Hydroxyamino Derivatives Research Articles

Quinate-based ligands for irreversible inactivation of the bacterial virulence factor DHQ1 enzyme-A molecular insight.

Irreversible inhibition of the enzyme type I dehydroquinase (DHQ1), a promising target for anti-virulence drug development, has been explored by enhancing the electrophilicity of specific positions of the ligand towards covalent lysine modification. For ligand design, we made use of the advantages offered by the intrinsic acid-base properties of the amino substituents introduced in the quinate scaffold, namely compounds 6-7 (R configuration at C3), to generate a potential leaving group, as well as the recognition pattern of the enzyme. The reactivity of the C2-C3 bond (Re face) in the scaffold was also explored using compound 8. The results of the present study show that replacement of the C3 hydroxy group of (-)-quinic acid by a hydroxyamino substituent (compound 6) provides a time-dependent irreversible inhibitor, while compound 7, in which the latter functionality was substituted by an amino group, and the introduction of an oxirane ring at C2-C3 bond, compound 8, do not allow covalent modification of the enzyme. These outcomes were supported by resolution of the crystal structures of DHQ1 from Staphylococcus aureus (Sa-DHQ1) and Salmonella typhi (St-DHQ1) chemically modified by 6 at a resolution of 1.65 and 1.90Å, respectively, and of St-DHQ1 in the complex with 8 (1.55Å). The combination of these structural studies with extensive molecular dynamics simulation studies allowed us to understand the molecular basis of the type of inhibition observed. This study is a good example of the importance of achieving the correct geometry between the reactive center of the ligand (electrophile) and the enzyme nucleophile (lysine residue) to allow selective covalent modification. The outcomes obtained with the hydroxyamino derivative 6 also open up new possibilities in the design of irreversible inhibitors based on the use of amino substituents.

Synthesis and biological in vitro evaluation of the effect of hydroxyimino steroidal derivatives on breast cancer cells

Breast cancer is the most common cause of cancer death in women, according to Global Cancer Observatory. This fact forces scientists to continue in the search for effective treatments against this aggressive type of cancer. Breast cancer frequently metastasizes to other organs, most often the bones, lungs, and liver. Breast cancer is normally associated with estrogen and progestogen levels and can be hormone or non-hormone dependent. In current experiments herein reported, some hydroxyimino spirostan derivatives showed great potential against MCF-7 breast cancer, a Luminal-A cancer. On the other hand, a set of synthesized 6-hydroxyimino-22-oxocholestane compounds had excellent activity against the MDA-MB-231 breast cancer cell line. The synthesis of hydroxyamino derivatives from spirostan and 22-oxocholestane compounds was improved. The hydroxyimino compounds enhanced the bioactivity when compared with their parent carbonyl skeletons.

Prediction of different antibacterial activity in a new set of formyl hydroxyamino derivatives with potent action on peptide deformylase using structural information

Due to the essential role of peptide deformylase (PDF) at the bacterial growth cycle, it is a noteworthy target for developing a novel antibacterial agent. In the current study, the antibacterial activities of a set of 44 new structures of formyl hydroxyamino derivatives as PDF inhibitors were quantified using quantitative structure–activity relationship (QSAR). Artificial neural networks (ANN) were used as a chemometrics tool for QSAR modeling. Three quantitative models were suggested to relate the chemical structural features of the formyl hydroxyamino derivatives to their antibacterial activities (pIC50) against Staphylococcus aureus, methicillin-susceptible S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA) peptide deformylase. The sufficiency of the model for prediction of the antibacterial activities of the desired PDF inhibitor compounds against S. aureus, MSSA, and MRSA was statistically demonstrated according to the validation parameters such as coefficient of determination (R2), mean square error (MSE) in training, validation, and prediction sets, and also using applicability domain (AD) and randomization test.

Synthesis, antibacterial activity, and biological evaluation of formyl hydroxyamino derivatives as novel potent peptide deformylase inhibitors against drug-resistant bacteria

Peptide deformylase (PDF) has been identified as a promising target for novel antibacterial agents. In this study, a series of novel formyl hydroxyamino derivatives were designed and synthesized as PDF inhibitors and their antibacterial activities were evaluated. Among the potent PDF inhibitors (1o, 1q, 1o′, 1q′, and 1x), in vivo studies showed that compound 1q possesses mild toxicity, a good pharmacokinetic profile and protective effects. The good in vivo efficacy and low toxicity suggest that this class of compounds has potential for development and use in future antibacterial drugs.

ChemInform Abstract: Design, Synthesis and Antibacterial Activity of 3‐Methylenepyrrolidine Formyl Hydroxyamino Derivatives as Novel Peptide Deformylase Inhibitors.

AbstractStructural modification of a recently developed PDF inhibitor by replacing the pyrrolidine functionality with 3‐methylenepyrrolidine leads to the discovery of derivatives (I) exhibiting better in vitro antibacterial activity than the reference compounds against drug‐resistant clinical isolates including MRSA, PRSP, and H.

Design, synthesis and antibacterial activity of 3-methylenepyrrolidine formyl hydroxyamino derivatives as novel peptide deformylase inhibitors

The synthesis and antibacterial activity of 3-methylenepyrrolidine formyl hydroxyamino derivatives are reported. The antibacterial activities of these derivatives were evaluated to discover SAR at P(1') and P(3') positions, and most of these derivatives exhibit better in vitro antibacterial activity than existing drugs against drug-resistant clinical isolates including MRSA, PRSP, and Haemophilus influenzae.

Design, synthesis, and antibacterial activity of 2,5-dihydropyrrole formyl hydroxyamino derivatives as novel peptide deformylase inhibitors

The synthesis and antibacterial activity of 2,5-dihydropyrrole formyl hydroxyamino derivatives are reported. The antibacterial activities of these derivatives were evaluated, and some of these derivatives showed better in vitro antibacterial activity than existing drugs, including penicillin, ciprofloxacin, vancomycin, and linezolid.

The ortho hydroxy-amino group: Another choice for synthesizing novel antioxidants

Four ortho hydroxy-amino derivatives have been designed based on the structures of flavonoids to explore the effect of the ortho hydroxy-amino group on the antioxidant properties of molecules, and their bond dissociation enthalpies (BDE), ionization potentials (IP), the highest occupied molecular orbitals (HOMO), and spin densities have been calculated. The results reveal that the ortho hydroxy-amino group plays an important role in promoting the antioxidant properties of molecules because of its lowering effect on BDE, IP, and spin density. The derivatives with ortho hydroxy-amino group show stronger antioxidant activity than the derivatives with mono hydroxy or ortho dihydroxy group. Thus, the ortho hydroxy-amino group can be used as another potential functional group to synthesize novel antioxidants as guessed.

Heterocyclic amines: Mutagens/carcinogens produced during cooking of meat and fish.

Research leading to the discovery of a series of mutagenic and carcinogenic heterocyclic amines (HCAs) was inspired by the idea that smoke produced during cooking of food, especially meat or fish, might be carcinogenic. More than ten kinds of HCAs, actually produced by cooking or heating of meat or fish, have now been isolated and their structures determined, most being previously unregistered compounds. They are highly mutagenic towards Salmonella typhimurium in the presence of S9 mix and are also mutagenic in vitro and in vivo toward mammalian cells. HCAs have now been chemically synthesized in quantity and subjected to long-term animal testing. When HCAs were fed in the diet, rodents developed cancers in many organs, including the colon, breast and prostate, and one HCA produced hepatomas in monkeys. The lesions exhibited alteration in genes including Apc, beta-catenin and Ha-ras, and these changes provide clues to the induction mechanisms. The HCAs are oxidized to hydroxyamino derivatives by cytochrome P450s, and further converted to ester forms by acetyltransferase and sulfotransferase. Eventually, they produce DNA adducts through the formation of N-C bonds at guanine bases. There are HCA-sensitive and resistant strains of rodents and a search for the responsible genes is now under way. While the content of HCAs in dishes consumed in ordinary life is low and not sufficient in itself to explain human cancer, the coexistence of many other mutagens/carcinogens of either autobiotic or xenobiotic type and the possibility that HCAs induce genomic instability and heightened sensitivity to tumor promoters suggest that avoidance of exposure to HCAs or reduction of HCAs' biological effects as far as possible are to be highly recommended. Usage of microwave ovens for cooking and supplementation of the diet, for example with soy-isoflavones, which have been found to suppress the occurrence of HCA-induced breast cancers, should be encouraged. Advice to the general public about how to reduce the carcinogenic load imposed by HCAs would be an important contribution to cancer prevention.

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) triggers apoptosis by DNA double-strand breaks caused by inhibition of topoisomerase I.

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is one of the dietary carcinogens. At the initial step in the carcinogenic process, its exocyclic amino group is metabolically activated to the hydroxyamino derivative by the cytochrome P450 (CYP) 1A and 1B subfamily and then form DNA adducts, which are considered to be the main cause of DNA damage during the carcinogenic process. On the other hand, our previous study has shown that Trp-P-1 exhibits cytotoxicity to primary cultured rat hepatocytes, via induction of caspase-9-dependent apoptosis without being metabolized by CYP 1A1. In the present study, we investigated what type of DNA damage would be involved in the induction of apoptosis induced by Trp-P-1. When RL-34 cells derived from normal rat liver were treated with a high (30 microM) concentration of Trp-P-1, apoptotic events such as the loss of cell viability, nuclear condensation and the activation of caspase-3 were observed. In these apoptotic cells, intracellular topoisomerase I activity was inhibited and histone H2AX phosphorylation, which occurs after introduction of DNA double-strand breaks (DSBs), was observed in the early phase of the apoptosis. On the other hand, treatment with a non-apoptotic concentration (1 microM) of Trp-P-1 increased the formation of 8-hydroxy-2'-deoxyguanosine. The formation of DNA adducts was detected at almost the same level in both cells exposed to the apoptotic and non-apoptotic concentrations of Trp-P-1. These results indicate that Trp-P-1-induced apoptosis was triggered by DNA DSBs through the inhibition of topoisomerase I but not the formation of DNA adducts.

Structures of mutagens produced by the co-mutagen norharman with o- and m-toluidine isomers

Norharman, abundantly present in cigarette smoke and cooked foods, is not mutagenic to Salmonella typhimurium strains. However, norharman shows mutagenicity to S. typhimurium TA98 and YG1024 in the presence of S9 mix when coexisting with aromatic amines, including aniline, o- and m-toluidines. We previously reported that the mutagenicity from norharman and aniline in the presence of S9 mix was due to the formation of a mutagenic compound, 9-(4′-aminophenyl)-9 H-pyrido[3,4- b]indole (aminophenylnorharman). In the present study, we analyzed the mutagens produced by norharman with o- or m-toluidine in the presence of S9 mix. When norharman and o-toluidine were reacted at 37°C for 20 min, two mutagenic compounds, which were mutagenic with and without S9 mix, respectively, were produced, and these were isolated by HPLC. The former mutagen was deduced to be 9-(4′-amino-3′-methylphenyl)-9 H-pyrido[3,4- b]indole (amino-3′-methylphenylnorharman) on the basis of various spectral data, and this new heterocyclic amine was confirmed by its chemical synthesis. The latter mutagen was identified to be the hydroxyamino derivative. Amino-3′-methylphenylnorharman induced 41,000 revertants of TA98, and 698,000 revertants of YG1024 per μg with S9 mix. Formation of the same DNA adducts was observed in YG1024 when amino-3′-methylphenylnorharman or a mixture of norharman plus o-toluidine was incubated with S9 mix. These observations suggest that norharman reacts with o-toluidine in the presence of S9 mix to produce amino-3′-methylphenylnorharman, and this compound is metabolically activated to yield its hydroxyamino derivative. After activation by O-acetyltransferase, it might bind to DNA and exert mutagenicity in S. typhimurium TA98 and YG1024. When norharman and m-toluidine were reacted in the presence of S9 mix, 9-(4′-amino-2′-methylphenyl)-9 H-pyrido[3,4- b]indole (amino-2′-methylphenylnorharman) was identified as a mutagen. Thus, the mutagenicity of norharman with m-toluidine may follow a mechanism similar to that with o-toluidine.

Structural determination of a mutagenic aminophenylnorharman produced by the co-mutagen norharman with aniline.

Norharman (9H-pyrido[3,4-b]indole), widely distributed in our environment, including cigarette smoke and cooked foodstuffs, is not mutagenic to Salmonella strains, but becomes mutagenic to S.typhimurium TA98 and YG1024 with S9 mix in the presence of non-mutagenic aromatic amines such as aniline and o-toluidine. To elucidate the mechanisms of co-mutagenicity, we tried to isolate the mutagen(s) produced by a reaction between norharman and aniline with S9 mix. By HPLC purification, two mutagenic compounds (I and II), one (I) showing mutagenicity with and the other (II) without S9 mix, were isolated. The structure of compound I was deduced to be a coupled compound of norharman and aniline, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman), by a variety of spectrometry techniques and this was confirmed by its chemical synthesis. The mutagenic activity of this novel heterocyclic amine was tested using the pre-incubation method and was found to induce 187,000 revertants in TA98 and 1,783,000 revertants in YG1024 per microg with S9 mix. Compound II was shown to be hydroxyaminophenylnorharman. Formation of the same DNA adducts was observed in YG1024 when aminophenylnorharman or a mixture of norharman plus aniline was incubated with S9 mix. The hydroxyamino derivative also yielded the same DNA adducts in YG1024. Thus, the appearance of mutagenicity by norharman with aniline in the presence of S9 mix suggests that the coupled mutagenic compound, aminophenylnorharman, is formed from norharman and aniline, then converted to the hydroxyamino derivative and forms DNA adducts to induce mutations in TA98 and YG1024.

Synthesis and antitumor activity of amino derivatives of pyridine-2-carboxaldehyde thiose micarbazone

Various substituted pyridine-2-carboxaldehyde thiosemicarbazones (12 compounds) have been synthesized and evaluated for antineoplastic activity in mice bearing the L1210 leukemia. Oxidation of 3-nitro-2-picoline,5-nitro-2-picoline,3-nitro-2,4-lutidine, and 5-nitro-2,4-lutidine with selenium dioxide was employed to generate the corresponding pyridine-2-carboxaldehydes, which were then converted to cyclic ethylene acetals and subsequently reduced to amino and hydroxyamino derivatives by catalytic hydrogenation. Condensation of nitro aldehydes and acetals with thiosemicarbazide afforded the respective thiosemicarbazones. Acetylation of the amino acetals and alkylsulfonation of the 5-amino acetal, followed by condensation with thiosemicarbazide was employed to yield amide thiosemicarbazones. The most active compounds synthesized were 3-aminopyridine-2-carboxaldehyde thiosemicarbazone and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone which produced against the L1210 leukemia, % T/C values of 246 and 255, and 40% 60-day long-term survivors at two daily doses of 40 mg/kg and 10 mg/kg, respectively, for six consecutive days.

Synthesis of 2- and 4-Nitropyrimidines and 2-Nitro-sym-triazines by ozonization of hydroxyamino and nitroso derivatives

The action of ozone on aryl(methyl)-substituted 2- and 4-hydroxyamino- or -nitrosopyrimidines in chloroform gave 2- and 4-nitropyrimidines. The unambiguous character of the process depends on the molar ratio of the substrate and ozone; the side formation of azoxy-, chloro-, and hydroxypyrimidines is possible. 2-Nitro-sym-triazines were obtained by ozonization of substituted 2-hydroxyamino-sym-triazines.

Radiation-induced reduction of nitroimidazole derivatives in aqueous solution.

The radiation-induced reduction of N1-alkyl substituted 2- and 5-nitroimidazoles in aqueous solution containing sodium formate or 2-propanol was studied at pH 7.0 +/- 0.1 under deaerated conditions. Irrespective of 2- or 5-nitroimidazole, N1-unsubstituted nitroimidazoles (2-nitro-(1a), 4(5)-nitro-(2a), 2-methyl-4(5)-nitro (3a), and 4(5)-methyl-5(4)-nitro- (4a) imidazoles) were reduced stepwise to consume 6 electrons per molecule, whereas N1-alkyl substituted nitroimidazoles (1-methyl-2-nitro (5a) and 1-methyl-5-nitro (6a) imidazoles, misonidazole (7a), and metronidazole (8a] reacted with consumption of 4 electrons. In accord with the stoichiometry for the reduction of N1-unsubstituted nitroimidazoles, the formation of the amino derivatives of (1a)-(4a) was shown by HPLC or colour identification tests. 4-Electron-reduction products of N1-alkyl substituted 2-nitroimidazoles (5a) and (7a) were characterized by 13C and 1H n.m.r. and FDMS measurements, indicating that the hydroxyamino derivative of (5a) as a 4-electron-reduction product isomerizes to an oxime form. The formation of an analogous oxime-type product was also suggested for (7a) together with a product bearing the partially cleaved imidizole ring. The HPLC analysis showed that 4-electron-reduction products of N1-alkyl substituted 5-nitroimidazoles (6a) and (8a) are unstable relative to those of the corresponding 2-nitroimidazoles (5a) and (7a).

Reactivity of 4‐hydroxy‐2‐methyl‐7,8,9,10‐tetrahydrobenzo[h] quinoline towards base‐catalyzed cyclization, mannich and turpin reactions

AbstractMannich reaction upon 4‐hydroxy‐2‐methyl‐7,8,9,10‐tetrahydrobenzo[h]quinoline (1) as well as its nitration were studied. Condensation of the chloroquinoline 6b with sodium azide, benzylamine and ethanolamine gave the quinoline derivatives 6c, 6f and 6g, respectively. Phenylhydrazine and sodium borohydride effected reduction of the azidoquinoline 6c to the corresponding amino‐ and hydroxyamino derivatives 6d and 6e, respectively. Also, Turpin's reaction gave the benzoquinobenzoxazines 7a‐d when applied to 6b. Treatment of 6f, 6g with alkali and the condensation of 6b with glycine in alcoholic sodium carbonate solution afforded the imidazo[4,5‐c]quinoline derivatives 9a‐c, respectively.

Amino and hydroxyamino derivatives of arylfurans

Amino and hydroxyamino derivatives of arylfurans

Hydrolysis products of menazon

Extensive breakdown of menazon (I; X = S) occurs on heating with dilute hydrochloric acid (1:1). The formation of 2,4-dihydroxy-6-methyl-1,3,5-triazine (IV) under these conditions was unexpected; elemental sulphur was eliminated in this reaction, and both amino groups hydrolysed to ammonia. 2,4-diamino-6-mercaptomethyl-1,3,5-triazine (III; Y = SH) is the main product formed on milder acid hydrolysis, whilst methanolic potassium hydroxide treatment of menazon yields 2,4-diamino-6-methylthiomethyl-1,3,5-triazine (III; Y = MeS). The secondary dithiophosphate ester, or des-methyl menazon (II), is formed in a trans-methylation reaction of menazon with sodium OO-dimethylphosphorodithioate. The preparation and characterisation of hydroxyamino and dihydroxytriazine derivatives related to menazon are also described.

CONTROLLED POTENTIAL ELECTROLYSIS. X. POLAROGRAPHIC BEHAVIOR AND ELECTROLYTIC REDUCTION PROCESS OF ESTERS OF ALIPHATIC ALPHA-NITROCARBOXYLIC ACIDS.

Polarographic reduction mechanism of aliphatic ethyl nitrocarboxylates was investigated. The decrease of the wave height in alkaline region was ascribed to the conversion of the nitro form to aci-nitro anion rather than the ester hydrolysis. Only ethyl nitroacetate developed a wave for the aci-nitro anion. The coulometric n values and the products obtained, combined with the polarographic results, suggest the scheme (1) as the most probable reduction mechanism. The production of amine is only possible through C=N double bond formation, but not through hydroxyamino derivatives as usually suggested.

Further Studies on Formation of N-Formyl Hydroxyaminoacetic Acid by Penicillium

The discovery, isolation, characterization, and some biological activities of N-formyl hydroxyaminoacetic acid, have been reported (4, 6). This compound is produced by a number of species of Penicillium with the best producers thus far belonging to the P. frequentans series (3). One may consider N-formyl hydroxyaminoacetic acid as an analogue of glycine in which a formyl and a hydroxyl substitute for the hydrogens on the amino nitrogen. It would be interesting to determine if Nformyl hydroxyamino derivatives of other amino acids are also produced. The studies reported herein are directed to this possibility as well as to basic prob'ems of the formation of N-formyl hydroxyaminoacetic acid, hereafter referred to as NFHAA.