Synthesis and in vitro antimicrobial activity of some novel substituted benzimidazole derivatives having potent activity against MRSA

The novel benzimidazole derivatives (3, 5, 8, 9, 12-14, 18-41) were prepared in this paper and the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA, standard and clinical isolates), Bacillus subtilis, Escherichia coli and Candida albicans were evaluated. Compounds 24-26 which have no substitution of N-1 position displayed better antibacterial activities than those of standards (ciprofloxacin, ampicillin and sultamicillin) against both the drug-resistant bacteria (MRSA, standard and clinical isolates). These derivatives (24-26), 2,5,6-trihalogenobenzimidazole analogues (8, 12), 5,6-dichloro-2-amino derivative (13), and 5-chloro-2-(4-benzyloxyphenyl)benzimidazole (35) exhibited the most potent antibacterial activity with MIC 3.12 microg/ml against S. aureus.     

Synthesis and antibacterial activity of nitroaryl thiadiazole-gatifloxacin hybrids

A number of gatifloxacin analogues containing a nitroaryl-1,3,4-thiadiazole moiety attached to the piperazine ring at C-7 position were prepared and evaluated as antibacterial agents against a panel of gram-positive and gram-negative bacteria. Among synthesized compounds, nitrofuran analog 6a exhibited more potent inhibitory activity against gram-positive bacteria including Staphylococcus epidermidis (MIC=0.0078 microg/mL), Bacillus subtilis (MIC=0.0039 microg/mL), Enterococcus faecalis (MIC=0.125 microg/mL) and Micrococcus luteus (MIC=0.125 microg/mL), with respect to other synthesized compounds and reference drug gatifloxacin. The target compounds were also assessed for their cytotoxic activity against normal mouse fibroblast (NIH/3T3) cells using MTT assay. The results indicated that these compounds exhibit antibacterial activity at non-cytotoxic concentrations.     

QSAR studies on benzoylaminobenzoic acid derivatives as inhibitors of beta-ketoacyl-acyl carrier protein synthase III

Fatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a attractive target since it is central to the initiation of fatty acid biosynthesis. Quantitative structure-activity relationship (QSAR) studies have been carried out on a series of benzoylaminobenzoic acid derivatives as potent inhibitors of FabH and antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Neisseria meningitidis and Escherichia coli, which demonstrate FabH inhibitory activity in cell free and whole cell system. The QSAR studies revealed that inhibitory activity increases with increase in hydrophobicity, molar refractivity, aromaticity, and presence of OH group (on x position of the nucleus). On the other side presence of hetero-atoms like N, O, or S at R(1) position of the nucleus decreases the inhibitory activity. The comparison of QSAR between the FabH inhibitory activity and antibacterial activity against S. aureus, S. pneumoniae, S. pyogenes, E. faecalis, N. meningitidis also demonstrates that the hydrophobicity, aromaticity and presence of OH group (on x position of the nucleus) are conducive for the inhibitory activity.     

Antibacterial and antifungal activity of lawsone and novel naphthoquinone derivatives

Introduction

Naphthoquinone derivatives are under investigation as potential therapeutic agents. The antibacterial and antifungal activity of lawsone and of some novel naphthoquinone derivatives was assessed in vitro.

Methods

The antimicrobial activity was determined using diffusion disk and the broth microdilution methods against seven bacteria and three Candida species, according to recommendations of the Clinical and Laboratory Standards Institute.

Results

Two compounds (P05 et P06) presented a good antibacterial effectiveness against two gram-positive bacteria. No antifungal potency was observed against the three Candida albicans strains used in the test.

Conclusion

Our results prove that the introduction of substituents on ketone function position 4 decreased the antimicrobial properties of the synthetized compounds.     

Synthesis and structure-activity relationships of new antimicrobial active multisubstituted benzazole derivatives

A series of multisubstituted benzoxazoles, benzimidazoles, and benzothiazoles (5-7) as non-nucleoside fused isosteric heterocyclic compounds was synthesized and tested for their antibacterial activities against various Gram-positive and Gram-negative bacteria and antifungal activity against the fungus Candida albicans. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 100 and 3.12 microg/ml. Structure-activity relationships (SAR) studies revealed that benzothiazole ring system enhanced the antimicrobial activity against Staphylococcus aureus. In these sets of non-nucleoside fused heterocyclic compounds electron withdrawing groups at position 5 of the benzazoles increased the activity against C. albicans.     

Synthesis and antibacterial evaluation of novel 4-alkyl substituted phenyl beta-aldehyde ketone derivatives

A series of novel 4-alkylphenyl beta-aldehyde ketones and their derivatives were designed and synthesized on the basis of the chemical structures of Houttuynin and beta-lactam antibiotics. Antibacterial activities of these compounds were investigated. The results demonstrated that most of the compounds tested had moderate antibacterial activities against gram-positive pathogen Staphylococcus aureus (ATTC-25923) than Houttuynin, and gram-positive bacteria were more susceptible to the compounds than gram-negative bacteria. Compound 23 was found to be the most potent compound with MIC of 1.0 microg/mL against S. aureus. Particularly, compounds 16, 22 and 23 showed more active antibacterial activities against the clinically important pathogenic bacteria, methicillin-resistant S. aureus (MRSA) than Houttuynin and levofloxacin. The preliminary structure-activity relationship (SAR) analysis suggested that (1) the introduction of appropriate alkyl substituents into position 4 of phenyl ring enhanced antibacterial activities of these compounds, and isopropyl substituent might be more favorable; (2) the presence of ketone carbonyl moiety might play a vital role in determining significant antibacterial activities of these compounds.     

Rapid synthesis of sulfone derivatives as potential anti-infectious agents

An original one-pot microwave reaction was developed for the synthesis of sulfone derivatives as new potent antimicrobial agents. This eco-friendly methodology conducted in 30min led to desired products with good yields. The sulfones (4a and 4b) were obtained via the reaction of 3a with the corresponding halo-derivatives in the presence of sodium hydride. All compounds were tested for their antibacterial and antifungal activities against four bacterial strains (two gram positive, and two gram negative ones) and two yeasts. The disk diffusion method has shown an interesting antibacterial activity for seven compounds (3b-g and 4b) against Staphylococcus aureus. Among these seven compounds, five derivatives (3b-e and 3g) showed activity against Candida tropicalis.     

Synthesis and in vitro antibacterial activity of 7-(3-alkoxyimino-4-amino-4-methylpiperidin-1-yl) fluoroquinolone derivatives

A series of novel 7-(3-alkoxyimino-4-amino-4-methylpiperidin-1-yl)fluoroquinolone derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cytotoxicity. All of the target compounds have potent antibacterial activity against the tested Gram-positive and Gram-negative strains, and exhibit good potency in inhibiting the growth of Staphylococcus aureus including MRSA, Staphylococcus epidermidis including MRSE and Streptococcus pneumoniae (MICs: 0.125-4 μg/mL). Compound 22, with the best activity against Gram-positive strains, is 4-16 fold more potent than gemifloxacin, gatifloxacin and levofloxacin against Enterococcus faecalis, and 16- and 4-fold more potent than levofloxacin against S. epidermidis 09-6 and S. pneumoniae 08-4, respectively.     

Post Groebke-Blackburn multicomponent protocol: synthesis of new polyfunctional imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives as potential antimicrobial agents

New antimicrobial agents [imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine] have been synthesized. Their antimicrobial activities were conducted against various Gram-positive and Gram-negative bacteria including Staphylococcus aureus. Compounds 5d, 7a, 10a, 11a and 12a proved to efficiently inhibit the growth of all the Gram-positive and Gram-negative strains investigated. Results of this study showed that the nature of the substituents on the armed phenyl groups determined the extent of the activity of the fused imidazopyridine and/or imidazopyrimidine derivatives. Preliminary structure-activity observations revealed that groups with positive sigma and positive bi values (e.g. 5d, 6c, 12a, 12d) were significantly more active compared to other bioisosteres (e.g. 5b). Furthermore, increasing the molar refractivity of the substitution pattern (e.g. 5b, 6b and 6d) sharply decreased the antibacterial activity.     

Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents

In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H(2)SO(4) and fuming HNO(3). Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, (1)H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative Staphylococcus. Derivative Ga (NAH) was found to show very high activity against the Candida colonies and derivative Gd (NiQNA) was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-negative bacteria included in our study was found to be inhibited by derivative Gb (QN).     

Synthesis and antibacterial activity of 2-(4-substituted phenyl)-3(2H)-isothiazolones

Several new and known 2-(4-substituted phenyl)-3(2H)-isothiazolone derivatives with or without chloro substituent at C-5 position were synthesized and their in vitro antibacterial activity against selected Gram-negative and Gram-positive bacteria were evaluated using agar dilution method. Most of compounds exhibited moderate to high activities against tested microorganisms, and in comparison with the reference drugs some compounds showed comparable or higher activities. In contrast to results of the previous studies, some 5-chloro derivatives showed lower or comparable activities against some tested microorganism, in comparison with analogues without C-5 substitution. In general, most of the compounds bearing electron withdrawing group at 4-position of the phenyl ring were more active against Gram-positive and most of those having piperazine derivatives were more active against Gram-negative bacteria.     

New triorganotin(IV) derivatives of dipeptides as anti-inflammatory-antimicrobial agents

New triorganotin(IV) derivatives of dipeptides with general formulae R(3)Sn(HL), where R = Me and/or n-Bu and/or Ph and HL is the monoanion of glycylglycine (H(2)L-1), glycylvaline (H(2)L-2), glycylleucine (H(2)L-3), glycyltryptophane (H(2)L-4) and glycyltyrosine (H(2)L-5) have been synthesized and characterized on the basis of infrared, multinuclear NMR and (119)Sn Mossbauer spectroscopic studies. All the newly synthesized compounds were examined for their in vivo anti-inflammatory activity (using the carrageenan-induced paw edema bioassay in rats), acute toxicity (LD(50)) and cardiovascular activity. These compounds were also screened for their in vitro antimicrobial activity against Staphylococcus aureus Mau (29/58) and (78/71), Bacillus subtilis (18/64), Escherichia coli (326/71), Candida albicans (Pn-10), Microsporum gypseum and Euglena gracillis. The results revealed that triphenyltin(IV) derivatives exhibited anti-inflammatory activity comparable to that of phenylbutazone with high safety margin (LD(50) > 500 mg kg(-1)). Further Ph(3)Sn(Gly-Val) displays a potent cardiovascular activity. Moreover, most of the compounds displayed appreciable antibacterial activities when compared with ampicillin and norfloxacin. Compounds Ph(3)Sn(Gly-Gly) and Ph(3)Sn(Gly-Val) are the most distinctive derivatives identified in the present study because of their promising in vivo anti-inflammatory activity and in vitro antibacterial activity against gram-positive and -negative bacteria.     

Synthesis, characterization and in vitro biological studies of novel cyano derivatives of N-alkyl and N-aryl piperazine

Cyano derivatives of N-alkyl and N-aryl piperazine have been synthesized and screened for antibacterial and antifungal activities. All the synthesized compounds showed the antibacterial activity against pathogenic strains of Staphylococcus aureus (MTCCB 737), Pseudomonas aeruginosa (MTCCB 741), Streptomyces epidermidis (MTCCB 1824) and Escherichia coli (MTCCB 1652) and antifungal activity against pathogenic strains of Aspergillus fumigatus (ITCC 4517), Aspergillus flavus (ITCC 5192) and Aspergillus niger (ITCC 5405). All compounds showed mild to moderate antimicrobial activity. However, compounds 3c, 4a and 6 showed potent antibacterial activity against pathogenic strains used in the study. Compounds 3a, 3b, 4b, and 4d showed mild to moderate antifungal activity against Aspergillus pathogenic strains. The compounds reported in this study were assessed for there cytotoxicity using MTT colorimetric assay on Hela cells. All the compounds showed cell viability more than the control drug gentamicin, with compound 2 having highest i.e. 95% cell viability.     

Synthesis and antibacterial activity of levofloxacin derivatives with certain bulky residues on piperazine ring

A number of levofloxacin analogues carrying a 2-aryl-2-oxoethyl or a 2-aryl-2-oxyiminoethyl moiety attached to the piperazine ring at C-10 position have been prepared and evaluated as antibacterial agents against a series of Gram-positive and Gram-negative bacteria. Some of them exhibited significant inhibitory activity against Gram-positive bacteria.     

Synthesis and antimicrobial activity of new bromine-rich pyrrole derivatives related to monodeoxypyoluteorin

The synthesis and antimicrobial activity of new pyrrole derivatives structurally related to monodeoxypyoluteorin are described. The insertion of a keto or methylene spacer between the phenol group and the pyrroloyl moiety of brominated 2-(2'-hydroxybenzoyl)pyrroles leads to a decrease of the antibacterial activity.     

Synthesis and antibacterial evaluation of novel 8-fluoro Norfloxacin derivatives as potential probes for methicillin and vancomycin-resistant Staphylococcus aureus

A series of novel 8-fluoro Norfloxacin derivatives and the hybrids of its piperazinyl derivatives incorporated with 1,3,5-triazine and pyrimidine were synthesized. All the above compounds were evaluated for their antibacterial activity against Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus and methicillin & vancomycin-resistant S. aureus. Among all, compounds having Morpholine, N-methyl/phenyl/benzyl/pyrimidinyl piperazines and n-butylamine substitution at C-7 position, have shown increased potency in comparison to norfloxacin and ciprofloxacin.     

Synthesis and antimicrobial properties of 2-(benzylidene-amino)-benzo[d]isothiazol-3-ones

The in vitro antimicrobial activity of 2-amino-benzo[d]isothiazol-3-one and of several 2-arylideneamino derivatives carrying in the second position a substituted or unsubstituted aromatic ring or an arylalkenylidene moiety was determined by the broth dilution method against several strains selected to define their spectrum and potency. All the compounds demonstrated good antibacterial properties against Bacillus subtilis, streptococci, enterococci and staphylococci including penicillin-resistant clinical isolates. Several compounds showed excellent inhibitory properties against Streptococcus pyogenes, which is the most sensitive microorganism tested. Many benzisothiazolones exhibited good activity against Gram-negative Haemophilus influenzae. As regards antifungal activity, several of the tested compounds inhibited Saccharomyces cerevisiae at concentrations of 3-6 microg ml-1. In all cases the parent 2-amino-benzo[d]isothiazol-3-one was the most effective agent, with minimum inhibitory concentration (MIC) values ranging from 0.07 to 6 microg ml-1. The results obtained indicate that most of these compounds are wide-spectrum antimicrobial substances and promising agents against penicillin-resistant staphylococci.     

Contact-active microbicidal gold surfaces using immobilization of quaternary ammonium thiol derivatives

Contact-active auto-bactericidal surfaces were obtained by grafting of specially designed thiol derivatives containing antimicrobial quaternary ammonium moieties on gold substrates. The formation and quality of the self-assembled monolayers (SAMs) were characterized by X-ray photoelectron spectroscopy, cyclic voltammetry and contact angle measurements. The bactericidal activity of the modified gold surface was evaluated against Staphylococcus aureus using an original procedure. This activity was demonstrated to be dependent on the length of the alkyl chain borne by the charged nitrogen atom of the quaternary ammonium moiety, and on the contact time.     

Synthesis, antibacterial and antitubercular activities of some 7-[4-(5-amino-[1,3,4]thiadiazole-2-sulfonyl)-piperazin-1-yl] fluoroquinolonic derivatives

In the present study, a series of 7-[4-(5-amino-1,3,4 thiadiazole-2-sulfonyl)]-1-piperazinyl fluoroquinolonic derivatives VIIa-d were synthesized in good yields and characterized by IR, (1)H-NMR, (13)C-NMR, FAB Mass spectral and elemental analyses. The compounds were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria and selected compounds VIIa, b were screened for antitubercular activity against Mycobacterium tuberculosis H(37)Rv strain by broth dilution assay method. The antibacterial data of the tested N-sulfonylfluoroquinolones VIIa-d indicated that all the synthesized compounds showed better activity against Gram-positive bacteria S. aureus, E. faecelis, Bacillus sp. (MIC=1-5 microg ml(-1), respectively) compared to reference drugs. The MIC values of tested derivatives connotes that the sparfloxacin and gatifloxacin derivatives VIIc, d were most active against the tested Gram-positive bacterial strains (MIC=1-5 microg ml(-1)). All the tested compounds VIIa-d showed poor activity against the Gram-negative bacteria. The in vitro antitubercular activity reports of selected compounds VIIa, b against M. tuberculosis strain H(37)Rv showed moderate activity at MIC of 10 microg ml(-1).     

铜绿假单胞菌抗菌物质对屎肠球菌的体外抑菌作用研究

目的:为了观察铜绿假单胞菌对屎肠球菌的体外抑菌活性。方法:用交叉条带实验方法进行铜绿假单胞菌对12株屎肠球菌的体外抑制活性的测定。结果:铜绿假单胞菌抗菌物质对屎肠球菌体外抑菌活性良好,所试10株的铜绿假单胞菌对屎肠球菌均有一定的抗菌活性,其中第1、4、5、6号株的铜绿假单胞菌对屎肠球菌抑制率达100%。结论:铜绿假单胞菌抗菌物质对12株肠球菌具有良好的抗菌活性,无疑对肠球菌的抗菌研究方面开辟了新的思路。这是首次进行铜绿假单胞菌抗菌物质对屎肠球菌的抗菌活性研究报告。