene, 3β-hydroxy-C2-nicotinoylidene, 3β-nicotinoyloxy-, 2-cyano-3,4-seco-4(23)-ene, indolo-, lactame and azepane) were synthesized and screened for their cytotoxic activity against the NCI-60 cancer cell line panel. The results of the first assay of thirty-two tested compounds showed that eleven derivatives exhibited cytotoxicity against cancer cells, and six of them were selected for complete dose-response studies. A systematic study of local SARs has been carried out by comparative analysis of potency distributions and similarity relationships among the synthesized compounds using network-like similarity graphs.

Evaluation of Cytotoxicity and α-Glucosidase Inhibitory Activity of Amide and Polyamino-Derivatives of Lupane Triterpenoids.

A series of two new and twenty earlier synthesized branched extra-amino-triterpenoids obtained by the direct coupling of betulinic/betulonic acids with polymethylenpolyamines, or by the cyanoethylation of lupane type alcohols, oximes, amines, and amides with the following reduction were evaluated for cytotoxicity toward the NCI-60 cancer cell line panel, α-glucosidase inhibitory, and antimicrobial activities. Lupane carboxamides, conjugates with diaminopropane, triethylenetetramine, and branched C3-cyanoethylated polyamine methyl betulonate showed high cytotoxic activity against most of the tested cancer cell lines with GI that ranged from 1.09 to 54.

Structural modifications of 2,3-indolobetulinic acid: Design and synthesis of highly potent α-glucosidase inhibitors.

A series of nineteen nitrogen-containing lupane triterpenoids was obtained by modification of C2, C3, C20 and C28 positions of betulonic acid and their α-glucosidase inhibiting activity was investigated. Being a leader compound from our previous study, 2,3-indolo-betulinic acid was used as the main template for different modifications at C-(28)-carboxyl group to obtain cyano-, methylcyanoethoxy-, propargyloxy- and carboxamide derivatives. 20-Oxo- and 29-hydroxy-20-oxo-30-nor-analogues of 2,3-indolo-betulinic acid were synthesized by ozonolysis of betulonic acid followed by Fischer indolization reaction.