Synthesis in the fields of 5-nitrofuryl-2-polyalkenals and 5-nitrofuryl-2-polyalkenones. VII. Synthesis and investigation of the antibacterial properties of derivatives of α,β-unsaturated and polyene aldehydes and ketones of the 5-nitrofuran series

Antibacterial properties and toxicities were determined for 66 compounds of the 5-nitrofuran type to ascertain the connection between structure and biological activity.Unsaturated 5-nitrofuran aldehydes and some of their simplest derivatives (acetals, acylals) have high antibacterial activity and a broad spectrum. However, these compounds cannot be used in medicine because of their appreciable toxicities and low stabilities. One of the ,-unsaturated ketones in this series, 5-nitrofurfurylideneacetone, has a broad antibacterial spectrum combined with lower toxicity. Low-toxicity derivatives of 1-aminohydantoin and 3-amino-2-oxazolid-2-one are among the imino derivatives of high antibacterial activity investigated.For Part VI see [1].     

Synthesis and antibacterial activity of C-2(S)-substituted pleuromutilin derivatives

<正>In order to probe the effect of C-2(S)-substituted groups in the antibacterial activity,a series of novel C-2(S)-substituted pleuromutilin analogues of SB-225586 were synthesized and evaluated for their in vitro antibacterial activity.The results of antibacterial activities indicated that C-2(S)-substituted pleuromutilin derivatives retained appreciable antibacterial activity,and the 2-fluorination compounds 6a and 6b are more potent than the corresponding 2-hydroxylation analogues 7a and 7b.     

Infrared absorption spectra of functional derivatives of 5-nitrofurfuryl-2-polyalkenes and intramolecular interaction

The frequency characteristics of the vibration spectra of a number of polyalkene derivatives of 5-nitrofuran are examined. In particular, the IR spectra vibrations frequencies of the furan ring, nitro group, double bonds, and carbonyl group are examined with respect to the near and more remote intramolecular environment. The effects of intramolecular interaction, transmitted both through a chain of a 2-substituted system of the polyene type, and through a system of furan ring double bonds, are determined. The problem of the aromaticity of the furan ring is considered.     

Synthesis and antibacterial activity of Schiff bases of 5-substituted isatins

Based on the existing reports on the bioactive isatin derivatives, a number of Schiff bases were synthesized by reacting 5-substituted isatins with bioactive amines/hydrazides and their structures were confirmed using spectroscopic methods such as NMR, IR and mass spectrometry. Furthermore, Nbenzylation of isatin followed by the Schiff base formation furnished a new series of compounds(11a–13c) which allowed the analysis of the effect of isatin N-substitution on the bioactivity of the resulting compounds. The antibacterial activity of the synthesized derivatives was evaluated using a microtiter plate method on a series of gram positive and gram negative bacterial strains. Compounds 2d, 3b, 5c and 6a were among the most potent derivatives against Pseudomonas aeruginosa(MIC = 6.25 μg/m L).Analysis of the structure–activity relationship showed that the incorporation of(thio)urea-based Schiff bases lead to more potent derivatives with a broader spectrum of antibacterial activity. In addition,highly lipophilic compounds such as 11a–12c did not show any measurable antibacterial activity, which implies that an optimal lipophilicity might be an important requirement for the antibacterial activity of the studied isatins. Finally, the finding that hydantoin derivatives of N-benzylisatins(13a–13c) still exhibit some antibacterial activity prompted us to consider exploring the bioactivity of more diverse derivatives of isatin-aminohydantoin Schiff bases(compounds 1a–1d) in our future studies.     

1H and13C NMR spectra of 2-substituted 5-nitrofurans and conformation of chemotherapeutic preparations of the 5-nitrofuran series

The¹H and¹³NMR spectra of t-nitrofuran and 17 2-substituted 5-nitrofurans were investigated. The Δ¹H and Δ¹³C substituent increments [Δ = δ(2-X-5-nitrofuran) δ(5-nitrofuran)] in the spectra of these compounds were analyzed by comparison with the analogous 5-methylfuran and furan derivatives, and the change in the sensitivity of the chemical shifts of the ring protons and the carbon atoms to the effects of substituents X as a function of the electronic character of substituent R was also analyzed. The chemical shifts and the spin-spin coupling constants were used to determine the preferred orientation of the substituents relative to the furan ring. It was found that medicinal preparations of the 5-nitrofuran series (5-nitrofurfurylidenehydrazones) exist in the form of s-trans conformers in solutions in dimethyl sulfoxide and water, whereas furagin has primarily the structure of the E s-trans form. Translated from Khimiya Geterotsiklichesklkh Soedinenii, No. 2, pp. 167–176, February, 1980. The authors thank N. O. Saldabol, M. A. Trushule, and K. K. Venter for providing us with samples of the compounds, the synthesis of which has been described in the literature.     

Synthesis and Antimicrobial Studies of Organophosphates Derived From 2-(2″-Hydroxynaphthyl)Benzoxazole

Abstract

A series of biologically active phenoxy derivatives of 2-substituted benzoxazole organophosphates have been synthesized by the reaction of O-(naphthyl benzoxazolyl-2-) phosphorodichloridate/phosphorodichloridothioate with phenol/4-chlorophenol/4-nitroph- enol in 1:1 and 1:2 molar ratios. These compounds have been characterized on the basis of elemental analysis, IR, ¹H NMR, ³¹P NMR, and mass spectral studies. The antibacterial activity of these 2-substituted benzoxazole phenoxy derivatives has been evaluated against pathogenic bacteria Staphylococcus aureus (+ve) and Escherichia coli (?ve). The antifungal activity of these 2-substituted benzoxazole phenoxy derivatives has been evaluated against pathogenic fungi Aspergillus niger and Fusarium oxysporium. All compounds were found to have significant antibacterial and antifungal activity.     

1-(4-取代苯基)-4-苯基-5-(2-羟基苄基)氨基-1,2,3-三唑类衍生物的合成及抑菌活性

将邻羟苯基引入1,2,3-三唑结构中, 设计合成了10个1-(4-取代苯基)-4-苯基-5-取代-1,2,3-三唑类衍生物. 首先, 以对位取代的芳胺为原料, 经重氮化、叠氮化、闭环和缩合反应制得1-(4-取代苯基)-4-苯基-5-水杨醛亚胺-1,2,3-三唑类衍生物(3a~3e), 再用硼氢化钠还原制得1-(4-取代苯基)-4-苯基-5-(2-羟基苄基)氨基-1,2,3-三唑类衍生物(4a~4e). 目标化合物的结构经核磁、IR及元素分析确认. 抑菌活性测试表明, 当质量浓度为0.1 mg/L时, 除化合物3e和4e外, 所有化合物对白色念球菌的抑菌率均达95%以上, 对大肠杆菌的抑菌率达85%以上, 具有强抑菌活性, 表明该类化合物在抗菌药物开发方面有重要应用价值.     

Synthesis of 4-oxo-4H-quino[2,3,4-i,j][1,4]-benoxazine-5-carboxylic acid derivatives

The synthesis and antibacterial activity of 1-substituted amino-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benox-azine-5-carboxylic acid derivatives is described. Key steps in the synthesis include carbon homologation and two intramolecular nucleophilic displacement cyclization reactions to generate the 4-oxo-4H-quino[2,3,4-i,j]-[1,4]benoxazine-5-carboxylic acid nucleus.     

Synthesis and antibacterial activity of a new series of 2,3,5,7-substituted-pyrido[2,3-d]pyrimidin-4(3h)-one derivatives

A new series of 2,3,5,7-substituted-pyrido[2,3-d]pyrimidin-4(3H)-one derivatives were prepared from 2-amino-N,6-substituted phenyl-4-(trifluoromethyl or methyl)nicotinamides. The key intermediate 2-amino-N,6-substituted phenyl-4-(trifluoromethyl or methyl)nicotinamides were synthesized from 2-bromo-N,6-disubstituted phenyl-4-(trifluoromethyl or methyl)nicotinamides as well as from ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) coupling of 2-amino-4,6-substituted nicotinic acid and substituted arylamines. All the synthesized compounds were screened for antibacterial activity against Gram +ve and Gram -ve bacteria. Compound 7c showed better antibacterial activity against Gram +ve and Gram -ve bacteria.     

π-Electron structure of the nitrofuran system

Distribution of the unpaired electron in the first free MO, the partial bond orders created by this electron, and the energy level corresponding to it in anion radicals of the nitrofuran series have been examined on the basis of quantum-chemical calculations by the MOH method of the -electron system of 5-nitrofuran and its 2-substituted derivatives. Distribution of the spin density of the electrons in the anion radicals has also been calculated by McLachlan's method. The parameters of the first free MO obtained by calculation agree satisfactorily with the physicochemical characteristics of the corresponding particulars measured experimentally (HFS constants in the EPR spectra and polarographic half-wave potentials).     

Microwave-assisted solvent-free synthesis and in vitro antibacterial screening of quinoxalines and pyrido[2, 3b]pyrazines

We report herein the microwave assisted synthesis, without solvents and catalysts, of 6-substituted quinoxalines and 7-substituted pyrido[2,3b]pyrazines. The compounds were obtained in good yields and short reaction times using the mentioned procedure and two new structures are reported. A complete 1H- and 13C-NMR assignment was performed using 1D and 2D-NMR. Additionally, an in vitro screening was performed on Gram-positive and Gram-negative bacteria using amoxicillin as positive reference. Compounds bearing a pyridyl group tended to have higher antibacterial activity, but the best activity against Bacillus subtilis and Proteus mirabilis was observed with quinoxaline derivatives.     

Synthesis of 4,12-dihydro-4-oxoquino-[1,8a,8-a,b]quinoxaline-5-carboxylic acid derivatives

The synthesis and antibacterial activity of 1-substituted amino-2-fluoro-4,12-dihydro-4-oxoquino[1,8a,8-a,b]quinoxaline-5-carboxylic acid derivatives are described. The synthetic route includes a carbon homologation and two intramolecular nucleophilic displacement cyclization reactions leading to the novel 4,12-dihydro-4-oxoquino[1,8a,8-a,b]quinoxaline-5-carboxylic acid heterocycle.     

Synthesis and antifungal activity of some allylamine derivatives

Benzo- and mesitonitrile oxides react with allylamine to yield 5-aminomethyl-2-isoxazolines and open-chain N-substituted amidoximes. The allylamine derivatives were evaluated as potential antifungal and antibacterial agents. The N-allylbenzamidoxime 2a was found to be only moderately active against dermatophytes.     

An efficient synthesis of designed 4-thiazolidinone fused pyrimidine derivatives as potent antimicrobial agents

A novel series of hybrid 2-substituted ((pyrimidin-2-yl)hydrazinyl)thiazolidin-4-one derivatives were synthesized by means of aromatic nucleophilic displacement of chlorine atoms of 2,4,6-trichloro pyrimidine. Synthesis of some novel 2-(2-(6-morpholino-4-substituted(phenyl amino)pyrimidin-2-yl)hydrazinyl)thiazol-4(5H)-one derivatives have been carried out by the displacement of chlorine atoms on the basis of functionality concept on varying conditions. The synthesized hydrazinyl thiazolidin-4-one pyrimidine derivatives were evaluated for their expected antimicrobialactivity; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Afforded title analogs were subsequently characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR, Mass spectroscopy. SAR and HOMO-LUMO studies were also carried out for confirming the structure biological activity. Thus, these studies suggested that hydrazinyl pyrimidine derivatives bearing thiazolidinone moiety are interesting scaffolds for the development of novel antimicrobial agents.     

Studies on cardiotonic agents. VII. Potent cardiotonic agent KF15232 with myofibrillar Ca2+ sensitizing effect

A series of novel 4,5-dihydro-5-methyl-6-(2 or 4-substituted 7-quinazolinyl)-3(2H)-pyridazinones was synthesized and examined for cardiotonic activity in anesthetized dogs. The 4-substituted aminoquinazolines generally showed potent and long-lasting inotropic activity. Fall in the activity was observed on the introduction of substituent at the 2-position of the quinazoline ring. The 3-substituted 4 (3H)-quinazolinimines generally exhibited weak activity. Ca2+ sensitizing effect of the 4-substituted amino derivatives was also examined in chemically skinned fiber from papillary muscle of guinea pig. The alkylamino derivatives exhibited small sensitizing effect, while the benzylamino derivatives exhibited large effect. Among them, KF15232 (Ix) was found to have the most potent cardiotonic and Ca2+ sensitizing activities.     

3-(吗啉吡啶基)-5-取代异噁唑类化合物的合成及抗菌活性研究

以6-氯-3-吡啶甲醛为原料, 通过多步反应合成了一系列3-(吗啉吡啶基)-5-取代异噁唑类化合物, 并用IR, 1H NMR, 13C NMR和MS进行了结构确证. 这些化合物均以异噁唑为母核, 具有近似的平面结构, 在异噁唑环的3-位引入吗啉吡啶基, 而在5-位引入酯基、取代氨基、三唑环和噁唑烷酮环. 研究了这些化合物对金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌和大肠杆菌的抑制活性, 发现与噁唑烷酮类上市药物利奈唑胺相比, 目标化合物均显示出更低的抗菌活性, 最低抑制浓度(MIC)大于32 mg/L, 这些试验结果表明异噁唑母核的5-位缺乏sp3杂化结构, 可能会导致抗菌活性的显著降低.     

π-Electronic structure of the nitrofuran system

Anion radicals of 2-vinylene derivatives of 5-nitrofuran were obtained by electrochemical generation. The hyperfine structure (hfs) of the ESR spectra of these anion radicals indicates delocalization of the unpaired electron over their entire π-electron system. The effect of the vinylene grouping on the distribution of the unpaired electron in the anion radicals and on the distribution of the unpaired electron in the vinylene grouping itself was examined on the basis of the hfs constants. It was found that the vinylene grouping by localizing more than 10% of the density of the unpaired electron on itself reduces, by a factor of 1.4, the effect of substituents in the 2 position of 5-nitrofuran on the distribution of the spin of the unpaired electron in the nitrofuran framework.     

Synthesis, antibacterial activity and quantum-chemical studies of novel 2-arylidenehydrazinyl-4-arylthiazole analogues

A new series of 2-arylidenehydrazinyl-4-arylthiazole derivatives (2a-k) was designed and synthesized through a rapid, simple, and efficient methodology in excellent isolated yield. These compounds were screened for in vitro antimicrobial activities against eight bacteria, e.g. Bacillus cereus, Staphylococcus aureus, Bacillus subtilis, Bacillus megaterium, Pseudomonas aeruginosa, Shigella dysenteriae, Salmonella typhi, Escherichia coli, and three fungi e.g. Aspergillus oryzae, Candida albicans, and Saccharomyces cerevis. The results indicate that some of the compounds exhibit strong antibacterial activity, depending on the bacterial strain, but show virtually no antifungal activity. The structure-antibacterial activity relationships were studied using some physicochemical and quantum-chemical parameters with the ab initio Hartree-Fock model at the RHF/6-31G level of theory. A good qualitative correlation between predicted lipophilic parameters and antibacterial activity has been found.     

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 1. Conversion of 5-substituent on oxazolidinone

A structure-activity relationship (SAR) study on 5-substituted oxazolidinones as an antibacterial agent is described. The oxazolidinones, of which 5-acetylaminomethyl moiety was converted into other functions, were prepared and evaluated for antibacterial activity. Elongation of the methylene chain (8) and conversion of the acetamido moiety into guanidino moiety (12) decreased the antibacterial activity. The replacement of carbonyl oxygen (=O) by thiocarbonyl sulfur (=S) enhanced in vitro antibacterial activity. Especially, compound 16, which had the 5-thiourea group, showed 4-8 stronger in vitro activity than linezolid. Our SAR study revealed that the antibacterial activity was greatly affected by the conversion of 5-substituent.     

Synthesis,reactions and biological evaluation of some 1,2,4-triazine derivatives

6-Substituted benzyl-4-phenyl-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-5-ones 3a-d were prepared and converted into their corresponding 3-methylthio derivatives 4a-d . Reaction of compounds 4a-d with hydrazine hydrate gave the corresponding 4-amino-3-anilino-4,5-dihydro-1,2,4-triazin-5-ones 5a-d . 6-Substituted benzyl-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-diones 9a-c were synthesized and allowed to react with hydrazine hydrate to give the corresponding 6-substituted benzyl-4-amino-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-diones 10a-c . The biological evaluation of some of these triazines is described. All compounds were screened for antiviral, antibacterial, antimycobacterial, antifungal and antiyeast activity. No important biological activity was found.