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Background: Peptides and peptide-based therapeutics are biomolecules that demarcate a significant chemical space to bridge small molecules with biological therapeutics, such as antibodies, recombinant proteins, and protein domains. Introduction: Cyclooligopeptides and depsipeptides, particularly cyanobacteria-derived thiazoline-based polypeptides (CTBCs), exhibit a wide array of pharmacological activities due to their unique structural features and interesting bioactions, which furnish them as promising leads for drug discovery. Methods: In the present study, we comprehensively review the natural sources, distinguishing chemistries, and pertinent bioprofiles of CTBCs. We analyze their structural peculiarities counting the mode of actions for biological portrayals which render CTBCs as indispensable sources for emergence of prospective peptide-based therapeutics. In this milieu, metal organic frameworks and their biomedical applications are also briefly discussed. To boot, the challenges, approaches, and clinical status of peptide-based therapeutics are conferred. Results: Based on these analyses, CTBCs can be appraised as ideal drug targets that have always remained a challenge for traditional small molecules, like those involved in protein- protein interactions or to be developed as potential cancer-targeting nanomaterials. Cyclization-induced reduced conformational freedom of these cyclooligopeptides contribute to improved metabolic stability and binding affinity to their molecular targets. Clinical success of several cyclic peptides provokes the large library-screening and synthesis of natural product-like cyclic peptides to address the unmet medical needs. Conclusion: CTBCs can be considered as the most promising lead compounds for drug discovery. Adopting the amalgamation of advanced biological and biopharmaceutical strategies might endure these cyclopeptides to be prospective biomolecules for futuristic therapeutic applications in the coming times.

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

The structural and functional characterization of natural products is vastly outpaced by the bioinformatic identification of biosynthetic gene clusters (BGCs) that encode such molecules. Uniting our knowledge of bioinformatics and enzymology to predict and synthetically access natural products is an effective platform for investigating cryptic/silent BGCs. We report the identification, biosynthesis, and total synthesis of a minimalistic class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with the responsible BGCs encoding a subset of enzymes known from thiopeptide biosynthesis. On the basis of the BGC content, these RiPPs were predicted to undergo enzymatic dehydration of serine followed by [4+2]-cycloaddition to produce a trisubstituted, pyridine-based macrocycle. These RiPPs, termed "pyritides", thus contain the same six-membered, nitrogenous heterocycle that defines the thiopeptide RiPP class but lack the ubiquitous thiazole/thiazoline heterocycles, suggesting that thiopeptides should be reclassified as a more elaborate subclass of the pyritides. One pyritide product was obtained using an 11-step synthesis, and the structure verified by an orthogonal chemoenzymatic route using the precursor peptide and cognate pyridine synthase. This work exemplifies complementary bioinformatics, enzymology, and synthesis to characterize a minimalistic yet structurally intriguing scaffold that, unlike most thiopeptides, lacks growth-suppressive activity toward Gram-positive bacteria.

Cyclic peptides are excellent drug candidates, placing macrocyclization reactions at the apex of drug development. PatG and related dual-action proteases from cyanobactin biosynthesis are responsible for cleaving off the C-terminal recognition sequence and macrocyclizing the substrate to provide cyclic peptides. This reaction has found use in the enzymatic synthesis of diverse macrocycles. However, these enzymes function best on substrates that terminate with the non-proteinogenic thiazole/thiazoline residue, complicating synthetic strategies. Here, we biochemically characterize a new class of PatG-like macrocyclases that natively use proline, obviating the necessity of additional chemical or biochemical steps. We experimentally define the biochemical steps involved in synthesizing the widespread prenylagaramide-like natural products, including macrocyclization and prenylation. Using saturation mutagenesis, we show that macrocyclase PagG and prenyltransferase PagF are highly promiscuous, producing a library of more than 100 cyclic peptides and their prenylated derivatives in vitro. By comparing our results to known cyanobactin macrocyclase enzymes, we catalog a series of enzymes that collectively should synthesize most small macrocycles. Collectively, these data reveal that, by selecting the right cyanobactin macrocyclase, a large array of enzymatically synthesized macrocycles are accessible.

An operationally simple and efficient one-pot protocol for the synthesis of highly functionalized thiazolidin-4-ones and thiazolines has been devised via Rh(OAc)2-catalyzed annulative coupling of β-ketothioamides with diazo compounds under mild reaction conditions for the first time. This double functionalization of diazo compounds proceeds via selective S-alkylation followed by intramolecular N-cyclization enabling the formation of C-S and C-N bonds at moderate temperature. Notably, the products possess Z-stereochemistry with regard to the exocyclic C═C double bond at the 2-position of the ring. Further, the synthetic utility of the strategy has been revealed to access 2,3-dihydrobenzo[d]thiazoles. Remarkably, atom economy and tolerance of a wide range of functional groups are added characteristics to this strategy.

A series of novel sulfur-containing cycliclipopeptides named thioamycolamides A-E, with thiazoline, thioether rings, and fatty acid moieties, were identified from the culture broth of the rare actinomycete Amycolatopsis sp. 26-4. The planar structural elucidation was accomplished by HRMS and 1D/2D NMR spectroscopic data analyses. The absolute configurations were unambiguously determined by Marfey's method, CD spectroscopy, and synthesis of partial structures. Moreover, their growth inhibitory activities against human tumor cell lines were investigated.

This review provides a generalized and systematized analysis of literature data from the last 15 years regarding the methods of synthesis and properties of bi- and tricyclic assemblies constructed from 1,3-thiazolidine/thiazoline rings that are linked by an exocyclic С=С double bond. Examples of such assemblies which are of interest as biologically active compounds, sensitizing dyes for solar cells, and semiconductors are considered in details. The literature data have been arranged according to the types of chemical structures.

Iron(III) phthalocyaninate decorated with crown ether substituents, [(15C5)4PcFe]Cl, efficiently catalyzed the insertion of carbene derived from ethyl diazoacetate to six amines functionalized with thiazole, thiazoline and thiadiazole heterocycles. The reactions were carried out under practical conditions using EDA:amine stoechiometric ratio with 0.05 mol% catalyst loading. Turnover numbers up to 3360 have been achieved. The aminoacid derivatives bearing heterocyclic moieties were obtained under catalytic conditions for the first time with 36–69% yields in the case of single N–H insertion products and up to 77% in the case of double N–H insertion products.

Thioamycolamide A is a biosynthetically unique cytotoxic cyclic microbial lipopeptide that bears a d-configured thiazoline, a thioether bridge, a fatty acid side chain, and a reduced C-terminus. Based on the biosynthetic insights, a concise total synthesis of thioamycolamide A was accomplished.

The synthesis, reactivity, spectroscopic characterization and catalytic activities of a series of Pd(II) complexes bearing the chelating ligands 2-(4,5-dihydrothiazol-2-yl)aniline (2) and 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (3) are reported. The reactions of 2 with [Pd(COD)Cl2] in 1:1 and 1:2 (ligand into metal and metal into ligand) molar ratios afforded the mononuclear complexes, PdCl2{κ2−N,S − 2−(4,5-dihydrothiazol-2-yl)aniline} (4), Pd{κ2−N,N’−2−(4,5-dihydrothiazol-2-yl)aniline}2 (5) and Pd{κ12−N,N’−κ22−N,S − 2−(4,5-dihydrothiazol-2-yl)aniline}2 (6), respectively, in good yields. The neutral mononuclear palladium complexes PdCl2{κ2−N,N’−(4,5-dihydro-1H-imidazol-2-yl)aniline} (7) and Pd{κ2−N,N’−2−(4,5-dihydro-1H-imidazol-2-yl)aniline}2 (8) were synthesized using [Pd(COD)Cl2] with appropriate molar ratios. The palladium complexes 4–8 were evaluated for their catalytic activities in base assisted cross coupling reactions between acid chlorides and aryl halide with boronic acids. The complex 4 was found to be an efficient catalyst for producing unsymmetrical ketones (TOF = 19.8 min−1) while complex 7 was effective for making biaryls (TOF = 19.8 min−1).

The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin (VG) is used to treat type 2 diabetes. In rare cases, VG-induced liver injury has been reported. One case report suggested that immune responses were involved in the hepatotoxicity. However, the underlying mechanisms of VG-induced hepatotoxicity are uncertain. In the present study, we investigated whether VG has the potential to covalently bind to macromolecules in cells, a process that could initiate immune-mediated hepatotoxicity. For comparison, M20.7, a major metabolite of VG, and other DPP-4 inhibitors were also evaluated. We found that VG and anagliptin (ANG), which both contain a cyanopyrrolidine moiety, rapidly reacted in non-enzymatic manners on co-incubation with l -cysteine. Both VG and ANG had half-lives of 20–30 min. In contrast, incubation with GSH, rather than l -cysteine, failed to decrease the concentrations of VG or ANG. M20.7, sitagliptin, linagliptin, and alogliptin, having no cyanopyrrolidine moiety, were stable on incubation with l -cysteine or GSH. Structural analysis of the VG– and ANG–cysteine adducts, designated M407 and M487, respectively, revealed that the nitrile moieties of VG and ANG were irreversibly converted to a thiazoline acid. In conclusion, we found that VG and ANG have the potential to covalently bind to a thiol residue of l -cysteine in proteins. Such binding may lead to unpredictable immune responses in humans. l -Cysteine, rather than GSH, would likely be useful to detect the potential for covalent binding that could initiate immune-mediated hepatotoxicity.

The convergent and enantioselective synthesis of a highly potent human peroxisome proliferator-activated receptor delta agonist is presented. More specifically, the thiazoline structure, which constitutes the biosynthetically distinctive core structure of pulicatin (a secondary metabolite of symbiotic bacteria), was synthesized from a commercially available and inexpensive chiral pool of l-threonine.

The YcaO superfamily of proteins catalyzes the phosphorylation of peptide backbone amide bonds, which leads to the formation of azolines and azoles in ribosomally synthesized and post-translationally modified peptides (RiPPs). Bottromycins are RiPPs with potent antimicrobial activity, and their biosynthetic pathway contains two divergent, stand-alone YcaO enzymes, IpoC and PurCD. From an untargeted metabolomics approach, it had been suggested that PurCD acts with a partner protein to form the 12-membered macroamidine unique to bottromycins. Here we report the biochemical characterization of IpoC and PurCD. We demonstrate that IpoC installs a cysteine-derived thiazoline, whereas PurCD alone is sufficient to create the macroamidine structure. Both enzymes are catalytically promiscuous, and we generated 10 different macroamidines. Our data provide important insights into the versatility of YcaO enzymes, their ability to utilize different nucleophiles and provide a framework for the creation of novel bottromycin derivatives with enhanced bioactivity.

Peroxisome proliferator-activated receptor delta (PPARδ) is considered as a promising biological target for the development of new drugs to treat metabolic syndrome including hyperlipidemia. In this study, a simple and efficient method for the preparation of a unique dimethyl thiazoline containing intermediate (13) of new PPARδ agonists as GW501516 analogue is described. The intermediate 13 was readily obtained by coupling reaction of 4-(chloromethyl)-5,5-dimethyl-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrothiazole (11) with 4-mercapto-2-methylphenol (12) in the presence of tetrabutylammonium hydrogensulfate (TBAHS) and Cs2CO3 in DMF at 80 °C for 1 h. This unique intermediate could be useful for the synthesis of various novel PPARδ agonists to understand the structural and biological significance of PPARδ.

As part of our ongoing studies related with the coordination chemistry of 2-thiazoline derivatives with transition ions, we report the synthesis of a new class of structurally novel complexes containing in their structures a 2-aminobenzimidazole ring. The resulting compound, 2-(2-aminobenzimidazole-1-yl)-2-thiazoline (BzTn), and two cobalt(II) complexes have been structurally characterized by means of physical measurements. The crystal structures of BzTn, [CoCl2(BzTn)2] (1) and [CoBr2(BzTn)2] (2) have been determined by single crystal X-ray diffraction. In both Co(II) complexes, BzTn acts as a monodentate ligand through nitrogen atom of benzimidazole ring. The distorted tetrahedral environmental around the Co(II) ions is completed with two halide ions. Besides that, the newly synthesized compounds were screened for their antimicrobial activity against 6 strains of bacteria: S. aureus, E. coli, S. epidermidis. B. subtilis, E. faecalis y P. aeruginosa.

Endo-β-N-acetylglucosaminidases are a class of endoglycosidases that deglycosylate N-glycans from glycoproteins. We describe here a facile synthesis of a complex type N-glycan thiazoline as a new mechanism-based inhibitor for this class of enzymes. The synthesis started with the readily available sialoglycopeptide (SGP) and its conversion into the glycan thiazoline through several enzymatic and chemical reactions. The synthetic glycan thiazoline showed potent inhibitory activity against several endoglycosidases including the two antibody-deactivating enzymes, Endo-S and Endo-S2, from human pathogen Streptococcus pyogenes, which would be useful as tools for structural and functional studies of these enzymes.

We have demonstrated design, synthesis, and biological evaluation of apratoxin A mimetics. In the first generation, the moCys moiety was replaced with seven simple amino acids as their 3D structures can be similar to that of apratoxin A. Apratoxins M1-M7 were synthesized using solid-phase peptide synthesis and solution-phase macrolactamization. Apratoxin M7, which contains a piperidinecarboxylic acid moiety, exhibited potent cytotoxicity against HCT-116 cells. In the second generation, substitution of each amino acid residue in the tripeptide Tyr(Me)-MeAla-MeIle moiety in apratoxin M7 led to the development of the highly potent apratoxin M16 possessing biphenylalanine (Bph) instead of Tyr(Me), which exhibited an IC50 value of 1.1 nM against HCT-116 cells. Moreover, compared to apratoxin A, apratoxin M16 exhibited a similarly high level of growth inhibitory activity against various cancer cell lines. The results indicate that apratoxin M16 could be a potential candidate as an anticancer agent.

Macrocyclic peptides have promising therapeutic potential but the scaling up of their chemical synthesis is challenging. The cyanobactin macrocyclase PatGmac is an efficient tool for production but is limited to substrates containing 6–11 amino acids and at least one thiazoline or proline. Here we report a new cyanobactin macrocyclase that can cyclize longer peptide substrates and those not containing proline/thiazoline and thus allows exploring a wider chemical diversity.

Nonribosomal peptide synthetases (NRPSs) are a family of multidomain, multimodule enzymes that synthesize structurally and functionally diverse peptides, many of which are of great therapeutic or commercial value. The central chemical step of peptide synthesis is amide bond formation, which is typically catalyzed by the condensation (C) domain. In many NRPS modules, the C domain is replaced by the heterocyclization (Cy) domain, a homologous domain that performs two consecutive reactions by using hitherto unknown catalytic mechanisms. It first catalyzes amide bond formation, and then the intramolecular cyclodehydration between a Cys, Ser, or Thr side chain and the backbone carbonyl carbon to form a thiazoline, oxazoline, or methyloxazoline ring. The rings are important for the form and function of the peptide product. We present the crystal structure of an NRPS Cy domain, Cy2 of bacillamide synthetase, at a resolution of 2.3 Å. Despite sharing the same fold, the active sites of C and Cy domains have important differences. The structure allowed us to probe the roles of active-site residues by using mutational analyses in a peptide synthesis assay with intact bacillamide synthetase. The drastically different effects of these mutants, interpreted by using our structural and bioinformatic results, provide insight into the catalytic mechanisms of the Cy domain and implicate a previously unexamined Asp-Thr dyad in catalysis of the cyclodehydration reaction.

A sponge-derived Brevibacillus sp. TP-B0800 produces new polycyclic thiazoline derivatives designated ulbactins F and G which possess inhibitory activity against tumor cell migration. To elucidate the biosynthetic pathway of ulbactins, we read the genome sequence of this strain. The genome harbors six gene clusters related to nonribosomal peptides, one of which was identified to be responsible for ulbactin biosynthesis. We propose the putative ulbactin-biosynthetic pathway based on bioinformatics analysis. The genome information reported here also suggested potential of this strain to produce edeine, tyrocidin, and unidentified secondary metabolites.

The ribosomally synthesized and post-translationally modified peptide (RiPP) bottromycin A2 possesses potent antimicrobial activity. Its biosynthesis involves the enzymatic formation of a macroamidine, a process previously suggested to require the concerted efforts of a YcaO enzyme (PurCD) and an amidohydrolase (PurAH) in vivo. In vitro, PurCD alone is sufficient to catalyze formation of the macroamidine, but the process is reversible. We set out to probe the role of PurAH in macroamidine formation in vitro. We demonstrate that PurAH is highly selective for macroamidine-containing precursor peptides and cleaves C-terminal of a thiazoline, thus removing the follower peptide. After follower cleavage, macroamidine formation is irreversible, indicating PurAH as the gatekeeper of bottromycin biosynthesis. The structure of PurAH suggests residues involved in catalysis, which were probed through mutagenesis.

A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-α-methylcysteine makes the molecule more amenable to chemical synthesis and, coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.

Human O-GlcNAcase (GH 84) and human β-N-acetyl-D-hexosaminidase (GH 20) from Homo sapiens are two therapeutic enzyme targets that share the same catalytic mechanism but play different physiological roles in vivo. Selective inhibition toward one of these enzymes is therefore of importance to regulate the corresponding bioprocess. Here ten new NAM-thiazoline derivatives were synthesized and subsequently characterized by NMR and HRMS. A preliminary bioassay showed that most of the synthesized compounds exhibited obvious selective inhibition against human O-GlcNAcase over human β-N-acetyl-D-hexosaminidase. Among the compounds tested, compound 7d (IC50 = 6.4 µM, hOGA; IC50>1 mM, hHex) and 7f (IC50 = 11.9 µM, hOGA; IC50>1 mM, hHex) proved to be a highly selective and potent inhibitor. Structure-activity relationship analysis indicated a correlation between the inhibitory activity and the size of the groups linked to the thiazoline ring.

Piano-stool ([(p-cymene)Ru(thz)Cl], 2) and six-coordinated ([Ru(thz)2(PPh3)2], 3) ruthenium complexes derived from 2-phenylthiazoline-4-carboxylic acid (Hthz, 1) were synthesized for the first time, and fully characterized using conventional methods. Also, the molecular structure of complex 3 was determined using X-ray analysis. These complexes were evaluated as catalysts for transfer hydrogenation of carbonyl compounds in the presence of isopropyl alcohol and KOtBu. Complex 2 was found to be more active than 3 in transfer hydrogenation. Copyright © 2016 John Wiley & Sons, Ltd.

An efficient metal-free synthesis of thiazolines, dihydrothiazole and enureas or thioureas from methyl enol ether with urea or thiourea derivatives in the presence of TFA (trifluoroacetic acid) are reported here. This synthetic protocol involves the formation of two bonds, C–N as well as C–S, in one step for the synthesis of thiazoline derivatives, dihydrothiazoles and a direct C–N bond for the synthesis of enamides with good to excellent yields. Further, this method was employed for the synthesis of wilsoniamine B alkaloid.

The five-membered nitrogen plus heteroatom rings known as azolines or in their oxidized form as azoles are very common in natural products and drugs. The oxidation of thiazoline to thiazole in the cyanobactin class of natural products is one of the several important transformations that are known to alter the biological properties of the compound. The ordering of the various chemical reactions that occur during cyanobactin biosynthesis is not fully understood. The structure of the flavin-dependent enzyme responsible for the oxidation of multiple thiazolines reveals it contains an additional domain that in other enzymes recognizes linear peptides. We characterize the activity of the enzyme on two substrates: one with a peptide leader and one without. Kinetics and biophysics reveal that the leader on the substrate is not recognized by the enzyme. The enzyme is faster on either substrate than the macrocyclase or protease in vitro. The enzyme has a preferred order of oxidation of multiple thiazolines in the same linear peptide. Postprint

The New Delhi metallo-β-lactamase (NDM-1) is an important clinical target for antimicrobial research, but there are insufficient clinically useful inhibitors and the details of NDM-1 enzyme catalysis remain unclear. The aim of this work is to provide a thermodynamic profile of NDM-1 catalysed hydrolysis of β-lactams using an isothermal titration calorimetry (ITC) approach and to apply this new method to the identification of new low-molecular-weight dicarboxylic acid inhibitors. The results reveal that hydrolysis of penicillin G and imipenem by NDM-1 share the same thermodynamic features with a significant intrinsic enthalpy change and the release of one proton into solution, while NDM-1 hydrolysis of cefazolin exhibits a different mechanism with a smaller enthalpy change and the release of two protons. The inhibitory constants of four carboxylic acids are found to be in the micromolar range. The compounds pyridine-2,6-dicarboxylic acid and thiazolidine-2,4-dicarboxylic acid show the best inhibitory potency and are confirmed to inhibit NDM-1 using a clinical strain of Escherichia coli. The pyridine compound is further shown to restore the susceptibility of this E. coli strain to imipenem, at an inhibitor concentration of 400 μM, while the thiazoline compound also shows a synergistic effect with imipenem. These results provide valuable information to enrich current understanding on the catalytic mechanism of NDM-1 and to aid the future optimisation of β-lactamase inhibitors based on these scaffolds to tackle the problem of antibiotic resistance.

Cell active inhibitors of glycoside processing enzymes are valuable research tools that help us understand the physiological roles of this diverse class of enzymes. endo-N-Acetylglucosaminidases have gained increased attention for their important roles in both mammals and human pathogens; however, metabolically stable cell active inhibitors of these enzymes are lacking. Here, we describe a divergent synthetic strategy involving elaboration of a thiazoline core scaffold. We illustrate the potential of this approach by using the copper catalysed azide-alkyne click (CuAAC) reaction, in combination with a suitable catalyst to avoid poisoning by the thiazoline moiety, to generate a targeted panel of candidate inhibitors of endo-N-acetylglucosaminidases and chitinases.

The bottromycins belong to the ribosomally synthesized and posttranslationally modified peptide (RiPP) family of natural products. Bottromycins exhibit unique structural features, including a hallmark macrolactamidine ring and thiazole heterocycle for which divergent members of the YcaO superfamily have been biosynthetically implicated. Here we report the in vitro reconstitution of two YcaO proteins, BmbD and BmbE, responsible for the ATP-dependent cyclodehydration reactions that yield thiazoline- and macrolactamidine-functionalized products, respectively. We also establish the substrate tolerance for BmbD and BmbE and systematically dissect the role of the follower peptide, which we show serves a purpose similar to canonical leader peptides in directing the biosynthetic enzymes to the substrate. Lastly, we leverage the expanded capabilities of YcaO proteins to conduct an extensive bioinformatic survey to classify known YcaO chemistry. This analysis predicts new functions remain to be uncovered within the superfamily.

Ethyl 1-aminofuro(thieno)[2,3-b]pyridine-2-carboxylates 1 reacted with benzoyl isothiocyanate and gave the relevant thioureido derivatives 2, whose intramolecular cyclization under the action of potassium hydroxide furnished the relevant 9(10)-thioxopyrido[3′,2′:4,5]furo(thieno)[3,2-d]pyrimidin-7(8)-ones 3. Compounds 3 with methyl iodide could give the S-methyl 4 and S,N-dimethyl 5 derivatives. Interestingly 3 by alkylation with alkyl dichlorides (bifunctional reagents) the cyclization to a thiazoline or to a thiazine ring on the [a] side of the pyrimidine ring occurs, with formation of the new pentacyclic systems: furo(thieno)[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-7(8)-ones 6 and furo(thieno)[3′,2′:4,5]pyrimido[2,1-b][1,3]thiazin-7(8)-ones 7. Moreover compounds 3 by alkylation with p-chlorophenacyl bromide (again a bifunctional reagent) led to the formation of the corresponding S-alkylated compounds 9, whose cyclization furnished structural analogues of compounds 6: p-chlorophenyl-substituted thiazolo[3,2-a]pyrimidin-7(8)-ones 10. The structure of the obtained compounds has been unambiguously confirmed by using a wide spectrum of physico-chemical methods and, in the instance of compounds 6 and 7, also by an alternative synthesis via a double-annelation reaction using a BMMA reagent. Biological tests have shown promising antimicrobial activity against Staphylococcus aureus for some of the synthesized compounds.

We thank G. Mann and Dr. A. Bent, for supplying the enzymes and the useful discussions, and Dr. T. Lebl for the useful NMR discussions. This work was supported by the European Research Council (339367), UK Biotechnology and Biological Sciences Research Council (K015508/1), the Wellcome Trust (TripleTOF 5600 mass spectrometer (094476), the MALDI TOF- TOF Analyser (079272AIA), 700 NMR) and the EPSRC UK National Mass Spectrometry Facility at Swansea University. J.H.N. is a Royal Society Wolfson Merit Award Holder and 1000 talent scholar at Sichuan University. JHN, MAJ and NJW are named on patents that have been filed by St Andrews and Aberdeen University to commercialize the enzymes (PatG) and (LynD) used in the study. No income derives from the patent. Natural products comprise a diverse array of molecules many of which are biologically active. Most natural products derive from combinations of polyketides, peptides, sugars and fatty acid building blocks. Peptidic macrocycles have attracted attention as potential therapeutics possessing cell permeability, stability and easy to control variability. Here we show that enzymes from the patellamide biosynthetic pathway can be harnessed to make macrocycles that are hybrids of amino acids and a variety of man- made chemical building blocks, including aryl rings, polyethers and alkyl chains. We have made macrocycles with only three amino acids, one of which can be converted to a thiazoline or a thiazole ring. We report the synthesis of 18 peptide hybrid macrocycles, 9 of which have been isolated and fully characterized. Publisher PDF

The aim of the work. Synthesis of new non-condenced pyridine-thiazole/thiazolidinones and study of their antitrypanosomal activity in vitro. Materials and Methods. All starting materials were purchased from commercial sourses and used without purification. The 1 H and 13 C NMR spectra were recorded on a Varian Gemini 400-MHz and Varian Mercury-400 100 MHz instruments. LC-MS spectra were obtained on a Agilent 1100 Series LCMS. Melting points are uncorrected and were measured in open capillary tubes on a BUCHI B-545 melting point apparatus. Results and Discussion. Series of thiazole, thiazoline and 5-substituted 4-thiazolidinones containing pyridine fragment were synthesized using reactions of [2+3]-cyclocondensations. Thiosemicarbazones of 3- and 4-peridinecarbaldehyses as S,N-binucleophiles and some equivalents of dielectrophilic synthone [C 2 ] 2 + ( α -halogen-carboxylic acids, ethyl-2-chloroacetoacetate, methyl-2-bromo-3-(3methylphenyl)propionate and maleimides) were used. Antitrypanosomal activity screening in vitro on the Trypanosoma brucei gambiense strain allowed to identify highly active non-condensed furan-pyridine-thiazoline derivative with trypanocide effect in micromolar concentrations (IC 50 = 3.32 mM), and 5-ethyl-2-(pirydynilmethylenhidrazyne)thiazol-4-ones with promising activity for further optimization. Conclusions. New non-condensed pyridine-thiazole/thiazolidinones as promising drugs for pharmacotherapy of sleeping sickness were obtained.

Sugars with heteroatoms other than oxygen have attained considerable importance in glycobiology and in drug design since they are often more stable in blood plasma due to their resistance to enzymes, such as glycosidases, phosphorylases and glycosyltransferases. The replacement of oxygen atoms in sugars with sulfur forms thio-sugars, which are potentially useful for the treatment of diabetes and some bacterial and viral infections. Here, we evaluated the antibacterial activity of thio-functionalized carbohydrate derivatives. A set of 21 compounds was screened against acid-fast Mycobacterium tuberculosis (Mtb), gram-negative Escherichia coli and gram-positive Staphylococcus aureus. The tested carbohydrate derivatives were most effective against tubercle bacilli, with as many as five compounds (thioglycoside 6, thiosemicarbazone 16A, thiosemicarbazone 20, aminothiadiazole 23, and thiazoline 26) inhibiting its growth with MIC50 ≤ 50 µM/CFU. Only two compounds (aminothiadiazole 23 and thiazoline 26) were able to inhibit the growth of E. coli at concentrations below 1 mM, and one of them, aminothiadiazole 23, inhibited the growth of S. aureus at a concentration ≤1 mM. The five compounds affecting the growth of mycobacteria were either thiodisaccharides (6, 16A, and 20) or thioglycosides (23 and 26). All of these compounds (6, 16A, 20, 23, and 26) were able to inhibit the growth of Mtb deposited within human macrophages. However, three of the five selected compounds (6, 23, and 26) exhibited relatively high cytotoxicity in mouse fibroblasts at micromolar concentrations. The selected thio-sugars are very promising compounds, thus making them candidates for further modifications that would decrease their cytotoxicity against eukaryotic cells without affecting their antimycobacterial potential.

A convenient synthesis of a privileged pharmaceutical motif, thiazoline is accomplished. This reaction utilizes simple and readily available alkene and thioamide substrates in an intermolecular fashion via a simple one-pot procedure. A wide range of functional groups is tolerated, and the thiazoline product has been further utilized for the synthesis of the corresponding β-aminothiol and thiazole from routine hydrolysis and oxidation protocols.

A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.1 mM-23.9 mM). A docking study using the crystal structure of human liver Glycogen Phosphorylase, provided insight into the interactions of heterocycles 5, 7, 9-13 and 19 with Glycogen Phosphorylase.

A series of bipyrazoles functionalized with sulfonamide, N(1),N(3)-disubstituted sulfonylurea, sulfonylthiourea pharmacophores, and some derived thiazolidinone and thiazoline ring systems were synthesized. The structures of the newly synthesized compounds were substantiated by analytical and diverse spectroscopic data. The anti-inflammatory and antioxidant activity of some of the newly synthesized compounds were tested and the results reveled that compounds 14, 16, 20, 24 and 25 proved to be the most active anti-inflammatory agents according to the Carrageenan-induced rat paw edema bioassay. Whereas, the analogs 14, 16 and 24 were able to exhibit good to moderate antioxidant activity in the DPPH radical-scavenging assay. Hence, compounds 14, 16 and 24 can be considered as lead structures for dual anti-inflammatory and antioxidant activities.

WOS: 000333780800025, PubMed ID: 24480358, N'-(3,4-Diarylthiazol-2(3H)-ylidene)-2-(arylthio)acetohydrazides were synthesized and evaluated for their antimicrobial activity and cytotoxicity against NIH/3T3 cells. Compound 22 bearing 1-phenyl-1H-tetrazole and p-chlorophenyl moieties was found to be the most promising antibacterial agent against Pseudomonas aeruginosa, whereas compound 23 bearing 1-phenyl-1H-tetrazole and p-bromophenyl moieties was the most promising antifungal agent against Candida albicans. The most effective derivatives were also evaluated for their cytotoxicity against C6 glioma cells. The results indicated that compound 17 bearing 1-phenyl-1H-tetrazole and nonsubstituted phenyl moieties (IC50 = 8.3 +/- 2.6 mu g/mL) was more effective than cisplatin (IC50 = 13.7 +/- 1.2 mu g/mL) against C6 glioma cells. Compound 17 also exhibited DNA synthesis inhibitory activity on C6 cells. Furthermore, compound 17 showed low toxicity to NIH/3T3 cells (IC50 = 416.7 +/- 28.9 mu g/mL), Anadolu University Scientific Research Projects Commission [1105S087], This study was supported by Anadolu University Scientific Research Projects Commission under the grant no: 1105S087.

An approach to the synthesis of modified methyl ether-protected dimethyloxyluciferin derivatives is presented, focusing on the enlargement of the π-system. This was achieved by introducing an alkene bridge at the 4-position of the thiazoline moiety to link the two chromophoric substructures. The resulting derivatives show strong absorbing properties over a wide range of the visible spectrum. Also, the fluorescence properties of these novel dimethyl­oxyluciferin derivatives are unique and might lead to new photophysical studies and bioanalytical applications.

A procedure is reported for the introduction of both the thiazoline and (E)-dehydrobutyrine components into a tetrapeptide-derived fragment of vioprolides B and D. The (E)-dehydrobutyrine is introduced first but, as the carbon–carbon double-bond of the dehydrobutyrine appeared incompatible with an adjacent thiol, the thiazoline was assembled by dehydration of a serine containing thioamide not by dehydration of a cysteinyl analogue.

Two new structurally unique compounds bearing a nitrogen- and sulfur-containing tricyclic ring system, ulbactin F (1) and its diastereomeric isomer ulbactin G (2), were isolated from the culture extract of a sponge-derived Brevibacillus sp. The structures and absolute configurations of 1 and 2 were determined by NMR analysis and X-ray crystallographic analysis. These compounds inhibit the migration of tumor cells in the submicromolar to micromolar range.

Two new structurally unique compounds bearing a nitrogen- and sulfur-containing tricyclic ring system, ulbactin F (1) and its diastereomeric isomer ulbactin G (2), were isolated from the culture extract of a sponge-derived Brevibacillus sp. The structures and absolute configurations of 1 and 2 were determined by NMR analysis and X-ray crystallographic analysis. These compounds inhibit the migration of tumor cells in the submicromolar to micromolar range.

Ethyl 1-aminofuro(thieno)[2,3-b]pyridine-2-carboxylates 1 reacted with benzoyl isothiocyanate and gave the relevant thioureido derivatives 2, whose intramolecular cyclization under the action of potassium hydroxide furnished the relevant 9(10)-thioxopyrido[3′,2′:4,5]furo(thieno)[3,2-d]pyrimidin-7(8)-ones 3. Compounds 3 with methyl iodide could give the S-methyl 4 and S,N-dimethyl 5 derivatives. Interestingly 3 by alkylation with alkyl dichlorides (bifunctional reagents) the cyclization to a thiazoline or to a thiazine ring on the [a] side of the pyrimidine ring occurs, with formation of the new pentacyclic systems: furo(thieno)[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-7(8)-ones 6 and furo(thieno)[3′,2′:4,5]pyrimido[2,1-b][1,3]thiazin-7(8)-ones 7. Moreover compounds 3 by alkylation with p-chlorophenacyl bromide (again a bifunctional reagent) led to the formation of the corresponding S-alkylated compounds 9, whose cyclization furnished structural analogues of compounds 6: p-chlorophenyl-substituted thiazolo[3,2-a]pyrimidin-7(8)-ones 10. The structure of the obtained compounds has been unambiguously confirmed by using a wide spectrum of physico-chemical methods and, in the instance of compounds 6 and 7, also by an alternative synthesis via a double-annelation reaction using a BMMA reagent. Biological tests have shown promising antimicrobial activity against Staphylococcus aureus for some of the synthesized compounds.

The thiazolinyl imine reductase from Yersinia enterocolitica (Irp3) catalyzes the NADPH-dependent reduction of a thiazoline ring in an intermediate for the formation of the siderophore yersiniabactin. Two structures of Irp3 were determined in the apo (1.85 A) and NADP(+)-bound (2.31 A) forms. Irp3 is structurally homologous to sugar oxidoreductases such as glucose-fructose oxidoreductase and 1,5-anhydro-d-fructose reductase, as well as to biliverdin reductase. A homology model of the thiazolinyl imine reductase from Pseudomonas aeruginosa (PchG) was generated. Extensive loop insertions are observed in the C-terminal domain that are unique to Irp3 and PchG and not found in the structural homologues that recognize small molecular substrates. These loops are hypothesized to be important for binding of the nonribosomal peptide synthetase modules (found in HMWP1 and PchF, respectively) to which the substrate of the reductase is covalently attached. A catalytic mechanism for the donation of a proton from a general acid (either histidine 101 or tyrosine 128) and the donation of a hydride from C4 of nicotinamide of the NADPH cofactor is proposed for reduction of the carbon-nitrogen double bond of the thiazoline.

Pseudomonas sp. F12 isolated from soil could transform dl-2-amino-Δ2-thiazoline-4-carboxylic acid (DL-ATC) to l-cysteine. It could grow in minimal medium containing DL-ATC as the sole carbon and nitrogen source, and the apparent activity of l-cysteine synthesis (CS) achieved 122 U/mL in a 5-L bioreactor. Pseudomonas sp. F12 could utilize glucose as carbon source and ammonia as nitrogen source for growth, but no CS activity was formed. To reduce the cost of DL-ATC, the cultivation process was divided into a growth stage on glucose and ammonia and a production stage induced by DL-ATC. The excessive glucose led to the production of byproduct(s) which seriously inhibited cell growth and CS production. Ammonium was accumulated when DL-ATC was consumed, and ammonium did not inhibit CS activity formation until 60 mM. Based on the above features, fed-batch cultivation of the growth stage was developed by supplying glucose restrictively. The volumetric CS activity was enhanced more than two times that obtained under the initial conditions.

A concise and efficient one-pot four-step synthesis of 2,4-disubstituted thiazoline via a cascade disulfide bond cleavage/thiocarbonylation/Staudinger reduction/aza-Wittig reaction is established. Treatment of various carboxylic acids with β-azido disulfides under this one-pot procedure obtained the desired thiazolines in good to excellent isolated yields.

The ligands N-(diphenylphosphino)-thiazoline-2-amine (1), N-(diphenylphosphino)thiazol-2-amine (2) and N-(diphenylphosphino)-1,3,4-thiadiazol-2-amine 3, readily reacted with [AuCl(THT)] in dichloromethane to form the linearly coordinated complexes [AuCl(1-κP)] (5), [AuCl(2-κP)] (6) and [AuCl(3-κP)] (7), respectively. Facile deprotonation with t-BuOK or Na2CO3 of 5–7 afforded the stable, neutral dinuclear complexes [AuCl(1—H-κP,κN)]2 (8), [AuCl(2—H-κP,κN)]2 (9) and [AuCl(3—H-κP,κN)]2 (10), respectively. The crystal structures of the mononuclear complexes 5, 6 and 7 and of the dinuclear complexes 8, 9 and 10 have been determined by X-ray diffraction. The latter represent rare examples of neutral complexes supported by bridging P,N-ligands which display intramolecular Au(I)···Au(I) d10–d10 interactions, in the range 2.8592(4)–2.8831(4) A.

The enantiopure non-natural amino acids 1 have been synthesized by insitu generation of iminium and iminium triflates from lactams using triflic anhydride in pyridine buffered media. These molecules with remote chiral centers may be useful in synthesis of natural product particularly Kopsia derived alkaloids.

The peptide antibiotic bacitracin is widely used as an inhibitor of protein disulfide isomerase (PDI) to demonstrate the role of the protein-folding catalyst in a variety of molecular pathways. Commercial bacitracin is a mixture of at least 22 structurally related peptides. The inhibitory activity of individual bacitracin analogs on PDI is unknown. For the present study, we purified the major bacitracin analogs, A, B, H, and F, and tested their ability to inhibit the reductive activity of PDI by use of an insulin aggregation assay. All analogs inhibited PDI, but the activity (IC(50) ) ranged from 20 μm for bacitracin F to 1050 μm for bacitracin B. The mechanism of PDI inhibition by bacitracin is unknown. Here, we show, by MALDI-TOF/TOF MS, a direct interaction of bacitracin with PDI, involving disulfide bond formation between an open thiol form of the bacitracin thiazoline ring and cysteines in the substrate-binding domain of PDI.