N-(Phenoxyalkyl)amides as MT1 and MT2 ligands: Antioxidant properties and inhibition of Ca2+/CaM-dependent kinase II

Recently a series of chiral N-(phenoxyalkyl)amides have been reported as potent MT(1) and MT(2) melatonergic ligands. Some of these compounds were selected and tested for their antioxidant properties by measuring their reducing effect against oxidation of 2',7'-dichlorodihydrofluorescein (DCFH) in the DCFH-diacetate (DCFH-DA) assay. Among the tested compounds, N-[2-(3-methoxyphenoxy)propyl]butanamide displayed potent antioxidant activity that was stereoselective, the (R)-enantiomer performing as the eutomer. This compound displayed strong cytoprotective activity against H(2)O(2)-induced cytotoxicity resulting slightly more active than melatonin, and performed as Ca(2+)/calmodulin-dependent kinase II (CaMKII) inhibitor, to

Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use-Dependent Inhibitors of Voltage-Gated Sodium Channels

Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated in vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation

Molecular simplification of natural products: Synthesis, antibacterial activity, and molecular docking studies of berberine open models

Berberine, the main bioactive component of many medicinal plants belonging to various genera such as Berberis, Coptis, and Hydrastis is a multifunctional compound. Among the numerous interesting biological properties of berberine is broad antimicrobial activity including a range of Gram-positive and Gram-negative bacteria. With the aim of identifying berberine analogues possibly endowed with higher lead-likeness and easier synthetic access, the molecular simplification approach was applied to the secondary metabolite and a series of analogues were prepared and screened for their antimicrobial activity against Gram-positive and Gram-negative bacterial test species. Rewardingly, the berberine simplified analogues displayed 2–20-fold higher potency with respect to berberine. Since our berberine simplified analogues may be easily synthesized and are characterized by lower molecular weight than the parent compound, they are further functionalizable and should be more suitable for oral administration. Molecular docking simulations suggested FtsZ, a well-known protein involved in bacterial cell division, as a possible target

A Mini-Review on Thalidomide: Chemistry, Mechanisms of Action, Therapeutic Potential and Anti-Angiogenic Properties in Multiple Myeloma

Thalidomide is a drug with interesting therapeutic properties but also with severe side effects which require a careful and monitored use. Potential immunomodulatory, anti-inflammatory, anti-angiogenic and sedative properties make thalidomide a good candidate for the treatment of several diseases such as multiple myeloma. Through an increase in the degradation of TNF alpha-mRNA, thalidomide reduces the production of TNF alpha by monocytes and macrophages stimulated by lipopolysaccharide or by T lymphocytes induced by mitogenic stimuli. The decreased level of TNF alpha alters the mechanisms of intracellular transduction by preventing the activation of NF-kB and by decreasing the synthesis of proteins, in particular IL-6, involved in cell proliferation, inflammation, angiogenesis and protection from apoptosis. Furthermore, thalidomide affects VEGF levels by down-regulating its expression. Nowadays, new safer and less toxic drugs, analogs of thalidomide, are emerging as beneficial for a more targeted treatment of multiple myeloma and several other diseases such as Crohn's disease, rheumatoid arthritis, sarcoidosis, erythema nodosum leprosum, graft-versus-host disease

Combined Modifications of Mexiletine Pharmacophores for New Lead Blockers of Nav1.4 Channels

AbstractPreviously identified potent and/or use-dependent mexiletine (Mex) analogs were used as template for the rational design of new Nav-channel blockers. The effects of the novel analogs were tested on sodium currents of native myofibers. Data and molecular modeling show that increasing basicity and optimal alkyl chain length enhance use-dependent block. This was demonstrated by replacing the amino group with a more basic guanidine one while maintaining a proper distance between positive charge and aromatic ring (Me13) or with homologs having the chirality center nearby the amino group or the aromatic ring. Accordingly, a phenyl group on the asymmetric center in the homologated alkyl chain (Me12), leads to a further increase of use-dependent behavior versus the phenyl Mex derivative Me4. A fluorine atom in paraposition and one ortho-methyl group on the xylyloxy ring (Me15) increase potency and stereoselectivity versus Me4. Charge delocalization and greater flexibility of Me15 may increase its affinity for Tyr residues influencing steric drug interaction with the primary Phe residue of the binding site. Me12 and Me15 show limited selectivity against Nav-isoforms, possibly due to the highly conserved binding site on Nav. To our knowledge, the new compounds are the most potent Mex-like Nav blockers obtained to date and deserve further investigation

Yoga a scuola - Una ricerca nella scuola primaria

Si tratta di una ricerca Promossa dall’Associazione Nazionale Yoga Educazione che ha coinvolto una rete di quattro scuole pugliesi e la cattedra di pedagogia sperimentale diretta dal prof. Michele Baldassarre dell’Università di Bari. La metodologia di lavoro è quella codificata dalla dott.ssa Cavalluzzi nel libro “bimbi a scuola” di yoga Ed. Lulu. Il libro “Yoga a scuola” si divide in cinque aree. La prima parte presenta il disegno di ricerca, la seconda, come abbiamo lavorato; la terza, la ricaduta sui processi di apprendimento; la quarta, le osservazioni e riflessioni di docenti genitori e alunni; la quinta, le riflessioni dei docenti sulla ricerca

Covid-19, chloroquine repurposing, and cardiac safety concern: Chirality might help

The desperate need to find drugs for COVID-19 has indicated repurposing strategies as our quickest way to obtain efficacious medicines. One of the options under investigation is the old antimalarial drug, chloroquine, and its analog, hydroxychloroquine. Developed as synthetic succedanea of cinchona alkaloids, these chiral antimalarials are currently in use as the racemate. Besides the ethical concern related to accelerated large-scale clinical trials of drugs with unproven efficacy, the known potential detrimental cardiac effects of these drugs should also be considered. In principle, the safety profile might be ameliorated by using chloroquine/hydroxychloroquine single enantiomers in place of the racemate

Lactoferrin-derived peptides as a control strategy against skinborne staphylococcal biofilms

Coagulase-negative staphylococci (CoNS) widely colonize the human skin and play an active role in host defense. However, these bacteria may cause malodours and increase infection incidence rate in immune-compromised patients and individuals with catheters and implants. CoNS spreading is favored by biofilm formation that also promotes the release of virulence factors and drug resistance. Biofilm control or eradication by antimicrobial peptides (AMPs) represents an attractive strategy which is worth investigating. In this work, bovine lactoferrin (BLF) hydrolysate (HLF) was in vitro evaluated for its antimicrobial and antibiofilm activities against skin-related coagulase negative and positive staphylococci. Despite a minimal inhibitory concentration (MIC) recorded for HLF ranging from 10 to more than 20 mg/mL, a minimal biofilm inhibitory concentration (MIBC) equal to 2.5 mg/mL was found for most target strains. Conversely, MIBC values referred to the individual peptides, LFcinB or LFmpin (herein purified and identified) were significantly lower. Finally, the application of 2.5 mg/mL HLF solution by dipping and spraying on biofilm-attached glass surfaces also caused a high biofilm eradication rate depending on the incubation time, thus attracting interest for future applications in cosmetic formulation for skin care.Coagulase-negative staphylococci (CoNS) widely colonize the human skin and play an active role in host defense. However, these bacteria may cause malodours and increase infection incidence rate in immune-compromised patients and individuals with catheters and implants. CoNS spreading is favored by biofilm formation that also promotes the release of virulence factors and drug resistance. Biofilm control or eradication by antimicrobial peptides (AMPs) represents an attractive strategy which is worth investigating. In this work, bovine lactoferrin (BLF) hydrolysate (HLF) was in vitro evaluated for its antimicrobial and antibiofilm activities against skin-related coagulase negative and positive staphylococci. Despite a minimal inhibitory concentration (MIC) recorded for HLF ranging from 10 to more than 20 mg/mL, a minimal biofilm inhibitory concentration (MIBC) equal to 2.5 mg/mL was found for most target strains. Conversely, MIBC values referred to the individual peptides, LFcinB or LFmpin (herein purified and identified) were significantly lower. Finally, the application of 2.5 mg/mL HLF solution by dipping and spraying on biofilm-attached glass surfaces also caused a high biofilm eradication rate depending on the incubation time, thus attracting interest for future applications in cosmetic formulation for skin care