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PubMed2004

Macrocyclic diacylglycerol-bis-lactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C.

A series of macrocyclic diacylglycerol (DAG)-bis-lactones were investigated as extreme conformationally constrained analogues of DAG-lactones in order to seek more potent protein kinase C (PKC) ligands with higher binding affinities and less lipophilicity than previous compounds. The additional constraint achieved the desired objective as exemplified by the macrocyclic DAG-bis-lactone 57, which exhibited a 6-fold higher binding affinity for PKCalpha (K(i) = 6.07 nM) than the corresponding nonmacrocyclic 3-alkylidene DAG-lactone 6. A structure-activity relationship (SAR) analysis of the macrocyclic DAG-bis-lactones demonstrated a parabolic relationship between activity and lipophilicity, as well as a predilection for the Z-alkylidene isomers as the preferred ligands. Molecular docking studies revealed that macrocyclic DAG-bis-lactone 57 bound to the C1b domain of PKCalpha exclusively in the sn-1 binding mode in contrast to DAG-lactone 6, which showed both sn-1 and sn-2 binding modes. It is proposed that the high potency displayed by these macrocyclic DAG-bis-lactones results from a set of more favorable hydrogen bonding and hydrophobic interactions with PKCalpha as well as from a reduced entropy penalty due to conformational restriction.

Diglycerides↗

PubMed2004

Shape-persistent macrocycles with intraannular polar groups: synthesis, liquid crystallinity, and 2D organization.

The synthesis of macrocycles with intraannular polar ester groups and extraannular oligo-alkyl groups is described. The compounds exhibit stable liquid crystalline phases showing fan-shaped textures under the polarizing microscope, typical for a columnar order of the molecules. X-ray powder diffraction data of the LC phase indicate that the unit cell contains two symmetry-related units, a feature pointing most probably to a restricted rotation of the macrocycles within a stack. The X-ray data were further supported by solid-state NMR experiments, showing that the rigid core of the compounds does not rotate with kHz or higher frequencies within the column in the LC phase. Apart from the organization of the molecules in the LC phase, the 2D organization of the macrocycles at the solvent-highly oriented pyrolytic graphite (HOPG) interface was investigated and showed that these compounds are capable of nanofunctionalizing the HOPG surface in the multinanometer regime.

Journal Article↗

PubMed2006

Parasite field study in central Kentucky on thoroughbred foals (born in 2004) treated with pyrantel tartrate daily and other parasiticides periodically.

Foals (79), born in 2004 on three thoroughbred horse farms (C, M, and S) in central Kentucky, were fed pyrantel tartrate daily, beginning at about 3 months of age. In addition, other parasiticides [fenbendazole (FBZ), ivermectin (IVM) alone or with praziquantel (PRAZ), oxibendazole (OBZ), pyrantel pamoate (PRT), and moxidectin (MOX)] were given periodically. All treatments were administered by farm personnel. Over a 14-month period, from May 2004 to July 2005, collections (n=989) of feces were made from the foals for determination of presence of internal parasite eggs/oocysts by qualitative and/or quantitative methods. Conclusions on drug activity are based necessarily on considering the combined effect of pyrantel tartrate and the other compounds. For small strongyles, this was related to which specific additional compound was given. Based on the percentage of foals with strongyle-egg-positive feces and/or the level of eggs per gram of feces (EPG) counts for the foals after treatment, drug activity on small strongyles was highest to lowest for MOX, IVM and IVM/PRAZ, FBZ, OBZ, PRT, and FBZ (2x for 5 days). The macrocyclic lactones (MOX and IVM) were highly superior to the other compounds. Some of the strongyle counts were high (over 2,000), especially on one farm (S), during periods when foals received only pyrantel tartrate, but a few days after administration of therapeutic dose rates of the drugs IVM or MOX, they were negative or very low. Ascarid eggs were present in feces of three foals after treatment with a combination of IVM and PRAZ. The qualitative method was more efficient than the quantitative method in detection of ascarid and strongyle eggs in the feces. Prevalence of eggs of ascarids (Parascaris equorum) was low (0, 4, and 31%), of strongyles high (80, 100, and 100%), of Strongyloides westeri very low (only one infected foal), and oocysts of Eimeria leuckarti medium to high (36, 41, and 85%) for the three farms, C, M, and S, respectively. It is uncertain whether the low ascarid prevalence was from activity of pyrantel tartrate and/or the other drugs or to a limited source of infective eggs.

Animals↗

PubMedDate not supplied

Synthesis and cellular studies of porphyrin-cobaltacarborane conjugates.

The total syntheses of five new porphyrin-cobaltacarborane conjugates (1-5) have been achieved in 88-98% yields in a single-step reaction between a nucleophilic meso-pyridyl-containing porphyrin and zwitterionic cobaltacarborane [3,3'-Co(8-C(4)H(8)O(2)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))]. These unique zwitterionic compounds have one to four cobaltabisdicarbollide anions conjugated to the porphyrin macrocycle via (CH(2)CH(2)O)(2) chains. The X-ray structure of one of these conjugates (1) is presented and discussed. The cellular uptake, cytotoxicity, and subcellular localization of cobaltacarboraneporphyrins 1-5 were investigated in human HEp2 cells. The number and distribution of cobaltacarborane residues linked to the porphyrin macrocycle has a significant effect on the cellular uptake of the conjugates.

Boranes↗

PubMed2003

A convergent solution-phase synthesis of the macrocycle Ac-Phe-[Orn-Pro-D-Cha-Trp-Arg], a potent new antiinflammatory drug.

Relatively few cyclic peptides have reached the pharmaceutical marketplace during the past decade, most produced through fermentation rather than made synthetically. Generally, this class of compounds is synthesized for research purposes on milligram scales by solid-phase methods, but if the potential of macrocyclic peptidomimetics is to be realized, low-cost larger scale solution-phase syntheses need to be devised and optimized to provide sufficient quantities for preclinical, clinical, and commercial uses. Here, we describe a cheap, medium-scale, solution-phase synthesis of the first reported highly potent, selective, and orally active antagonist of the human C5a receptor. This compound, Ac-Phe[Orn-Pro-d-Cha-Trp-Arg], known as 3D53, is a macrocyclic peptidomimetic of the human plasma protein C5a and displays excellent antiinflammatory activity in numerous animal models of human disease. In a convergent approach, two tripeptide fragments Ac-Phe-Orn(Boc)-Pro-OH and H-d-Cha-Trp(For)-Arg-OEt were first prepared by high-yielding solution-phase couplings using a mixed anhydride method before coupling them to give a linear hexapeptide which, after deprotection, was obtained in 38% overall yield from the commercially available amino acids. Cyclization in solution using BOP reagent gave the antagonist in 33% yield (13% overall) after HPLC purification. Significant features of the synthesis were that the Arg side chain was left unprotected throughout, the component Boc-d-Cha-OH was obtained very efficiently via hydrogenation of d-Phe with PtO(2) in TFA/water, the tripeptides were coupled at the Pro-Cha junction to minimize racemization via the oxazolone pathway, and the entire synthesis was carried out without purification of any intermediates. The target cyclic product was purified (>97%) by reversed-phase HPLC. This convergent synthesis with minimal use of protecting groups allowed batches of 50-100 g to be prepared efficiently in high yield using standard laboratory equipment. This type of procedure should be useful for making even larger quantities of this and other macrocyclic peptidomimetic drugs.

Anti-Inflammatory Agents↗

PubMed2000

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 microM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC(50) 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC(50) 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 A (1) and 1.85 A (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

Anti-HIV Agents↗

PubMed1998

Synthesis and Electrochemistry of Tin(IV) Octaethylcorroles, (OEC)Sn(C(6)H(5)) and (OEC)SnCl.

Two Sn(IV) corroles were synthesized and electrochemically examined. The investigated compounds are represented as (OEC)Sn(C(6)H(5)) and (OEC)SnCl, where OEC = trianion of 2,3,7,8,12,13,17,18-octaethylcorrole. (OEC)Sn(C(6)H(5)) represents the first example of a sigma-bonded metallocorrole which does not undergo a metal-centered electrode reaction. Both compounds undergo three reversible one-electron oxidations, all of which occur at the conjugated macrocycle. The reduction of (OEC)SnCl involves an overall two electrons, with the product being spectroscopically identified as a Sn(II) corrole after bulk electrolysis of the starting compound. (OEC)Sn(C(6)H(5)) is reversibly reduced by a single electron to give a Sn(IV) corrole pi-anion radical. The electrochemically measured HOMO-LUMO gap (defined as the absolute potential difference between the first-ring centered reduction and first ring-centered oxidation) is equal to 2.25 V in benzonitrile, a value which closely approximates what is observed for porphyrins containing octaethylporphyrin (OEP) or tetraphenylporphyrin (TPP) macrocycles. An X-ray crystallographic analysis for the molecular structure of (OEC)Sn(C(6)H(5)) is also presented: monoclinic, P2(1)/n, with a = 13.235(4) Å, b = 14.502(4) Å, c = 18.387(5) Å, beta = 95.45(2) degrees, Z = 4, R = 0.0619.

Journal Article↗

PubMed1999

Macrocyclic hexapeptide analogues of the thrombin receptor (PAR-1) activation motif SFLLRN.

The thrombin receptor (PAR-1) is activated by alpha-thrombin to stimulate various cell types, including platelets, through the tethered-ligand sequence SFLLRN. Macrocyclic peptide analogues of SFLLRN were synthesized and evaluated in vitro. In general, the compounds were much less potent in inducing platelet aggregation relative to SFLLRN-NH2 and did not act as antagonists of alpha-thrombin. Derivative 3c was the most potent macrocycle in activating PAR-1, with an EC50 of 24 microM.

Blood Platelets↗

PubMed1990

Lipophilic 1,3-xylyl-21-crown-6 macrocyclic polyether 2-carboxylic acids as biological mimics of the ionophore antibiotics.

Twelve lipophilic 1,3-xylyl-21-crown-6 macrocyclic polyether 2-carboxylic acids, two lariat ether 1,3-xylyl-21-crown-6 macrocyclic polyether 2-carboxylic acids, and two 1,3-xylyl-28-crown-8 macrocyclic polyether 2-carboxylic acids were synthesized and tested for in vitro antibacterial activity, in vitro stimulation of rumen propionic acid production, and in vivo anticoccidial activity in chickens. These are biological screens relevant to animal health areas where the ionophore antibiotics such as monensin have found application. While the parent structure 1 without lipophilic substituents was biologically inactive, the lipophilic macrocycles were active in the two in vitro tests but not against chicken coccidiosis. One compound was tested in cattle and was found to increase levels of propionic acid in the rumen fermentation. This effect is considered an important factor for increasing the efficiency of feed utilization in cattle exhibited by the ionophore antibiotic monensin. The alkali ion salts of these lipophilic macrocyclic polyether carboxylic acids are very soluble in organic solvents and insoluble in water. These compounds are proposed to act as ion-transport agents and functional mimics of the ionophore antibiotics in the biological systems described above.

Animals↗

PubMed1992

The toxicity of macrocyclic trichothecenes administered directly into the rat brain.

The tested macrocyclic trichothecenes are produced by Myrothecium fungi and by the plant Baccharis megapotamica. The toxicity of five macrocyclic trichothecenes has been measured by intracerebral and subcutaneous injection into rats. It is assumed that the toxic effects are based on inhibition of protein synthesis. Intoxication of rats by these compounds finds expression in slowly progressing respiratory depression and paralysis of skeletal muscles. The macrocyclics are derived from verrucarol, which lacks ring D and exhibits only low toxicity. The high toxicity of the macrocyclics, established by intracerebral and subcutaneous applications, may thus be attributed to the presence of the large ring D.

Animals↗

PubMed2000

DNA double helix destabilizing properties of cyclobisintercaland compounds and competition with a single strand binding protein.

The DNA helix destabilizing activity of a series of cyclobisintercaland compounds (CBIs) has been evaluated by measuring their ability to displace a 32P-labelled oligonucleotide primer (17-mer) hybridized to the single stranded DNA of M13. This destabilizing activity appears to be strongly dependent on the cyclic structure (the linear acyclic references are inactive) and the size of the macrocycle; both features being known to determine the preferential binding of the compound to ssDNA. Interestingly, CBIs induced the dissociation of the duplex template in a concentration range (0.5-1 microM) close to that required for the destabilizing activity of single stranded DNA binding proteins (SSBs). Therefore competition experiments between CBIs and an SSB protein (Eco SSB) for binding to a single stranded oligonucleotide target (36-mer) have been performed through gel electrophoresis and nitrocellulose binding assays and strong inhibitory effects on the formation of the SSB:36-mer complex have been observed.

Base Sequence↗

PubMed2001

Systemic activity of the avermectins against the cat flea (Siphonaptera: Pulicidae).

Ivermectin has potent systemic activity against numerous species of nematodes and arthropods, but there are some important species in these two groups, such as the cat flea, Ctenocephalides felis (Bouché), that appear to be refractory to it. In an effort to determine if the lack of systemic activity against C. felis is specific to ivermectin, or if it is a class-wide phenomenon, 20 avermectin derivatives were tested in an artificial membrane flea feeding system at concentrations of 20, 10, and 1 microg/ml. Results showed that ivermectin had LC90 and LC50 values against fleas of 19.1 and 9.9 microg/ml, respectively. Only four of the other 19 compounds evaluated possessed both LC90 and LC50 values more potent than ivermectin and even then the advantage was modest. Among those four compounds was a two-fold increase in potency relative to ivermectin when the LC90 values were considered (range, 9.2-10.3 microg/ml) and a two- to eight-fold increase when the LC50 values were examined (range, 1.23-5.26 microg/ml). Neither the possession nor the number of oleandrosyl sugars on the macrocyclic backbone were relevant for additional flea activity because among these four compounds were two disaccharides, a monosaccharide and an aglycone. Also, bond disposition between C-22 and 23 did not contribute to increase in activity because these molecules comprise members with either single or double bonds. One of these avermectin analogs was scaled-up and tested subcutaneously in a dog at >100 times the commercial ivermectin dosage and zero efficacy was observed against the flea. We conclude that even the best in vitro avermectin does not have the in vivo potential to become a commercial oral or subcutaneous flea treatment for companion animals.

Animals↗

PubMed1997

Molecular mechanisms of apoptosis in HL-60 cells induced by a nitric oxide-releasing compound.

Nitric oxide (NO) generated from 1-hydroxy-2-oxo-3, 3-bis(2-aminoethyl)-1-triazene (NOC 18), an NO-releasing compound, induced monocytic differentiation of human promyelocytic leukemia HL-60 cells as assessed by expression of nonspecific esterases and morphologic maturation. Simultaneously, DNA fragmentation and morphological alterations typical of apoptosis were also induced. To investigate the mechanisms of apoptosis during differentiation of HL-60 cells induced by NO, the endogenous levels of Bcl-2 and Bax were assessed by immunoblotting. Treatment of cells with NOC 18 slightly reduced the level of Bcl-2 followed by Bax. These changes might be involved in the induction of apoptosis. The involvement of the activation of the interleukin-1 beta converting enzyme (ICE) family of proteases (caspases), such as ICE and CPP32, in the pathways was also investigated. CPP32, but not ICE, was strongly activated in response to NOC 18 stimulation, thereby implicating CPP32-like activity in the induction of apoptosis. Moreover, the possible involvement of tyrosine phosphorylation in apoptosis was investigated. Pretreatment of cells with herbimycin A, an inhibitor of tyrosine kinases, suppressed DNA fragmentation and CPP32-like activity, whereas pretreatment with vanadate, an inhibitor of tyrosine phosphatases, enhanced both parameters, suggesting that tyrosine phosphorylation might be involved in the pathways of apoptosis in HL-60 cells induced by NO.

Apoptosis↗

PubMed2004

Steric control in the oligomerisation of phosphazane dimers; towards new phosphorus-nitrogen macrocycles.

The reaction of [ClP(mu-NtBu)]2 (1) with H2O (1 : 2 equivalents) in the presence of excess Et3N gives the new chain compound [(mu-O)[P(mu-NtBu)2P(H)=O]2] (3), consisting of two P2N2 rings linked by a mu-O atom and terminating in P(V)(H)=O groups. A similar chain species is obtained from the reaction of the lithiate of [(tBuNH)P(mu-NtBu)2P(H)=O] (5) with [ClP(mu-NtBu)2P(NHtBu)] (2), the product being [(mu-O)[P(mu-NtBu)2P(NHtBu)]2] (6). Compounds 3 and 6 are the first examples of O-bridged chain phosphazanes and potential precursors to new phosphorus-nitrogen macrocycles. The syntheses and X-ray structures of 3, 5 and 6 are reported.

Journal Article↗

PubMed2006

Importance of the structure of vancomycin binding pocket in designing compounds active against vancomycin-resistant enterococci (VRE).

16-Membered meta, para-cyclophanes mimicking the vancomycin binding pocket (D-O-E ring) are designed and synthesized. The structural features of these biaryl ether containing macrocycles are: a) the deletion of the carboxyl group of vancomycin's central amino acid (amino acid D); b) the elongation of the N-terminal; c) the presence of lipidated aminoglucose at the D-ring. Cycloetherification by way of an intramolecular nucleophilic aromatic substitution reaction (S(N)Ar) is used as a key step for the construction of the macrocycle. Minimum inhibitory concentrations for all of the derivatives are measured using a standard microdilution assay. Compounds 2a-2c and 3a-3c displayed weak activities against resistant strain Enterococcus faecalis L560 and were inactive against Enterococcus faecium resistant strain L2215.

Anti-Bacterial Agents↗

PubMed2004

Substituent effects on the site of electron transfer during the first reduction for gold(III) porphyrins.

Gold(III) porphyrins of the type (P-R)AuPF(6), where P = 5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)porphyrin and R is equal to H (1), NO(2) (2), or NH(2) (3) which is substituted at one of the eight beta-pyrrolic positions of the macrocycle, were investigated as to their electrochemistry and spectroelectrochemistry in nonaqueous media. Each compound undergoes three reductions, the first of which involves the central metal ion to give a Au(II) porphyrin or a Au(III) porphyrin pi-anion radical depending upon the nature of the porphyrin ring substituent. A similar metal-centered reduction also occurs for compounds 1, 3, and Au(III) quinoxalinoporphyrin, (PQ)AuPF(6) (4), where PQ = 5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)quinoxalino[2,3-b]porphyrin, and these results on the three Au(III) porphyrins overturn the long held assumption that reductions of such complexes only occur at the macrocycle. In contrast, when a NO(2) group is introduced on the porphyrin ring to give (P-NO(2))AuPF(6) (2), the site of electron transfer is changed from the gold metal to the macrocycle to give a porphyrin pi-anion radical in the first reduction step. This change in the site of electron transfer was examined by electrochemistry combined with thin-layer UV-vis spectroelectrochemistry and ESR spectroscopy of the singly reduced compound produced by chemical reduction. The reorganization energy (lambda) of the metal-centered electron transfer reduction for (P-H)AuPF(6) (1) in benzonitrile was determined as lambda = 1.23 eV by analyzing the rates of photoinduced electron transfer from the triplet excited states of an organic electron donor to 1 in light of the Marcus theory of electron transfer. The lambda value of the metal-centered electron transfer of gold porphyrin (1) is significantly larger than lambda values of ligand-centered electron transfer reactions of metalloporphyrins.

Journal Article↗

PubMed2003

Octalkoxy-substituted phosphorus(V) triazatetrabenzcorroles via ring contraction of phthalocyanine precursors.

As part of efforts toward developing the synthesis of novel corrole analogues, the new triazatetrabenzcorrole (TBC) phosphorus(V) compounds (BuO)8(TBC)P(OCH3)2 (3), [(BuO)8(TBC)P(OH)]+OH- (4) ((BuO)8TBC=3,6,10,13,17,20,24,27-octabutoxytriazatetrabenzcorrolate), and [(BuO)8Cl8(TBC)P(OH)]+OH- (7) ((BuO)8Cl8TBC=3,6,10,13,17,20,24,27-octabutoxy-4,5,11,12,18,19,25,26-octachlorotriazatetrabenzcorrolate) were prepared. These TBCs were synthesized via a ring-contraction reaction mediated by PBr3 in pyridine in which a meso-nitrogen atom is extruded from an appropriate phthalocyanine precursor. Two of the compounds prepared, 3 and 4, are contracted analogues of the parent phthalocyanine (BuO8)PcH2 (1) 1,4,8,11,15,18,22,25-octabutoxy-29H,31H-phthalocyanine, which has been shown for the first time to be susceptible to ring-contraction despite the potential steric crowding imposed by the butoxy substituents. Likewise, the octachloro-substituted (BuO8)Cl8PcH2 (6), 1,4,8,11,15,18,22,25-octabutoxy-2,3,9,10,16,17,23,24-octachlorophthalocyanine, has also been shown to smoothly afford 7 via the same ring-contraction method. In addition, a rare example of a bona fide phosphorus(V) phthalocyanine, [(BuO)8(Pc)P(OCH3)2]+OH- (2), has been prepared for spectroscopic comparisons with the TBC compounds. These molecules are all extremely soluble in common organic solvents because of the octabutoxy substituents and have been characterized in detail by 1H NMR, 31P NMR, UV-vis, MALDI-MS, elemental analysis, and electrochemical studies. A clear trend in the phosphorus chemical shifts for 5 versus 6 coordination has been delineated: 31P NMR for 2, -179.8; 3, -186.1; 4, -105.1; and 7, -105.1. These data are compared to the 31P chemical shifts for related porphyrinoid(P(V)) molecules. The MALDI-MS data reveal the tendency of the TBC macrocycles to ionize as the radical cations (M(+*)) and has been useful in determining the axial ligands at phosphorus. A consequence of ring-contraction is reflected in the dramatic red-shifts (approximately 200 nm) observed for the Soret bands of the TBC compounds relative to the parent phthalocyanines. The magnitude of the red-shift is much greater than that reported for other TBCs. In addition, insertion of phosphorus causes a large red-shift in the Q-band of 2 found at 889 nm compared to 760 nm for 1. Cyclic voltammetry of the compounds in this study reveals multiple oxidation and reduction waves for each compound, and some interesting trends in redox potentials have been observed. The CV data for the octachloro-substituted compounds 6 and 7 show that the Cl substituents have an expected strong electron-withdrawing effect on the macrocycles. In general, the TBC compounds are significantly easier to oxidize and harder to reduce than the Pc counterparts, supporting the notion that corrole-type macrocycles favor higher oxidation states.

Journal Article↗

PubMed2004

Macrocyclic inhibitors for peptide deformylase: a structure-activity relationship study of the ring size.

Peptide deformylase (PDF) catalyzes the removal of the N-terminal formyl group from newly synthesized polypeptides in eubacteria. Its essential role in bacterial cells but not in mammalian cells makes it an attractive target for antibacterial drug design. We have previously reported an N-formylhydroxylamine-based, metal-chelating macrocyclic PDF inhibitor, in which the P(1)' and P(3)' side chains are covalently joined. In this work, we have carried out a structure-activity relationship study on the size of the macrocycle and found that 15-17-membered macrocycles are optimal for binding to the PDF active site. Unlike the acyclic compounds, which are simple competitive inhibitors, the cyclic compounds all act as slow-binding inhibitors. As compared to their acyclic counterparts, the cyclic inhibitors displayed 20-50-fold higher potency against the PDF active site (K(I) as low as 70 pM), improved selectivity toward PDF, and improved the metabolic stability in rat plasma. Some of the macrocyclic inhibitors had potent, broad spectrum antibacterial activity against clinically significant Gram-positive and Gram-negative pathogens. These results suggest that the macrocyclic scaffold provides an excellent lead for the development of a new class of antibiotics.

Amidohydrolases↗