guanidino compounds

Antimicrobial resistance (AMR) represents one of the most challenging global Public Health issues, with an alarmingly increasing rate of attributable mortality. This scenario highlights the urgent need for innovative medicinal strategies showing activity on resistant isolates (especially, carbapenem-resistant Gram-negative bacteria, methicillin-resistant S. aureus, and vancomycin-resistant enterococci) yielding new approaches for the treatment of bacterial infections. We previously reported AlkylGuanidino Ureas (AGUs) with broad-spectrum antibacterial activity and a putative membrane-based mechanism of action...

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes...

BACKGROUND: Interleukin (IL)-33, when cleaved into smaller fragments by proteases, becomes hyperactive, contributing to allergic inflammation. Povidone-iodine (PVP-I) is an iodine-based compound that exhibits antimicrobial properties and inhibits proteases. This study aimed to investigate whether PVP-I treatment inhibits IL-33 cleavage, improves allergic rhinitis (AR) symptoms, and suppresses allergic inflammation in a mouse model. METHODS: In vitro experiments using full-length recombinant human IL-33 and allergens, including house dust mites or Dermatophagoides pteronyssinus 1, were conducted using western blotting...

The transition metal frustrated Lewis pair compounds [(Cym)M(κ3 S,P,N-HL1)][SbF6 ] (Cym = η6 - p -MeC6 H4 iPr; H2L1 = N -( p -tolyl)- N '-(2-diphenylphosphanoethyl)thiourea; M = Ru (5), Os (6)) have been prepared from the corresponding dimer [{(Cym)MCl}2 (μ-Cl)2 ] and H2L1 by successive chloride abstraction with NaSbF6 and AgSbF6 and NH deprotonation with NaHCO3 . Complexes 5 and 6 and the previously reported phosphano-guanidino compounds [(Cym)M(κ3 P,N,N'-HL2)][SbF6 ] [H2L2 = N , N '-bis( p -tolyl)- N ''-(2-diphenylphosphanoethyl) guanidine; M = Ru (7), Os (8)] and pyridinyl-guanidino compounds [(Cym)M(κ3 N,N',N''-HL3)][SbF6 ] [H2L3 = N , N '-bis( p -tolyl)- N ''-(2-pyridinylmethyl) guanidine; M = Ru (9), Os (10)] heterolytically activate H2 in a reversible manner affording the hydrido complexes [(Cym)MH(H2L)][SbF6 ] (H2L = H2L1; M = Ru (11), Os (12); H2L = H2L2; M = Ru (13), Os (14); H2L = H2L3; M = Ru (15), Os (16))...

Guanidino compounds such as dimethylarginines (SDMA, ADMA) and L-homoarginine ((L-)hArg) can interfere with bioavailability and function of the main NO-donor L-arginine (L-Arg). High ADMA and SDMA but low L-hArg concentrations have been associated with cardio- and cerebrovascular events and mortality in adults. The role of guanidino compounds in paediatric patients remains less clear. We, therefore, compared guanidino compound levels in plasma samples of 57 individuals with chronic kidney disease (CKD) and 141 individuals without CKD from the age of 0 to 17 years, including patients with different comorbidities by correlation and regression analyses...

The angiotensin converting enzyme inhibiting activity of linear rgd-containing peptides was investigated using in silico approach. The synthesized compound (parent compound) using experimental approach as well as its derivatives was subjected to computational examination using appropriate software. The investigated compounds were optimized using Spartan 14 while the docking study was executed via Pymol, AutoDock Tool, AutoDock Vina and discovery studio. The descriptors obtained (2D and 3D) were screened and the descriptor with highest capacity (squared correlation coefficient) was correlated to the calculated binding affinity...

Protein arginine methyltransferases (PRMTs) catalyze the methylation of the terminal nitrogen atoms of the guanidino group of arginine of protein substrates. The aberrant expression of these methyltransferases is linked to various diseases, making them promising therapeutic targets. Currently, PRMT inhibitors are at different stages of clinical development, which validated their significance as drug targets. Structural Genomics Consortium (SGC) has reported several small fragment inhibitors as Class I PRMT inhibitors, which can be the starting point for rational drug development...

Molecular manipulation of guanidino-containing biomolecules in a cellular environment is fundamental to exploiting protein function and drug release, but currently, there is a lack of suitable methods for reaction screening and monitoring. To exploit the potential of the fluorescent method in this respect, herein, we evaluated a novel array of 7-guanidinyl coumarins by incorporating different substituted guanidino moieties into a coumarin scaffold. These compounds were prepared by guanidinylation reagent S -methylisothiourea or TFA-protected pyrazole-carboxamidine...

In an extreme thermophile, Thermus thermophilus, sym-homospermidine is synthesized by the actions of two enzymes. The first enzyme coded by dhs gene (annotated to be deoxyhypusine synthase gene) catalyzes synthesis of an intermediate, supposed to be 1,9-bis(guanidino)-5-aza-nonane (=N1 , N11 -bis(amidino)-sym-homospermidine), from two molecules of agmatine in the presence of NAD. The second enzyme (aminopropylagmatinase) coded by speB gene catalyzes hydrolysis of the intermediate compound to sym-homospermidine releasing two molecules of urea...

Arginine (Arg)-rich peptides are one of the typical cell-penetrating peptides (CPPs), which can deliver membrane-impermeable compounds into intracellular compartments. Guanidino groups in Arg-rich peptides are critical for their high cell-penetrating ability, although it remains unclear whether peptide secondary structures contribute to this ability. In the current study, we designed four Arg-rich peptides containing α,α-disubstituted α-amino acids (dAAs), which prefer to adopt a helical structure...

Glycoside hydrolases (GHs) are a class of enzymes with emerging roles in various diseases. Selective GH inhibitors are sought to better understand their functions and assess the therapeutic potential of modulating their activities. Iminosugars are a promising class of GH inhibitors but typically lack the selectivity required to accurately perturb biological systems. Here, we describe a concise synthesis of iminosugar inhibitors of N-acetyl-α-galactosaminidase (α-NAGAL), the GH responsible for cleaving terminal α-N-acetylgalactosamine residues from glycoproteins and glycoconjugates...

Aminoglycosides are one of the first classes of antibiotics to have been used clinically, and they are still being used today. They have a broad spectrum of antimicrobial activity, making them effective against many different types of bacteria. Despite their long history of use, aminoglycosides are still considered promising scaffolds for the development of new antibacterial agents, particularly as bacteria continue to develop resistances to existing antibiotics. We have synthesized a series of 6″-deoxykanamycin A analogues with additional protonatable groups (amino-, guanidino or pyridinium) and tested their biological activities...

Two classes of new polyketides, allopteridic acids A-C (1-3) and allokutzmicin (4), were isolated from the culture extract of an actinomycete of the genus Allokutzneria. The structures of 1-4 were elucidated through the interpretation of NMR and MS analytical data. Compounds 1-3 possess the same carbon skeleton with pteridic acids but their monocyclic core structures are distinct from the spiro-bicyclic acetal structures of pteridic acids. Compound 4 is a linear polyketide of an unprecedented class, featured by a guanidino-terminus and an epoxide modification...

Impairment of excretion and enzymatic processing of nitrogen, for example, because of liver or kidney failure, or with urea cycle and creatine synthesis enzyme defects, surprisingly leads to primarily neurologic symptoms, yet the exact mechanisms remain largely mysterious. In guanidinoacetate N-methyltransferase (GAMT) deficiency, the guanidino compound guanidinoacetate (GAA) increases dramatically, including in the cerebrospinal fluid (CSF), and has been implicated in mediating the neurological symptoms in GAMT-deficient patients...

Chitinases are important glycoside hydrolases that are closely related to bacterial pathogenesis, fungal cell wall remodelling, and insect moulting. Consequently, chitinases have become attractive targets for therapeutic drugs and pesticides. In this study, we designed and synthesised a series of novel chitinase inhibitors based on the N-methylcarbamoylguanidinyl group of the natural product argifin. The most active compound 8h showed strong inhibitory activity against the group I chitinases HsChit1, SmChiB, and OfChi-h, with IC50 values of 0...

Arginase 1 Deficiency (ARG1-D) is a rare urea cycle disorder that results in persistent hyperargininemia and a distinct, progressive neurologic phenotype involving developmental delay, intellectual disability, and spasticity, predominantly affecting the lower limbs and leading to mobility impairment. Unlike the typical presentation of other urea cycle disorders, individuals with ARG1-D usually appear healthy at birth and hyperammonemia is comparatively less severe and less common. Clinical manifestations typically begin to develop in early childhood in association with high plasma arginine levels, with hyperargininemia (and not hyperammonemia) considered to be the primary driver of disease sequelae...

Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases...

In recent years, a rise in the number of contact lens users in the UK and worldwide coincided with an increased incidence of microbial keratitis. The aim of this study was to investigate the antimicrobial activities of polyhexamethylene guanidine (PHMG), polyaminopropyl biguanide (PAPB), and guazatine in comparison to the common contact lens disinfectant constituent, polyhexamethylene biguanide (PHMB). The study investigated these compounds against a broad range of organisms, including Acanthamoeba castellanii , Acanthamoeba polyphaga , Staphylococcus aureus , Pseudomonas aeruginosa, and Candida albicans ...

Atmospheric amines are considered to be an effective enhancer for methanesulfonic acid (MSA)-driven nucleation. However, out of the 195 detected atmospheric amines, the enhancing potential (EP) has so far only been studied for five amines. This severely hinders the understanding of the contribution of amines to MSA-driven nucleation. Herein, a two-step procedure was employed to probe the EP of various amines on MSA-driven nucleation. Initially, the formation free energies (Δ G ) of 50 MSA-amine dimer clusters were calculated...

The synthesis and biological evaluation of novel guanidino sugars as isonucleoside analogs is described. 5-Guanidino xylofuranoses containing 3- O -saturated/unsaturated hydrocarbon or aromatic-containing moieties were accessed from 5-azido xylofuranoses via reduction followed by guanidinylation with N , N '-bis( tert -butoxycarbonyl)- N ''-triflylguanidine. Molecules comprising novel types of isonucleosidic structures including 5-guanidino 3- O -methyl-branched N -benzyltriazole isonucleosides and a guanidinomethyltriazole 3'- O -dodecyl xylofuranos-5'-yl isonucleoside were accessed...