Semicarbazone-based inhibitors of cathepsin K,are they prodrugs for aldehyde inhibitors?

Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.     

Potent transglutaminase inhibitors,aryl β-aminoethyl ketones

Aryl β-aminoethyl ketones were discovered as potent inhibitors of tissue transglutaminase. Heteroaryl-like thiophene groups and N-benzyl N-t-butyl aminoethyl group are critical to the strong inhibitory activity of aryl β-aminoethyl ketones.     

Potent transglutaminase inhibitors, dithio β-aminoethyl ketones

Potent transglutaminase inhibitors were obtained from disulfide compounds, cystamine, dimethyl cystine, and dimethyl homocystine. The disulfide bond and thiophene ring play an important role in inhibitory activity of synthesized aryl β-amino ketones.     

Substituted α-mercaptoketones,new types of specific neprilysin inhibitors

New neprilysin inhibitors containing an α-mercaptoketone HSC(R¹R²)CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S₁, S₁′ or S₂′ domain of the enzyme and the nature of the substituents R¹, R² of the mercaptoketone group. Introduction of a cyclohexyl chain in R¹, R² position and a (3-thiophen)benzyl group in position R³ (compound 12n) yielded to the most potent inhibitor of this series with a Ki value of 2 ± 0.3 nM. This result suggests that this new inhibitor interacts within the S₁, S₁′ domain of NEP allowing a pentacoordination of the catalytic Zn²⁺ ion by the mercaptoketone moiety.     

Carbonic anhydrase inhibitors: Two-prong versus mono-prong inhibitors of isoforms I,II, IX,and XII exemplified by photochromic cis-1,2-α-dithienylethene derivatives

We investigated the inhibition of five physiologically relevant CA isoforms with photochromic cis-1,2-α-dithienylethene-based compounds incorporating either a benzenesulfonamide and Cu(II)-iminodiacetic acid (IDA)-, bis-benzenesulfonamide-, bis-Cu(II)-IDA-, and bis-ethyleneglycol-methyl ether moieties, in both their open- and closed-ring forms. For hCA I the best inhibitors were the mono-prong bis-sulfonamide and the bis-Cu-IDA complexes (K_Is of 2–3 nM) in their open form. For hCA II, best inhibitors were the open and closed forms of the mono-prong bis-sulfonamide (K_Is of 13–18 nM). hCA IX was moderately inhibited by these compounds (K_Is of 9–376 nM) whereas hCA XII and XIV were less susceptible to inhibition (K_Is of 1.12–16.7 μM).     

Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13nM) and cellular (IC(50)=21nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.     

Design, synthesis, and structure-activity relationship studies of N-arylsulfonyl morpholines as γ-secretase inhibitors

Design and synthesis of cis-2,6-disubstituted N-arylsulfonyl morpholines as novel γ-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. Several different small alkyl groups are installed on the left-hand side to lower the CYP3A4 liability while maintaining excellent in vitro potency.     

Synthesis,structure-activity relationships studies of benzoxazinone derivatives as α-chymotrypsin inhibitors

A series of benzoxazinones 1–28 were synthesized via reaction of anthranilic acid with various substituted benzoyl chlorides in the presence of triethylamine in chloroform. Compounds 1–18 showed a good inhibition of α-chymotrypsin with IC₅₀ ± SEM values between 6.5 and 341.1 μM. Preliminary structure-activity relationships studies indicated that the presence of substituents on benzene ring reduces the inhibitory potential of benzoxazinone. Also the increased inhibitory potential due to fluoro group at phenyl substituent was observed followed by chloro and bromo substituents. Compounds with strong electron donating or withdrawing groups on phenyl substituent, showed a good inhibitory potential at ortho > meta > para position. Kinetics studies showed diverse types of inhibition, except uncompetitive-type inhibition. The Ki values ranged between 4.7 and 341.2 μM. Interestingly, most of these compounds were non-cytotoxic to 3T3 cell line at 30 μM, except compounds 6, 14 and 15. Competitive inhibitors of chymotrypsin are like to inhibit other α-chymotrypsin-like serine proteases due to structural and functional similarities between them. The inhibitors identified during the current study deserve to be further studied for their therapeutic potential against abnormalities mediated by chymotrypsin or other serine protease.     

Carbonic anhydrase inhibitors: Thioxolone versus sulfonamides for obtaining isozyme-selective inhibitors?

Inhibition of 13 mammalian isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA I–XV, with thioxolone (6-hydroxy-1,3-benzoxathiol-2-one) and two sulfonamides was investigated. Thioxolone was inefficient for generating isozyme-selective inhibitors, since except for CA I which is inhibited in the nanomolar range (K_I of 91 nM), the remaining 12 isoforms were inhibited with a very flat profile (K_Is in the range of only 4.93–9.04 μM). In contrast to thioxolone, 3,5-dichloro-4-hydroxybenzenesulfonamide as well as the clinically used heterocyclic sulfonamide acetazolamide showed K_Is in the range of 58 nM–78.6 μM and 2.5 nM–200 μM, respectively, against the 13 investigated mammalian CAs. The sulfonamide zinc-binding group is thus superior to the thiol one for generating CA inhibitors with a varied and sometimes isozyme-selective inhibition profile against the mammalian enzymes.     

Design,synthesis, and structure–activity relationships of pyrazole derivatives as potential FabH inhibitors

Fatty acid biosynthesis is essential for bacterial survival. FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Fifty-six 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-(4-fluorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (12) and 1-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (13) were potent inhibitors of E. coli FabH.     

Structure–activity relationships of tulipalines,tuliposides, and related compounds as inhibitors of MurA

The enzyme MurA performs an essential step in peptidoglycan biosynthesis and is therefore a target for the discovery of novel antibacterial compounds. We report here the inhibition of MurA by natural products from tulips (tulipalines and tuliposides), and the structure–activity relationships of various derivatives. The inhibition of MurA can be related to antibacterial activity, and MurA is probably one of the relevant molecular targets of the tulipaline derivatives. MurA inhibition by this class of compounds depends on the presence of the substrate UNAG, which indicates non-covalent suicide inhibition as observed previously for cnicin. With respect to selectivity, however, the reactivity against arbitrary sulfhydryl groups, such as in glutathione, could not yet be sufficiently separated from MurA inhibition in the present dataset.     

γ-Secretase inhibitors and modulators

γ-Secretase is a fascinating, multi-subunit, intramembrane cleaving protease that is now being considered as a therapeutic target for a number of diseases. Potent, orally bioavailable γ-secretase inhibitors (GSIs) have been developed and tested in humans with Alzheimer's disease (AD) and cancer. Preclinical studies also suggest the therapeutic potential for GSIs in other disease conditions. However, due to inherent mechanism based-toxicity of non-selective inhibition of γ-secretase, clinical development of GSIs will require empirical testing with careful evaluation of benefit versus risk. In addition to GSIs, compounds referred to as γ-secretase modulators (GSMs) remain in development as AD therapeutics. GSMs do not inhibit γ-secretase, but modulate γ-secretase processivity and thereby shift the profile of the secreted amyloid β peptides (Aβ) peptides produced. Although GSMs are thought to have an inherently safe mechanism of action, their effects on substrates other than the amyloid β protein precursor (APP) have not been extensively investigated. Herein, we will review the current state of development of GSIs and GSMs and explore pertinent biological and pharmacological questions pertaining to the use of these agents for select indications. This article is part of a Special Issue entitled: Intramembrane Proteases.     

Hit discovery of Mycobacterium tuberculosis inosine 5′-monophosphate dehydrogenase,GuaB2, inhibitors

Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5′-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.     

Phytochrome-mediated synthesis of novel growth inhibitors,A-2α and β, and dwarfism in peas

Variations in the content of A-2α and β, novel endogenous growth inhibitors, andcis,trans- andtrans, trans-xanthoxins were determined in 6- or 7-d-old, dark-grown seedlings of peas (Pisum sativum L. cvs. Progress No. 9, dwarf, and Alaska, tall) under various treatments with red light (R), and compared with R-induced growth inhibition. After transfer of the plants to continuous R the contents of the A-2s in cv. Progress increased after a 20-min lag, and reached plateaus after 12 h, whereas they remained almost unchanged in darkness. Both the rates of increase of the A-2s and the plateau levels were proportional to the logarithm of the irradiance applied. After a 10-min R pulse, the contents of both A-2α and β increased with the same rapidity to reach peaks after 6 h, and then gradually decreased to the initial levels after about 24 h. The effect of R was shown to be phytochrome-dependent, being nullified by far-red light. The level of neithercis,trans- nortrans,trans-xanthoxin showed such a close correlation with growth inhibition, although both xanthoxins increased as a result of phytochrome action. It is highly suggestive that the A-2s, rather than the xanthoxins, are responsible for phytochrome-dependent growth inhibition in cv. Progress. In cv. Alaska, in contrast, R-induced increase of the A-2s was rapid but slight, and could not explain the transient growth inhibition, which was found to be as large as that in cv. Progress shortly after the onset of R. The large content of the A-2s in cv. Progress in the steady state under continuous R, compared with that in cv. Alaska, may explain the dwarfism of cv. Progress. Dedicated to Professor Hans Mohr on the occasion of his 60th birthday     

Conversion of carbazole carboxamide based reversible inhibitors of Bruton’s tyrosine kinase (BTK) into potent,selective irreversible inhibitors in the carbazole,tetrahydrocarbazole, and a new 2,3-dimethylindole series

Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.     

Design,synthesis, and evaluation of resveratrol derivatives as Aß1–42 aggregation inhibitors,antioxidants, and neuroprotective agents

A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer’s disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.