血吸虫病化学治疗取代水楊酰苯胺类和笨 唑衍生物的合成

三十四种取代水杨酰苯胺类化合物是以取代水锡酸或取代水杨酸苯酯和取代苯胺缩合,或用取代水杨酰苯胺类经硝化而成.九种苯骈咪唑衍生物是以取代水杨酸和邻苯二胺,用多磷酸为环合剂缩合而成.所合成的化合物有几个经初步预防和治疗日本血吸虫病动物筛选试验,发现N-(5-氯水杨酰)-2′-氯-4′-硝基苯胺和N-(3,5-二氯水杨酰)-2′-氯-4′-硝基苯胺有预防作用,N-(3,5-二碘水杨酰)-2′,4′-二氯苯胺有治疗作用.     

N-碘炔丙基氧羰基氨基酸及其酯类化合物的合成和抗菌活性的研究

合成了７ 个Ｎ－碘炔丙基氧羰基氨基酸及其酯类化合物,并与防霉抗菌剂９３１ 进行比较。初步抗菌实验表明,上述大部分化合物对常见的霉菌、细菌均有不同程度的抑制作用,其中化合物４ｆ的抗菌效果较好。     

Synthesis of hydrazides of heterocyclic amines and their antimicrobial and spasmolytic activity

Un unsolvable issue of a significant number increase of drug multi resistant strains of microorganisms including Mycobacterium tuberculosis force researchers for continuous design novel pharmaceuticals.The purpose of the study is the establishment of the correlation between the structure of novel heterocyclic hydrazide derivatives and their biological activity. Several hydrazide derivatives of N-piperidinyl and N-morpholinyl and propionic acids and N-piperidinyl acetic and their derivatives were synthesized via condensation of corresponding esters with hydrazine hydrate.The structure of synthesized compounds were confirmed by the use of FTIR, H1NMR, Mass-spectroscopy and element analysis. Investigation of synthesized substances using PASS software was carried out to predict probability of pharmacological activity in silico. The antibacterial, antifungal and spasmolytic activity as well as acute toxicity of obtained compounds were evaluated in vivo. 2-(N-piperidinyl)acetic acid hydrazide and 2-methyl-3-N-piperidinyl)propanacid hydrazide revealed antibacterial and spasmolytic activities comparable to the model drugs (drotaverin) in vitro study. Synthesized compounds in in vivo experiment showed significantly low acute toxicity (LD50 520–5750 mg/kg) compared to commercially available drugs (streptomicine, ciprofloxacinum and drotaverin LD50 100–215 mg/kg). The structure- activity relationship was established that the increasing of the length of the linker between heterocyclic amine and hydrazide group results in a decrease of antimicrobial activity against studied strains (Escherichia coli, Salmonella typhymurium, Salmonella choleraesuis, Staphylococcus aureus).     

Potent antibacterial activity of halogenated compounds against antibiotic-resistant bacteria

Common Gram-positive clinical pathogens are showing an increasing trend for resistance to conventional antimicrobial agents. New drugs with potent antibacterial activities are urgently needed to remediate this problem. Halogenated compounds isolated from several species of the red algae genus Laurencia were examined for their antibacterial activity against 22 strains of human pathogenic bacteria, 7 strains of which were antibiotic-resistant bacteria. Four phenolic sesquiterpenes and a polybrominated indole showed wide spectra of antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis and E. faecium (VRE). In addition, laurinterol and allolaurinterol displayed potent bactericidal activity against three strains of MRSA at 3.13 microg mL(-1), and three strains of vancomycin-susceptible Enterococcus, at 3.13 microg mL(-1) and 6.25 microg mL(-1), respectively.     

Antibacterial activity of dipropofol and related compounds

Phenolic compounds, in general, exhibit antioxidant and antibacterial activities. We studied antimicrobial activity of the phenolic antioxidants, propofol (2,6-diisopropylphenol), tocopherol, eugenol, butylated hydroxyanisole (BHA), and several of their dimer compounds. Dipropofol (dimer of 2,6-diisopropylphenol) showed strong antibacterial activity against gram-positive strains including methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE), while propofol and other monomeric and dimeric phenols having methyl or tert-butyl groups showed no remarkable activity. The results indicated that the dimeric structure of 2,6-diisopropylphenol moiety may play an important role in the antibacterial activity.     

5-(Alkylsulfonyl)salicylanilides as potential dental antiplaque agents

A series of 22 5-(alkylsulfonyl)salicylanilides was synthesized and evaluated for in vitro antibacterial and antiplaque activity against Actinomyces viscosus and Streptococcus mutans, adherent microorganisms implicated in periodontal disease and dental caries. The minimum inhibitory concentrations of 25 salicylanilides (including 5-acyl-, 5-alkyl-, and 5-(alkylsulfonyl)-4'-bromo- and -4'-(trifluoromethyl)salicylanilides) were found to correlate (r = 0.94) with estimated log D values. Several salicylanilides, such as 5-(decylsulfonyl)- and 5-(dodecylsulfonyl)-4'-(trifluoromethyl)salicylanilides (15 and 19) were found to exhibit high levels of in vitro antibacterial and antiplaque activity against A. viscosus and S. mutans.     

Antimicrobial activities of hydrophobic 2-arylbenzofurans and an isoflavone against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus

Eight 2-arylbenzofurans and an isoflavone isolated from medicinal plants were tested for their antimicrobial activities against vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Among these compounds, six hydrophobic 2-arylbenzofurans (log P = 4.4-8.7) exhibited considerable antibacterial activity against five VRE strains(VanA-, VanB-, and VanC-phenotypes) (MICs = 3.13-6.25 microg/mL). Five compounds also showed antibacterial activity against ten MRSA strains (MIC80 = 3.13 microg/mL).     

Evaluation of the antimicrobial potency of tannins and related compounds using the microdilution broth method.

The antimicrobial activity of a total of 27 tannins and related compounds was evaluated against 8 microorganisms, including 2 Gram-positive (Bacillus subtilis, Staphylococcus aureus), 4 Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis), and 2 yeasts (Candida albicans, Cryptococcus neoformans). The compounds tested were generally found to possess only weak to moderate antibacterial, but fairly high anticryptococcal activities. Attention is given to structure-activity relationships with emphasis on simple galloyl esters, hydrolyzable tannins and proanthcyanidins among this class of secondary products.     

Evaluation of WO2012177707 and WO2012097269: Vertex's phosphate prodrugs of gyrase and topoisomerase antibacterial agents

The two patent applications describe two novel compounds in the benzimidazole class of GyrB/ParE antibacterial agents and multiple phosphate prodrugs derived from these compounds. The new benzimidazole compounds have excellent antibacterial activity on Gram-positive strains. But like previous benzimidazoles, they have limited solubility and are highly protein bound. The phosphate prodrugs offer a drug substance with high aqueous solubility that should aid both intravenous and oral formulations. The potential utility of the prodrugs was demonstrated in efficacy studies.     

Antibacterial activity of ceftriaxone against various clinical strains isolated in 2004

The susceptibility of clinical strains isolated from patients with infection to ceftriaxone (CTRX) and injectable beta-lactam antibiotics was determined in Japanese medical institutions in 2004. The in vitro antibacterial activity of the above antibiotics against clinical strains isolated in 2004 was compared with that against part of the clinical strains isolated about ten years ago (1994 - 1996). The antibacterial activity of CTRX against Streptococcus including penicillin-intermediate and penicillin-resistant Streptocuccus pneumoniae was potent and there were no large differences between clinical strains isolated in 1994 - 1996 and those in 2004 in the antibacterial activity of CTRX. CTRX inhibited the growth of all the strains of Haemophilus influenzae including beta-lactamase-negative, ampicillin-resistant (BLNAR) strains at 0.5 microg/mL or less and showed the potent antibacterial activity against these strains. In addition, since there are no large differences between strains isolated in the past and those isolated in 2004 in the antibacterial activity, CTRX is considered to be a useful antibiotic in the treatment of BLNAR infections which are increased by the causative organism of infections especially in the field of pediatrics in recent years. CTRX showed the excellent antibacterial activity against Escherichia coli and Klebsiella pneumoniae but one of the 50 strains of E. coli tested was highly resistant. The antibacterial activity of CTRX against Neisseria gonorrhoeae was the most potent in all the antibiotics tested. These results indicate that CTRX shows excellent antimicrobial activity against fresh strains isolated from patients with infections. CTRX is thus useful as a therapeutic antimicrobial for the treating a variety of infections.     

Towards eradicating antibiotic-resistant bacteria: synthesis and antibacterial activities of substituted N-(2-nitrophenyl)pyrrolidine- and piperidine-2-carboxylic acids

Antibacterial resistance is a source of great concern in the effective prevention and treatment of infections caused by bacteria, making the development of requisite therapeutics a major challenge. N-(Nitrophenyl)cycloamino acids are important compounds in the synthesis of poly-condensed nitrogen-containing heterocycles with marked activities in many biological systems. A series of substituted N-(o-nitrophenyl)cycloamino-2-carboxylic acids 3a–3g were synthesized via the condensation reaction of substituted o-halogenonitrobenzenes with L-proline 2a and D,L-pipecolinic acid 2b, under refluxing alcoholic basic conditions in excellent yields. The synthesized compounds were characterised by FT-IR, (¹H & ¹³C) NMR, UV-Vis, mass spectroscopy and elemental analysis. Their antibacterial activities were evaluated against five Gram-positive and five Gram-negative bacterial strains using the broth micro-dilution procedure. The antibacterial activities of the synthesized compounds were compared with streptomycin and nalidixic acid as standard antibiotic drugs. The minimum inhibitory concentration (MIC) values of compounds 3a–3g revealed good antibacterial activities against the tested microorganisms. Compounds 3a–3g were more potent than nalidixic acid against Enterococcus faecalis, Mycobacterium smegmatis, Escherichia coli and Proteus vulgaris and also more potent than streptomycin against Enterobacter cloacae and Staphylococcus aureus. Compounds 3a, 3c and 3g displayed the highest antibacterial potency with an MIC value of 15.6 μg/mL against E. cloacae, E. faecalis and P. mirabilis, respectively. These results indicated that these aryl cycloamino acids with antibacterial activities had potential applications as substitutes for antimicrobial peptide antibiotics, which are not susceptible to bacterial resistance, to solve the problem of drug resistance.     

Synthesis and Biological Evaluation of 2‐Mercapto‐1,3‐benzothiazole Derivatives with Potential Antimicrobial Activity

The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat. So, intensive efforts are underway worldwide to develop new antimicrobial agents. To identify compounds with a potent antimicrobial profile, we designed and synthesized low molecular weight 2‐mercaptobenzothiazole derivatives 2a – 2l and 3a – 3l . Both series were screened for in‐vitro antibacterial activity against the representative panel of Gram‐positive and Gram‐negative bacteria strains. The biological screening identified compounds 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 3.12 μg/mL against Staphylococcus aureus and 25 μg/mL against Escherichia coli, respectively. The replacement of the S‐H by the S‐Bn moiety resulted in considerable loss of the antibacterial action of the 3a – 3l series. The antibiotic action of compounds 2e and 2l was also investigated by testing their activity against some clinical isolates with different antimicrobial resistance profile. Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our molecules was evaluated. Finally, in this paper, we also describe the cytotoxic activity of the most interesting compounds by MTS assay against HeLa and MRC‐5 cell lines.     

Diamidines as antitrypanosomal, antileishmanial and antimalarial agents

Diamidine-containing compounds have a long history of use in the treatment of African trypanosomiasis and leishmaniasis. The discovery that diamidine prodrugs possess in vivo antimicrobial activity when administered orally has led to a renewed interest in this class of compounds for the treatment of parasitic infections. In this review, the selectivity of diamidines against trypanosomes, Leishmania and Plasmodium is rationalized through mechanism-of-action studies. An overview of the antiprotozoal activities of newer diamidines and diamidine prodrugs is also presented, along with a summary of the progress made toward the clinical development of new diamidines for use against these parasitic diseases.     

Synthesis and effect of silver nanoparticles on the antibacterial activity of different antibiotics against Staphylococcus aureus and Escherichia coli

Silver nanoparticles (Ag-NPs) have been known to have inhibitory and bactericidal effects. Resistance to antimicrobial agents by pathogenic bacteria has emerged in recent years and is a major health problem. The combination effects of Ag-NPs with the antibacterial activity of antibiotics have not been studied. Here, we report on the synthesis of metallic nanoparticles of silver using a reduction of aqueous Ag(+) ion with the culture supernatants of Klebsiella pneumoniae. Also in this article these nanoparticles are evaluated for their part in increasing the antimicrobial activities of various antibiotics against Staphylococcus aureus and Escherichia coli. The antibacterial activities of penicillin G, amoxicillin, erythromycin, clindamycin, and vancomycin were increased in the presence of Ag-NPs against both test strains. The highest enhancing effects were observed for vancomycin, amoxicillin, and penicillin G against S. aureus.     

Antimicrobial, antimalarial, and antileishmanial activities of mono- and bis-quaternary pyridinium compounds

Pyridinium-based oxime compounds have been utilized worldwide as antidotes following exposure to anticholinesterase agents. In the event of combined chemical and biological incident, it is of vital importance to know the ability of antidotes to provide additional protection against biological threats. This paper reports results of in vitro antimicrobial and antiprotozoal activities of a series of quaternary pyridinium oximes against a number of lower pathogenicity BSL-1 and 2 agents. In general, our compound panel had little to no antimicrobial action except for thiophene- and benzothiophene-substituted monoquaternary pyridinium compounds 21 and 24 that showed moderate antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus with IC(50) values ranging from 12.2 to 17.7 μg/mL. Compounds 21 and 24 also exhibited antileishmanial activity against Leishmania donovani with IC(50) values of 19 and 18 μg/mL, respectively. Another monoquaternary pyridinium compound with a bromobutyl side chain 17 showed antimalarial activity against both a chloroquine sensitive and resistant strains of Plasmodium falciparum with IC(50) values of 3.7 and 4.0 μg/mL, respectively. None of the bisquaternary pyridinium compounds showed antimicrobial or antiprotozoal activity. None of the compounds showed cytotoxic effects toward mammalian kidney fibroblasts. Results of this study indicate that the pyridinium compounds, some of which are already in use as antidotes, do not have significant antimicrobial and antiprotozoal activities and cannot be relied upon for additional protection in the event of combined chemical-biological incident.     

莫西沙星前药的合成及其体内外抗菌活性

分别以N-叔丁氧羰基氨基酸和莫西沙星为原料，经缩合、脱氨基保护基、中和得到8种含有氨基酰基的前药，按同样程序，还得到了2种含有二肽的前药。测定了10种莫西沙星前药及对照药对20株临床分离的革兰氏阳性菌的最小抑菌浓度以及对小鼠腹腔感染金黄色葡萄球菌01193和肺炎链球菌01182的体内保护疗效，结果表明，10种前药的体内外抗菌活性均低于左氧氟沙星和盐酸莫西沙星。     

7-(3-氨基-4-烷氧亚胺基-1-哌啶基)喹诺酮类化合物的合成与抗菌作用

为寻找新的更加优秀的喹诺酮类抗菌药，设计合成了21个7-(3-氨基-4-烷氧亚胺基-1-哌啶基)喹诺酮类化合物，并测定其体内外抗菌活性。化合物结构经¹H NMR和HRMS得到确证，并用单晶X-衍射分析确定其双键构型。化合物14a和14m表现出优秀的广谱抗菌活性，它们对所实验的12株革兰氏阳性菌的活性，总体上明显优于3个对照药，特别是对包括MRSA和MRSE在内的金葡菌和表葡菌的活性是吉米沙星和巴罗沙星的4～16倍、左氧氟沙星的8～64倍。它们对金葡菌的MIC值分别是0.25～1 mg·L^-1和0.125～1 mg·L^-1，对表葡菌的MIC值分别是0.5～4 mg·L^-1和1～8 mg·L^-1，对小鼠系统感染的体内保护作用与吉米沙星、莫西沙星基本相当(P>0.05)。     

Synthesis and antimicrobial screening of some novel chalcones and flavanones substituted with higher alkyl chains

As a part of our program to generate some novel flavonoid frameworks substituted with higher alkyl groups as possible antimicrobial agents, we have in total synthesized twelve novel chalcones (11–16) and their corresponding flavanones (17–22) substituted with either nonyl or dodecyl chains in ring B in very good to excellent yields. The synthesized compounds have been screened for their antimicrobial potential against six bacterial and four fungal strains. The tested compounds, in general, showed significant antibacterial and comparable antifungal activities. While the chalcone (16) with a dodecyl chain showed highly promising antibacterial activity against almost all the organisms tested, the chalcone (13) with nonyl chain showed promising antifungal activity against Candida rugosa and Aspergillus niger strains.     

Synthesis of some novel amino and thiotetrazole purine derivatives and investigation of their antimicrobial activity and DNA interactions

A series of amino and thiotetrazole purine derivatives introduced with different alkyl groups in position 9 was synthesized. The structures of the synthesized compounds were characterized using spectroscopic methods. All the synthesized compounds were screened for their antibacterial activities against Gram-positive and Gram-negative bacteria and for their antifungal activities against yeast strains. The effect of the compounds on pBR322 plasmid DNA was studied by gel electrophoretic mobility measurements. The results of antimicrobial activity show that attachment of tetrazole group to purine bases results in disappearance of antimicrobial activity The results of the plasmid DNA interaction and the restriction studies suggest that while aminotetrazole purine derivatives cause DNA damages, thiotetrazole purine derivatives are believed to form a range of interstrand GG adducts with duplex DNA that induce global changes in the DNA conformation.     

Comparative antibacterial properties in vitro of seven olivanic acid derivatives: MM 4550, MM 13902, MM 17880, MM 22380, MM 22381, MM 22382 and MM 22383

Streptomyces olivaceus ATCC 31365 produces a family of novel beta-lactam antibiotics collectively referred to as the olivanic acids. Seven such compounds, MM 4550, MM 13902, MM 17880, MM 22380, MM 22381, MM 22382 and MM 22383 have been identified which have the same carbapenem nucleus but with different side chains attached to the nucleus. The compounds with an (8S) hydroxyethyl substituent and cis-orientated beta-lactam protons, MM 22380 and MM 22382, and their sulphate esters, MM 17880 and MM 123902, are potent antibiotic with MIC values against Gram-positive and Gram-negative bacteria in the range 0.1 3.1 microgram/ml. The corresponding (8S) hydroxyethyl compounds with trans-beta-lactam protons, MM 22381 and MM 22383, also have broad-spectrum activity but are rather less potent than the cis-compound. In addition to their antibiotic activity, the olivanic acids inhibit a number of beta-lactamases and enhance the activity of beta-lactams such as amoxycillin against beta-lactamase-producing bacteria. Significant differences are observed both in antibacterial activities and in beta-lactamase inhibition properties when the olivanic acids are compared with the related thienamycin antibiotics which have (8R) rather than (8S) stereochemistry and trans-beta-lactam protons.