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Lipid nanoparticles (LNPs) are widely used for mRNA delivery, with cationic lipids greatly affecting biodistribution, cellular uptake, endosomal escape and transfection efficiency. However, the laborious synthesis of cationic lipids limits the discovery of efficacious candidates and slows down scale-up manufacturing. Here we develop a one-pot, tandem multi-component reaction based on the rationally designed amine-thiol-acrylate conjugation, which enables fast (1 h) and facile room-temperature synthesis of amidine-incorporated degradable (AID) lipids. Structure-activity relationship analysis of a combinatorial library of 100 chemically diverse AID-lipids leads to the identification of a tail-like amine-ring-alkyl aniline that generally affords efficacious lipids. Experimental and theoretical studies show that the embedded bulky benzene ring can enhance endosomal escape and mRNA delivery by enabling the lipid to adopt a more conical shape. The lead AID-lipid can not only mediate local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics, but can also alter the tropism of liver-tropic LNPs to selectively deliver gene editors to the lung and mRNA vaccines to the spleen., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Diketopiperazine (DKP) derived cyclic amidine structures widely exist in peptide natural products according to the genome mining result. The largely unknown bioactivity and mode of action are partially caused by the poor availability of the compounds via microbiological and chemical approaches. To tackle this challenge, in this work, we have developed the on-resin ring-closing amidine formation strategy to synthesize peptides containing N-terminal DKP derived cyclic amidine structure, in which the 6-exo-trig cyclization mediated by HgCl 2 activation of thioamides was the key step. Leveraging from this new strategy, we finished the total syntheses of streptamidine and klebsazolicin. Meanwhile, eleven klebsazolicin analogues were synthesized for its structure-activity relationship study., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Lysine-specific peptide and protein modification strategies are widely used to study charge-related functions and applications. However, these strategies often result in the loss of the positive charge on lysine, significantly impacting the charge-related properties of proteins. Herein, we report a strategy to preserve the positive charge and selectively convert amines in lysine side chains to amidines using nitriles and hydroxylamine under aqueous conditions. Various unprotected peptides and proteins were successfully modified with a high conversion rate. Moreover, the reactive amidine moiety and derived modification site enable subsequent secondary modifications. Notably, positive charges were retained during the modification. Therefore, positive charge-related protein properties, such as liquid-liquid phase separation behaviour of α-synuclein, were not affected. This strategy was subsequently applied to a lysine rich protein to develop an amidine-containing coacervate DNA complex with outstanding mechanical properties. Overall, our innovative strategy provides a new avenue to explore the characteristics of positively charged proteins., (© 2024 Wiley-VCH GmbH.)

Background/aims: Endothelial cells (ECs) play a crucial role in various physiological processes, particularly those related to the cardiovascular system, but also those affecting the entire organism. The biology of ECs is regulated by multiple biochemical stimuli and epigenetic drivers that govern gene expression. We investigated the angiogenic potential of ECs from a protein citrullination perspective, regulated by peptidyl-arginine deiminases (PADs) that modify histone and non-histone proteins. Although the involvement of PADs has been demonstrated in several physiological processes, inflammation-related disorders and cancer, their role in angiogenesis remains unclear., Methods: To elucidate the role of PADs in endothelial angiogenesis, we used two human EC models: primary vein (HUVECs) and microvascular endothelial cells (HMEC-1). PADs activity was inhibited using irreversible inhibitors: BB-Cl-amidine, Cl-amidine and F-amidine. We analyzed all three steps of angiogenesis in vitro : proliferation, migration, and capillary-like tube formation, as well as secretory activities, gene expression and signaling in ECs., Results: All used PAD inhibitors reduced the histone H3 citrullination (H3cit) mark, inhibited endothelial cell migration and capillary-like tube formation, and favored an angiostatic activity in HMEC-1 cells, by increasing PEDF (pigment epithelium-derived factor) and reducing VEGF (vascular endothelial growth factor) mRNA expression and protein secretion. Additionally, BB-Cl-amidine reduced the total activity of MMPs (Matrix metalloproteinases). The observed effects were underlined by the inhibition of Akt phosphorylation.>., Conclusion: Our findings suggest that pharmacological inhibitors of citrullination are promising therapeutic agents to target angiogenesis., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Thioamides, amidines, and heterocycles are three classes of modifications that can act as peptide-bond isosteres to alter the peptide backbone. Thioimidate protecting groups can address many of the problematic synthetic issues surrounding installation of these groups. Historically, amidines have received little attention in peptides due to limitations in methods to access them. The first robust and general procedure for the introduction of amidines into peptide backbones exploits the utility of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. Further, amidines formed on-resin can be reacted to form (4H)-imidazolone heteorcycles which have recently been shown to act as cis-amide isosteres. General methods for heterocyclic installation capable of geometrically restricting peptide conformation are also under-developed. This work is significant because it describes a generally applicable and divergent approach to access unexplored peptide designs and architectures., (Copyright © 2024. Published by Elsevier Inc.)

Novel benzo[b]thienyl- and 2,2'-bithienyl-derived benzothiazoles and benzimidazoles were synthesized to study their antiproliferative and antitrypanosomal activities in vitro. Specifically, we assessed the impact that amidine group substitutions and the type of thiophene backbone have on biological activity. In general, the benzothiazole derivatives were more active than their benzimidazole analogs as both antiproliferative and antitrypanosomal agents. The 2,2'-bithienyl-substituted benzothiazoles with unsubstituted and 2-imidazolinyl amidine showed the most potent antitrypanosomal activity, and the greatest selectivity was observed for the benzimidazole derivatives bearing isopropyl, unsubstituted and 2-imidazolinyl amidine. The 2,2'-bithiophene derivatives showed most selective antiproliferative activity. Whereas the all 2,2'-bithienyl-substituted benzothiazoles were selectively active against lung carcinoma, the benzimidazoles were selective against cervical carcinoma cells. The compounds with an unsubstituted amidine group also produced strong antiproliferative effects. The more pronounced antiproliferative activity of the benzothiazole derivatives was attributed to different cytotoxicity mechanisms. Cell cycle analysis, and DNA binding experiments provide evidence that the benzimidazoles target DNA, whereas the benzothiazoles have a different cellular target because they are localized in the cytoplasm and do not interact with DNA., (© 2023 Wiley-VCH GmbH.)

Amidines are a structural surrogate for peptide bonds, yet have received considerably little attention in peptides due to limitations in existing methods to access them. The synthetic strategy developed in this study represents the first robust and general procedure for the introduction of amidines into the peptide backbone. We exploit and further develop the utility and efficiency of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. This work is significant because it describes a generally applicable path to access unexplored peptide designs and architectures for new therapeutics made possible by the unique properties of amidines.

Amidines are a ubiquitous class of bioactive compounds found in a wide variety of natural products; thus, efficient strategies for their preparation are in great demand. Specifically, their common structural core decorated with three substituents sets amidines as perfect candidates for multicomponent synthesis. Herein, we present a highly modular metal-free multicomponent strategy for the synthesis of sulfonyl amidines. This work was focused on selecting readily accessible reagents to facilitate the in situ formation of enamines by the addition of amines to ketones. These components were coupled with azides to provide a broad reaction scope with respect to all three coupling partners. Aromatic and aliphatic amines and ketones were tolerated under our reaction conditions. Likewise, the presence of a methyl group on the ketone was critical to reactivity, which was leveraged for the design of a highly regioselective reaction with aliphatic ketones. A biologically active compound was successfully synthesized in one step, demonstrating the practical utility of our methodology. Finally, the postulated mechanism was investigated and supported both experimentally and by means of a multivariate statistical model.

Allyl halides with triflamide under oxidative conditions form halogen-substituted amidines. Allyl cyanide reacts with triflamide in acetonitrile or THF solutions in the presence of NBS to give the products of bromotriflamidation with a solvent interception, whereas in CH 2 Cl 2 two regioisomers of the bromotriflamidation product without a solvent interception were obtained. The formed products undergo base-induced dehydrobromination to give linear isomers with the new C=C bond conjugated either with the nitrile group or the amidine moiety or alkoxy group. Under the same conditions, the reaction of allyl alcohol with triflamide gives rise to amidine, which was prepared earlier by the reaction of diallyl formal with triflamide. Unlike their iodo-substituted analogs, bromo-substituted amidines successfully transform into imidazolidines under the action of potassium carbonate.

The novel biocatalytic method for the synthesis of pharmaceutically relevant N-unsubstituted amidines was presented. The application of whole cells from commonly available vegetables allowed for the chemoselective reduction of the amidoxime moiety in the presence of other substituents prone to reduction or dehalogenation e.g. carbon-carbon double bond. Under optimized conditions several amidines were obtained with high yield up to 97% in aqueous medium at ambient temperature and atmospheric pressure. The practical potential of the newly developed method was shown in the preparative synthesis of anti-parasitic drug, phenamidine. Moreover, for the first time the enantioselective bioreduction of chiral racemic amidoximes to the corresponding amidines has been shown. The developed sustainable biocatalytic protocol fulfils the green chemistry rules and no application of metal catalysts meets the strict requirements of the pharmaceutical industry regarding metal contamination., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The goal of this study was the design and synthesis of bulky and polar-bulky galactonoamidines that have a potential to interact with both catalytic amino acids in the active site of human α-galactosidase. While a library of more than 25 compounds was previously synthesized following established protocols, the coupling of the selected amines with activated perbenzylated galactothionolactam yielded only small amounts for some of the perbenzylated targets. A computational approach disclosed relative energy differences of selected adducts and suggested a solvent change that then allowed a successful synthesis of the precursor compounds in 20-75%. Subsequent attempts to globally deprotect perbenzylated galactonoamidines by Pd catalyzed hydrogenation resulted in unwanted Pd coordination, incomplete debenzylation reactions, partial compound hydrolysis, and even complete decomposition. A lengthy protocol was elaborated to purify the targeted carbohydrate derivatives after modified debenzylation conditions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A common challenge for medicinal chemists is to reduce the pK a of strongly basic groups' conjugate acids into a range that preserves the desired effects, usually potency and/or solubility, but avoids undesired effects like high volume of distribution (V d ), limited membrane permeation, and off-target binding to, notably, the hERG channel and monoamine receptors. We faced this challenge with a 3,4,5,6-tetrahydropyridine-2-amine scaffold harboring an amidine, a key structural component of potential inhibitors of BACE1, the rate-limiting enzyme in the production of Aβ species that make up amyloid plaques in Alzheimer's disease. In our endeavor to balance potency with desirable properties to achieve brain penetration, we introduced a diverse set of groups in beta position of the amidine that modulate logD, PSA and pK a . Given the synthetic challenge to prepare these highly functionalized warheads, we first developed a design flow including predicted physicochemical parameters which allowed us to select only the most promising candidates for synthesis. For this we evaluated a set of commercial packages to predict physicochemical properties, which can guide medicinal chemists in their endeavors to modulate pK a values of amidine and amine bases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Glycosidases, the enzymes responsible for the breakdown of glycoconjugates, including di-, oligo- and polysaccharides, are present across all kingdoms of life. The extreme chemical stability of the glycosidic bond combined with the catalytic rates achieved by glycosidases makes them among the most proficient of all enzymes. Given their multitude of roles in vivo, inhibition of these enzymes is highly attractive with potential in the treatment of a vast array of pathologies ranging from lysosomal storage and diabetes to viral infections. Therefore great efforts have been invested in the last three decades to design and synthesize inhibitors of glycosidases leading to a number of drugs currently on the market. Amongst the vast array of structures that have been disclosed, sugars incorporating an amidine moiety have been the focus of many research groups around the world because of their glycosidase transition state-like structure. In this review, we report and discuss the structure, the inhibition profile, and the use of these molecules, including related structural congeners as transition state analogs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The electrophilic amination of nitrogen-based nucleophiles, including strong organic bases, was conducted in an Et 2 O solvent using O-(mesitylenesulfonyl)hydroxylamine. Aliphatic tert-amines and N,N,N'-(trialkyl)amidines rapidly formed precipitates of the corresponding aminated salts in high yields. The amination of the highly basic and sterically hindered N,N,N',N',N″-(pentaalkyl)guanidines was achieved under modified conditions, although the yields were moderate because of a competing side reaction caused by the acid-base equilibrium.

In the present work, a convenient and straightforward approach to the preparation of borylated amidines based on the closo -dodecaborate anion [B 12 H 11 NCCH 3 NHR]-, R=H, Alk, Ar was developed. This method has two stages. A nitrile derivative of the general form [B 12 H 11 NCCH 3 ] - was obtained, using a modified technique, in the first stage. On the second stage the resulting molecular system interacted with primary amines to form the target amidine products. This approach is characterised by a simple chemical apparatus, mild conditions and high yields of the final products. The mechanism of the addition of amine to the nitrile derivative of the closo -dodecaborate anion was studied, using quantum-chemical methods. The interaction between NH 3 and [B 12 H 11 NCCH 3 ] - ammonia was chosen as an example. It was found that the structure of the transition state determines the stereo-selectivity of the process. A study of the biological properties of borylated amidine sodium salts indicated that the substances had low toxicity and could accumulate in cancer cells in significant amounts.

A series of 6-amidinobenzothiazoles, linked via phenoxymethylene or directly to the 1,2,3-triazole ring with a p -substituted phenyl or benzyl moiety, were synthesised and evaluated in vitro against four human tumour cell lines and the protozoan parasite Trypanosoma brucei . The influence of the type of amidino substituent and phenoxymethylene linker on antiproliferative and antitrypanosomal activities was observed, showing that the imidazoline moiety had a major impact on both activities. Benzothiazole imidazoline 14a , which was directly connected to N -1-phenyl-1,2,3-triazole, had the most potent growth-inhibitory effect (IC 50 = 0.25 µM) on colorectal adenocarcinoma (SW620), while benzothiazole imidazoline 11b , containing a phenoxymethylene linker, exhibited the best antitrypanosomal potency (IC 90 = 0.12 µM). DNA binding assays showed a non-covalent interaction of 6-amidinobenzothiazole ligands, indicating both minor groove binding and intercalation modes of DNA interaction. Our findings encourage further development of novel structurally related 6-amidino-2-arylbenzothiazoles to obtain more selective anticancer and anti-HAT agents.

A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

The interaction of acetamidine and phenylamidine with peri-R-ethynyl-9,10-anthraquinones in refluxing n-butanol leads to the formation of cascade transformations products: addition/elimination/cyclization-2-R-7 H -dibenzo[ de , h ]quinolin-7-ones and(or) 2-R-3-aroyl-7 H -dibenzo[ de , h ]quinolin-7-ones. The anti-inflammatory and antitumor properties of the new 2-R-7H-dibenzo[ de,h ]quinolin-7-ones were investigated in vivo, in vitro, and in silico. The synthesized compounds exhibit high anti-inflammatory activity at dose 20 mg/kg (intraperitoneal injection) in the models of exudative (histamine-induced) and immunogenic (concanavalin A-induced) inflammation. Molecular docking data demonstrate that quinolinones can potentially intercalate into DNA similarly to the antitumor drug doxorubicin.

Immunomodulating enzyme IDO1 plays an important role in tumor immune resistance. Inhibiting IDO1 by small molecules with new mechanism of action is a potential strategy in IDO1 inhibitor development. Based on our urea derived compound originally binding with holo-IDO1, through scaffold hopping, a series of diisobutylaminophenyl hydroxyamidine compounds were designed. Unexpectedly, this novel class of IDO1 inhibitor does not target the holo form of IDO1 protein but displaces heme and binds to its apo form. Representative compound I-4 exhibits moderate potency with IC 50 value of 0.44 μM in cell-based IDO1 assay, which has the potential to be developed for IDO1-related cancer treatment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Dicationic diamidines have been well established as potent antiparasitic agents with proven activity against tropical diseases like trypanosomiasis and malaria. This work presents the synthesis of new mono and diflexible triaryl amidines (6a-c, 13a,b and 17), their aza analogues (23 and 27) and respective methoxyamidine prodrugs (5, 7, 12a,b, 22 and 26). All diamidines were assessed in vitro against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) where they displayed potent to moderate activities at the nanomolar level with IC 50 s = 11-378 nM for T. b. r. and 4-323 nM against P. f.. In vivo efficacy testing against T. b. r. STIB900 has shown the monoflexible diamidine 6c as the most potent derivative in this study eliciting 4/4 cures of infected mice for a treatment period of >60 days upon a 4 × 5 mg/kg dose i. p. treatment. Moreover, thermal melting analysis measurement ΔT m for this series of diamidines/poly (dA-dT) complexes fell between 0.5 and 19 °C with 6c showing the highest binding to the DNA minor groove. Finally, a 50 ns molecular dynamics study of an AT-rich DNA dodecamer with compound 6c revealed a strong binding complex supported by vdW and electrostatic interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Advances in supramolecular chemistry are often underpinned by the development of fundamental building blocks and methods enabling their interconversion. In this work, we report the use of an underexplored dynamic covalent reaction for the synthesis of stimuli-responsive [2]rotaxanes. The formamidinium moiety lies at the heart of these mechanically interlocked architectures, because it enables both dynamic covalent exchange and the binding of simple crown ethers. We demonstrated that the rotaxane self-assembly follows a unique reaction pathway and that the complex interplay between crown ether and thread can be controlled in a transient fashion by addition of base and fuel acid. Dynamic combinatorial libraries, when exposed to diverse nucleophiles, revealed a profound stabilizing effect of the mechanical bond as well as intriguing reactivity differences between seemingly similar [2]rotaxanes.

Peptidylarginine deiminase type III (PAD3) is an isozyme belonging to the PAD enzyme family that converts arginine to citrulline residue(s) within proteins. PAD3 is expressed in most differentiated keratinocytes of the epidermis and hair follicles, while S100A3, trichohyalin, and filaggrin are its principal substrates. In this study, the X-ray crystal structures of PAD3 in six states, including its complex with the PAD inhibitor Cl-amidine, were determined. This structural analysis identified a large space around Gly374 in the PAD3-Ca 2+ -Cl-amidine complex, which may be used to develop novel PAD3-selective inhibitors. In addition, similarities between PAD3 and PAD4 were found based on the investigation of PAD4 reactivity with S100A3 in vitro. A comparison of the structures of PAD1, PAD2, PAD3, and PAD4 implied that the flexibility of the structures around the active site may lead to different substrate selectivity among these PAD isozymes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

G-quadruplex (G4) DNA structures are widespread in the human genome and are implicated in biologically important processes such as telomere maintenance, gene regulation, and DNA replication. Guanine-rich sequences with potential to form G4 structures are prevalent in the promoter regions of oncogenes, and G4 sites are now considered as attractive targets for anticancer therapies. However, there are very few reports of small "druglike" optical G4 reporters that are easily accessible through one-step synthesis and that are capable of discriminating between different G4 topologies. Here, we present a small water-soluble light-up fluorescent probe that features a minimalistic amidinocoumarin-based molecular scaffold that selectively targets parallel G4 structures over antiparallel and non-G4 structures. We showed that this biocompatible ligand is able to selectively stabilize the G4 template resulting in slower DNA synthesis. By tracking individual DNA molecules, we demonstrated that the G4-stabilizing ligand perturbs DNA replication in cancer cells, resulting in decreased cell viability. Moreover, the fast-cellular entry of the probe enabled detection of nucleolar G4 structures in living cells. Finally, insights gained from the structure-activity relationships of the probe suggest the basis for the recognition of parallel G4s, opening up new avenues for the design of new biocompatible G4-specific small molecules for G4-driven theranostic applications.

In search of new Nitric Oxide Synthase (NOS) inhibitor agents, two isosteric series of derivatives with an imidamide scaffold (one of them with a hydroxyl group and the other with a carbonyl one) were synthesized and evaluated on inducible (iNOS) and neuronal (nNOS) isoforms. These compounds have been designed by combining a kynurenamine framework with an amidine moiety in order to improve selectivity for the inducible isoform. In general, the in vitro inhibitory assays exhibited better inhibition values on the iNOS isoform, being the N-(3-(2-amino-5-methoxyphenyl)-3-hydroxypropyl)-4-(trifluoromethyl)benzimidamide 4i the most active inhibitor with the highest iNOS selectivity, without inhibiting eNOS. Docking studies on the two most active compounds suggest a different binding mode on both isozymes, supporting the experimentally observed selectivity towards the inducible isoform. Physicochemical in silico studies suggest that these compounds possess good drug-likeness properties., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

1- and 1,5-Aminoalkylamine substituted anthraquinones (AAQs, 1C3 and 1,5C3) were peptide coupled to 1-, 2-, and 3-pyrrole lexitropsins to generate compounds that incorporated both DNA minor groove and intercalating moieties. The corresponding platinum(II) amidine complexes were synthesized through a synthetically facile amine-to-platinum mediated nitrile 'Click' reaction. The precursors as well as the corresponding platinum(II) complexes were biologically evaluated in 2D monolayer cells and 3D tumour cell models. Despite having cellular accumulation levels that were up to five-fold lower than that of cisplatin, the platinum complexes had cytotoxicities that were only three-fold lower. Accumulation was lowest for the complexes with two or three pyrrole groups, but the latter was the most active of the complexes exceeding the activity of cisplatin in the MDA-MB-231 cell line. All compounds showed moderate to good penetration into spheroids of DLD-1 cells with the distributions being consistent with active uptake of the pyrrole containing complexes in regions of the spheroids starved of nutrients.

A method for the enantio- and chemoselective iridium-catalyzed O -allylation of oximes is described. Kinetic resolution in an intramolecular setting provides enantioenriched oxime ethers and aliphatic allylic alcohols. The synthetic potential of the products generated with this method is showcased by their elaboration into a series of heterocyclic compounds and the formal synthesis of glycoprotein GP IIb-IIIa receptor antagonist (-)-roxifiban. Preliminary mechanistic experiments and computational data shed light on the remarkable chemoselectivity of the reaction.

Unlike the closely related and widely investigated amidino-substituted benzimidazoles and benzothiazoles with a range of demonstrated biological activities, the matching benzoxazole analogues still remain a largely understudied and not systematically evaluated class of compounds. To address this challenge, we utilized the Pinner reaction to convert isomeric cyano-substituted 2-aminophenols into their amidine derivatives, which were isolated as hydrochlorides and/or zwitterions, and whose structure was confirmed by single crystal X-ray diffraction. The key step during the Pinner synthesis of the crucial carboximidate intermediates was characterized through mechanistic DFT calculations, with the obtained kinetic and thermodynamic parameters indicating full agreement with the experimental observations. The obtained amidines were subjected to a condensation reaction with aryl carboxylic acids that allowed the synthesis of a new library of 5- and 6-amidino substituted 2-arylbenzoxazoles. Their antiproliferative features against four human tumour cell lines (SW620, HepG2, CFPAC-1, HeLa) revealed sub-micromolar activities on SW620 for several cyclic amidino 2-naphthyl benzoxazoles, thus demonstrating the usefulness of the proposed synthetic strategy and promoting amidino substituted 2-aminophenols as important building blocks towards biologically active systems.

3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains of Plasmodium falciparum (with IC 50 values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in the Plasmodium berghei mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in P. falciparum .

A novel polysaccharide (MFP1P) was isolated from Fructus Mori, followed by purification via DEAE-52 cellulose and 27 % ethanol fraction. The MFP1P had the molecular weight of 56.78 kDa and the total sugar content of 93.32±0.54 %. And the MFP1P is mainly composed of glucose, galactose, galacturonic acid and mannose with molar ratio of 66.62 %, 13.94 %, 18.24 % and 1.20 %, respectively. MFP1P was mainly composed of →3)-α-D-Gal (1→, β-D-Man-(1→ and →6)-α-D-Glc (1→ glycosidic bond and showed a spherical chain conformation with uniform distribution in solution. The MFP1P exhibited great antioxidant activity with oxygen-free radical absorption capacity (ORAC) values of 291.63±6.81 μmol TE/g and MDA IC 50 of 0.289±0.022 mg/mL., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Current therapeutic approaches to osteoporosis display some potential adverse effects and a limited efficacy on non-vertebral fracture reduction. Some sulfonylamidines targeting the scaffold proteins prohibitins-1 and 2 (PHB1/2) have been showed to inhibit the formation of osteoclasts in charge of bone resorption. Herein, we report the development of a second generation of anti-osteoclastic PHB ligands. The most potent compound, IN45, showed 88% inhibition at the low concentration of 5 μM, indicates that it might serve as a basis for the development of new antiosteoporotic drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Dextran-formamidine esters (dextran-N-[(dimethylamino)methylene]-β-alanine ester) with different degrees of substitution (0.45-0.92) are synthesized in an one-pot reaction. Dextran (Mw 60 000 g mol -1 ) is allowed to react with unprotected beta-alanine and iminium chloride and investigated regarding the potential as gene delivery system for the transfer of plasmid DNA. With degrees of substitution ≥ 0.63 improved DNA binding with formation of enzymatically stable complexes of about 130-160 nm with negative surface charges are obtained. These physicochemical characteristics correlated with increasing transfection rates in CHO-K1 cells determined by a luciferase reporter gene assay in dependency of the number of formamidine residues, N/P ratios and amount of DNA. The role of the number of formamidine groups is also highlighted by in vitro cyto- and hemotoxicity tests under the chosen conditions. These results indicate that dextran-formamidine esters are a very promising material for the safe and efficient gene delivery., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

The amidine functionality switches between hydrogen bond donor and acceptor roles depending on pH. Herein, the amidine was incorporated to select amides in cyclo(d-Ala-Pro-d-Phe-Pro-Gly). The unprotonated amidine-containing macrocyclic conformation resembles its oxoamide counterpart. Upon protonation, minimal alterations in the macrocyclic conformation were observed despite changes to the hydrogen bond network. The amidine disrupts hydrogen bonding at minimal steric cost, making it a useful functionality to study the effect of hydrogen bonding on the macrocyclic conformation.

Under different pathological conditions, aberrant induction of neuronal nitric oxide synthase (nNOS) generates overproduction of NO that can cause irreversible cell damage. The aim of this study was to develop an amidoxime prodrug of a potent nNOS inhibitor, the benzhydryl acetamidine. We synthesized the benzhydryl acetamidoxime, which was evaluated in vitro to ascertain the potential NOS inhibitory activity, as well as conducting bioconversion into the parent acetamidine. The prodrug was also profiled for in vitro physicochemical properties, by determining the lipophilicity, passive permeation through the human gastrointestinal tract and across the blood-brain barrier by PAMPA, and chemical, enzymatic, and plasma stability. The obtained data demonstrate that the amidoxime prodrug shows an improved pharmacokinetic profile with respect to the acetamidine nNOS inhibitor, thus suggesting that it could be a promising lead compound to treat all those pathological conditions in which nNOS activity is dysregulated., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

Hydroxycinnamic acids represent a versatile group of dietary plant antioxidants. Oxidation of methyl- p -coumarate ( pcm ) and methyl caffeate ( cm ) was previously found to yield potent antitumor metabolites. Here, we report the formation of potentially bioactive products of pcm and cm oxidized with peroxynitrite (ONOO¯), a biologically relevant reactive nitrogen species (RNS), or with α,α'-azodiisobutyramidine dihydrochloride (AAPH) as a chemical model for reactive oxygen species (ROS). A continuous flow system was developed to achieve reproducible in situ ONOO¯ formation. Reaction mixtures were tested for their cytotoxic effect on HeLa, SiHa, MCF-7 and MDA-MB-231 cells. The reaction of pcm with ONOO¯ produced two fragments, an o-nitrophenol derivative, and a new chlorinated compound. Bioactivity-guided isolation from the reaction mixture of cm with AAPH produced two dimerization products, including a dihydrobenzofuran lignan that exerted strong antitumor activity in vitro, and has potent in vivo antimetastatic activity which was previously reported. This compound was also detected from the reaction between cm and ONOO¯. Our results demonstrate the ROS/RNS dependent formation of chemically stable metabolites, including a potent antitumor agent ( 5 ), from hydroxycinnamic acids. This suggests that diversity-oriented synthesis using ROS/RNS to obtain oxidized antioxidant metabolite mixtures may serve as a valid natural product-based drug discovery strategy.

We report an alternative approach to the unnatural nucleobase fragment seen in remdesivir (Veklury). Remdesivir displays broad-spectrum antiviral activity and is currently being evaluated in Phase III clinical trials to treat patients with COVID-19. Our route relies on the formation of a cyanoamidine intermediate, which undergoes Lewis acid-mediated cyclization to yield the desired nucleobase. The approach is strategically distinct from prior routes and could further enable the synthesis of remdesivir and other small-molecule therapeutics.

We had observed in our previous study that the active fucoidan (JHCF4), isolated from the crude fucoidan in acid-processed Hizikia fusiforme, possessed an anticancer effect. In this study, the antioxidant effect of JHCF4 was evaluated. Among the fractions, JHCF4 showed the highest scavenging activity against 2, 2-diphenyl-1-picrylhydrazyl (DPPH), alkyl, and hydroxyl radicals, as well as protective effect against reactive oxygen species (ROS) in 2, 2'-azobis (2-amidinopropane) dihydrochloride (AAPH)-treated Vero cells. Furthermore, JHCF4 showed a protective activity against AAPH-induced apoptosis, as observed by nuclear staining with Hoechst 33342. Our results showed that JHCF4 can up-regulate Bcl-xL, down-regulate Bax and cleave caspase-3 with increased concentrations in AAPH-induced Vero cells. JHCF4 induced anti-apoptosis via a mitochondria-mediated pathway. Additionally, JHCF4 was selected for further in vivo screening in a zebrafish model, which markedly decreased ROS generation and lipid peroxidation. Thus, JHCF4 showed a potential protective activity against AAPH-induced ROS both in vitro and in the zebrafish model., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

l-glutamate is an excitatory neurotransmitter in the central nervous system (CNS), which can activate ionotropic receptors (iGluRs) and metabotropic (mGluRs) receptors. N-methyl-D-aspartate (NMDA) receptor is a ligand-gated ion channel belonging to the iGluRs family. Among NMDA receptor subtypes, GluN2B subtype plays a crucial role in CNS diseases. In this review, we summarize, classify and discuss the reports on GluN2B antagonists, published from the 1990s to 2020, to provide the therapeutic potential of GluN2B antagonists on various disorders. The GluN2B antagonists are broadly classified into two categories, which are prototypical antagonists and atypical antagonists. And the latter are further divided into amidine derivatives, 4-aminoquinolines, indole derivatives, benzimidazole derivatives, oxamide derivatives, carbamate derivatives, EVT-101 analogues, 1H-pyrrolo[3,2-b]pyridine derivatives, benzazepin derivatives, other heterocyles and radiotracers. This review will provide a comprehensive description including structure, structure-activity relationship (SAR), and pharmacology of novel GluN2B-subtype selective NMDA antagonists to the medicinal chemists, which would be helpful in rational designing effective drugs aimed toward related CNS disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Sodium cyanoborohydride-derived N -alkylnitriliumboranes were found to be versatile precursors for the synthesis of novel boron-containing heterocycles. The reaction between N -alkylnitriliumboranes and 2-aminopyridines, imidazoles, oxazoles, or isoxazoles leads to the incorporation of the [B-C] motif into a five-membered boramidine, which exists as a mixture of Z and E isomers. The resulting heterocycles are blue fluorescent in both the solid state and in solution with ca. 2700-8400 cm -1 Stokes shifts and quantum yields in the 65-74% range in water and in the 42-84% range in organic solvents. The combination of photophysical properties, structural tunability, stability, and solubility in various media is expected to find application in a range of disciplines.

Neurodegenerative diseases are associated with increased levels of nitric oxide (NO) mainly produced by microglial cells through inducible nitric oxide synthase (iNOS) whose expression is induced by inflammatory stimuli. NO can both exert cytotoxic functions and induce a metabolic switch by inhibiting oxidative phosphorylation and upregulating glycolytic flux. Here, we investigated whether two newly synthesized acetamidine based iNOS inhibitors, namely CM292 and CM544, could inhibit lipopolysaccharide (LPS)-induced BV2 microglial cell activation, focusing on both inflammatory and metabolic profiles. We found that CM292 and CM544, without affecting iNOS protein expression, reduced NO production and reverted LPS-induced inflammatory and cytotoxic response. Furthermore, in the presence of the inflammatory stimulus, both the inhibitors increased the expression of glycolytic enzymes. In particular, CM292 significantly reduced nuclear accumulation of pyruvate kinase M2, increased mitochondrial membrane potential and oxygen consumption rate, and augmented the expression of pyruvate dehydrogenase, pointing to a metabolic switch toward oxidative phosphorylation. These data confirm the role played by NO in the connection between cell bioenergetics profile and inflammation, and suggest the potential usefulness of iNOS inhibitors in redirecting microglia from detrimental to pro-regenerative phenotype.

Aldehyde is one of most synthetically versatile functional groups and can participate in numerous chemical transformations. While a variety of simple aromatic aldehydes are commercially available, those with a more complex substitution pattern are often difficult to obtain. Benzylic oxygenation of methylarenes is a highly attractive method for aldehyde synthesis as the starting materials are easy to obtain and handle. However, regioselective oxidation of functionalized methylarenes, especially those that contain heterocyclic moieties, to aromatic aldehydes remains a significant challenge. Here we show an efficient electrochemical method that achieves site-selective electrooxidation of methyl benzoheterocycles to aromatic acetals without using chemical oxidants or transition-metal catalysts. The acetals can be converted to the corresponding aldehydes through hydrolysis in one-pot or in a separate step. The synthetic utility of our method is highlighted by its application to the efficient preparation of the antihypertensive drug telmisartan.

The majority of current drugs against diseases, such as cancer, can bind to one or more sites in a protein and inhibit its activity. There are, however, well-known limits on the number of druggable proteins, and complementary current drugs with compounds that could selectively target DNA or RNA would greatly enhance the availability of cellular probes and therapeutic progress. We are focusing on the design of sequence-specific DNA minor groove binders that, for example, target the promoter sites of transcription factors involved in a disease. We have started with AT-specific minor groove binders that are known to enter human cells and have entered clinical trials. To broaden the sequence-specific recognition of these compounds, several modules that have H-bond acceptors that strongly and specifically recognize G·C base pairs were identified. A lead module is a thiophene- N -alkyl-benzimidazole σ-hole-based system with terminal phenyl-amidines that have excellent affinity and selectivity for a G·C base pair in the minor groove. Efforts are now focused on optimizing this module. In this work, we are evaluating modifications to the compound aromatic system with the goal of improving GC selectivity and affinity. The lead compounds retain the thiophene- N -alkyl-BI module but have halogen substituents adjacent to an amidine group on the terminal phenyl-amidine. The optimum compounds must have strong affinity and specificity with a residence time of at least 100 s.

Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. l-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five- or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors., (© 2019 Wiley Periodicals, Inc.)

Indoleamine 2,3-dioxygenase 1 (IDO1) is closely associated with immune escape in many tumor tissues, and is considered to be a valuable therapeutic target in cancer immunotherapy. In this study, the modification of amino sidechain was performed with the hydroxyamidine core kept intact to optimize lead compound Epacadostat. 19 new compounds with hydrazide, thietane or sulfonamide moiety as polar capping group in sidechain were prepared and their IDO1 inhibitory activities were evaluated. Sulfonamide 3a showed potent IDO1 inhibition in both enzymatic and cellular assays with the IC 50 value of 71 nM and EC 50 value of 11 nM, respectively. Furthermore, in vivo Lewis lung cancer (LLC) allograft studies of 3a indicated that it handicapped the tumor growth with similar efficacy to Epacadostat. Molecular docking demonstrated that the change of polar capping group affords influence on the orientation of amino ethylene side chain and forms new hydrogen bonding., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A general approach is proposed to large scale synthesize tadpole-like composite Janus nanoparticles (JNPs). Within the head of a starting JNP achieved by electrostatic-mediated intramolecular crosslinking, a free radical initiator is incorporated. By polymerizing vinyl monomers within the head nanoreactor, the composition and performance of the JNPs are broadly tunable.

A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. The results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the dissolution environment and PEO molecular weight., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The sphingosine-1-phosphate (S1P) signaling pathway is an attractive drug target due to its involvement in immune cell chemotaxis and vascular integrity. The formation of S1P is catalyzed by sphingosine kinase 1 or 2 (SphK1 or SphK2) from sphingosine (Sph) and ATP. Inhibition of SphK1 and SphK2 to attenuate levels of S1P has been reported to be efficacious in animal models of diseases such as cancer, sickle cell disease, and renal fibrosis. While inhibitors of both SphKs have been reported, improvements in potency and selectivity are still needed. Toward that end, we performed structure-activity relationship profiling of 8 (SLM6031434) and discovered a heretofore unrecognized side cavity that increased inhibitor potency toward SphK2. Interrogating this region revealed that relatively small hydrophobic moieties are preferred, with 10 being the most potent SphK2-selective inhibitor ( K i = 89 nM, 73-fold SphK2-selective) with validated in vivo activity.

In recent years, flexible perovskite solar cells have drawn tremendous attention in the field of wearable devices, and optimization of perovskite composition plays an important role in improving film quality and photophysical properties. At present, some researchers have only studied A-site organic cations mixing or X-site halide anions mixing in the ABX 3 structure of perovskite, but there are few reports on co-mixing of A-site and X-site ions in flexible perovskite solar cells. In this paper, we mainly try to study the effects of different concentrations of mixed formamidine methylamine halide (FA x MA 1-x Br x Cl y I 1-x-y ) precursor solutions on the quality and photophysical properties of perovskite films under low temperature process. We conclude that the film quality and photophysical properties reached the best results when the optimized precursor solution concentration was 60:6:6. The investigation on composition optimization in this experiment laid the foundation for the improvement of the performance of flexible perovskite solar cells. We also use the results of this experiment to prepare flexible perovskite solar cells based on carbon electrodes, which are expected to be applied in other flexible optoelectronic or electro-optical devices.

Aim and Objective: Platinum (II) and platinum (IV) of pyrophosphate complexes have been prepared and characterized to discover their potential as antitumor drugs. This study was conducted to prepare and characterize new ternary platinum (II) complexes with formamidine and pyrophosphate as an antitumor candidate., Materials and Methods: The complexes have been characterized by mass, infrared, UV-Vis. spectroscopy, elemental analysis, magnetic susceptibility, thermal analyses, and theoretical calculations. They have been tested for their cytotoxicity, which was carried out using the fastcolorimetric assay for cellular growth and survival against MCF-7 (breast cancer cell line), HCT- 116 (colon carcinoma cell line), and HepG-2 (hepatocellular cancer cell line)., Results: All complexes are diamagnetic, and the electronic spectral data displayed the bands due to square planar Pt(II) complexes. The optimized complexes structures (1-4) indicated a distorted square planar geometry where O-Pt-O and N-Pt-N bond angles were 82.04°-96.44°, respectively. Results also show that all complexes are neutral, stable and non-hygroscopic and have noticeable cytotoxicity with IC50 (μM): 0.035-0.144 MCF-7(breast cancer cell line), 0.042-0.187 HCT-116 (colon carcinoma cell line), and 0.063-0.168 HepG-2 (hepatocellular cancer cell line). Moreover, the results show that the complex (4) has the best IC50 value., Conclusion: The complexes showed noticeable cytotoxicity and are considered as promising antitumor candidates for further applications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Depsipeptides are biologically active peptide derivatives that possess a high therapeutic interest. The development of depsipeptide mimics characterized by a chemical diversity could lead to compounds with enhanced features and activity. In this work, an on-resin multicomponent procedure for the synthesis of amidino depsipeptide mimics is described. This approach exploits a metal-free 1,3-dipolar cycloaddition of cyclopentanone-proline enamines and sulfonylazides. In this reaction, the obtained primary cycloadduct undergoes a ring opening and molecular rearrangement giving access to a linear sulfonyl amidine functionalized with both a peptide chain and a diazoalkane. The so-obtained diazo function "one pot" reacts with the carboxylic group of N-Fmoc-protected amino acids leading to amidino depsipeptide mimics possessing a C4 aliphatic chain. An important advantage of this procedure is the possibility to easily obtain amidino-functionalized derivatives that are proteolytically stable peptide bond bioisosteres. Moreover, the conformational freedom given by the alkyl chain could promote the obtainment of cyclic depsipeptide with a stabilized secondary structure as demonstrated with both in silico calculations and experimental conformational studies. Finally, labeled depsipeptide mimics can be also synthesized using a fluorescent sulfonylazide in the multicomponent reaction.

Rocaglates share a common cyclopenta[b]benzofuran core that inhibits eukaryotic translation initiation by modifying the behavior of the RNA helicase, eIF4A. Working as interfacial inhibitors, rocaglates stabilize the association between eIF4A and RNA, which can lead to the formation of steric barriers that block initiating ribosomes. There is significant interest in the development and expansion of rocaglate derivatives, as several members of this family have been shown to possess potent anti-neoplastic activity in vitro and in vivo. To further our understanding of rocaglate diversity and drug design, herein we explore the RNA clamping activity of >200 unique rocaglate derivatives. Through this, we report on the identification and characterization of a potent class of synthetic rocaglates called amidino-rocaglates. These compounds are among the most potent rocaglates documented to date and, taken together, this work offers important information that will guide the future design of rocaglates with improved biological properties., (Copyright © 2019 Elsevier Ltd. All rights reserved.)