Fluoroquinolone Analogs Research Articles

Probing RNA-Small Molecule Interactions Using Biophysical and Computational Approaches.

Interest in small molecules that target RNA is flourishing, and the expectation set on them to treat diseases with unmet medical needs is high. However, several challenges remain, including difficulties in selecting suitable tools and establishing workflows for their discovery. In this context, we optimized experimental and computational approaches that were previously employed for the protein targets. Here, we demonstrate that a fluorescence-based assay can be effectively used to screen small molecule libraries for their ability to bind and stabilize an RNA stem-loop. Our screen identified several fluoroquinolones that bind to the target stem-loop. We further probed their interactions with the target using biolayer interferometry, isothermal titration calorimetry (ITC), and nuclear magnetic resonance spectroscopy. The results of these biophysical assays suggest that the fluoroquinolones bind the target in a similar manner. Armed with this knowledge, we built models for the complexes of the fluoroquinolones and the RNA target. Then, we performed fragment molecular orbital (FMO) calculations to dissect the interactions between the fluoroquinolones and the RNA. We found that the binding free energies obtained from the ITC experiments correlated strongly with the interaction energies calculated by FMO. Finally, we designed fluoroquinolone analogues and performed FMO calculations to predict their binding free energies. Taken together, the results of this study support the importance of conducting orthogonal assays in binding confirmation and compound selection and demonstrate the usefulness of FMO calculations in the rational design of RNA-targeted small molecules.

Fluoroquinolone Analogs, SAR Analysis, and the Antimicrobial Evaluation of 7-Benzimidazol-1-yl-fluoroquinolone in In Vitro, In Silico, and In Vivo Models.

Structure-activity relationship (SAR) studies allow the evaluation of the relationship between structural chemical changes and biological activity. Fluoroquinolones have chemical characteristics that allow their structure to be modified and new analogs with different therapeutic properties to be generated. The objective of this research is to identify and select the C-7 heterocycle fluoroquinolone analog (FQH 1-5) with antibacterial activity similar to the reference fluoroquinolone through in vitro, in silico, and in vivo evaluations. First, SAR analysis was conducted on the FQH 1-5, using an in vitro antimicrobial sensibility model in order to select the best compound. Then, an in silico model mechanism of action analysis was carried out by molecular docking. The non-bacterial cell cytotoxicity was evaluated, and finally, the antimicrobial potential was determined by an in vivo model of topical infection in mice. The results showed antimicrobial differences between the FQH 1-5 and Gram-positive and Gram-negative bacteria, identifying the 7-benzimidazol-1-yl-fluoroquinolone (FQH-2) as the most active against S. aureus. Suggesting the same mechanism of action as the other fluoroquinolones; no cytotoxic effects on non-bacterial cells were found. FQH-2 was demonstrated to decrease the amount of bacteria in infected wound tissue.

Design and synthesis of novel cytotoxic fluoroquinolone analogs through topoisomerase inhibition, cell cycle arrest, and apoptosis

To exploit the advantageous properties of approved drugs to hasten anticancer drug discovery, we designed and synthesized a series of fluoroquinolone (FQ) analogs via functionalization of the acid hydrazides of moxifloxacin, ofloxacin, and ciprofloxacin. Under the NCI-60 Human Tumor Cell Line Screening Assay, (IIIf) was the most potent among moxifloxacin derivatives, whereas (VIb) was the only ofloxacin derivative with significant effects and ciprofloxacin derivatives were devoid of activity. (IIIf) and (VIb) were further selected for five-dose evaluation, where they showed potent growth inhibition with a mean GI50 of 1.78 and 1.45 µM, respectively. (VIb) elicited a more potent effect reaching sub-micromolar level on many cell lines, including MDA-MB-468 and MCF-7 breast cancer cell lines (GI50 = 0.41 and 0.42 µM, respectively), NSCLC cell line HOP-92 (GI50 = 0.50 µM) and CNS cell lines SNB-19 and U-251 (GI50 = 0.51 and 0.61 µM, respectively). (IIIf) and (VIb) arrested MCF-7 cells at G1/S and G1, respectively, and induced apoptosis mainly through the intrinsic pathway as shown by the increased ratio of Bax/Bcl-2 and caspase-9 with a lesser activation of the extrinsic pathway through caspase-8. Both compounds inhibited topoisomerase (Topo) with preferential activity on type II over type I and (VIb) was marginally more potent than (IIIf). Docking study suggests that (IIIf) and (VIb) bind differently to Topo II compared to etoposide. (IIIf) and (VIb) possess high potential for oral absorption, low CNS permeability and low binding to plasma proteins as suggested by in silico ADME calculations. Collectively, (IIIf) and (VIb) represent excellent lead molecules for the development of cytotoxic agents from quinolone scaffolds.

Designing benign molecules: The influence of O-acetylated glucosamine-substituents on the environmental biodegradability of fluoroquinolones

Antibiotics are detected worldwide in the aquatic environment, with continuously rising concentrations. Antibiotics in the environment have the potential to damage ecosystems and contribute to the development of resistance. Whilst a few antibiotics, such as some β-lactams, are eliminated by effluent treatment, others, such as fluoroquinolones, are not or just partially removed and enter the environment. Therefore, approaches are needed to tackle those problems at the compound level. Benign by design (BbD), an important part of green pharmacy, has the goal to integrate environmental fate and end-of-use considerations at the very beginning, i.e., into the design of active pharmaceutical ingredients. Hence, pharmaceuticals should be designed to be sufficiently active and stable during storage and usage but should degrade after excretion into the environment, so that they cannot cause any adverse effects.Fluoroquinolones (FQs) are important broad-spectrum antibiotics. They are known to be persistent in the environment and to be neither inactivated nor degraded or even mineralized during sewage treatment. The addition of new substituents via amidation, like glucosamine moieties, at the carboxylic group of FQs, led to better antimicrobial activity compared to its parent compounds against various microorganisms. To investigate if the addition of sugar moieties could improve the overall environmental biodegradability of FQs, eight novel quinolone and fluoroquinolone analogs conjugated with 1,3,4,6-Tetra-O-acetyl-β-d-glucosamine and 2-deoxy-d-glucopyranose have been investigated regarding their ready biodegradability (OECD 301D/F) and their degradation pathways have been analyzed. According to the OECD 301D test, none of the substances could be classified as readily biodegradable. However, the O-acetyl analogs did undergo a partial degradation of the O-acetyl glucosamine moiety, via stepwise deacetylation and the degradation of the whole glucosamine moiety. The degradation resulted in Fluoroquinolone-3-carboxamide derivatives.Those insights could be further used as input for fragment-based design of benign APIs that will degrade once they reached the environment.

QSCR Analysis of Cytotoxicity of 6-Fluoro-3-(4H-1,2,4-triazol-3- yl)quinolin-4(1H)-ones on Chinese Hamster Ovary Cell Line: Design of REPUBLIC1986.

6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-ones are promising antitumor agents with enormous data on their profound cytotoxic effects on the human cancer cell lines. We sought to perform a Quantitative structure cytotoxicity relationship (QSCR) analysis of a series of previously reported fluoroquinolone analogues using computerassisted multiple regression analysis and investigate the cytotoxicity-inducing structural parameters among these congeners. The dataset was segregated into training and test sets of 6-Fluoro-3-(4H-1,2,4- triazol-3-yl)quinolin-4(1H)-ones by using a random selection method embedded in Vlife MDS 4.6 software and subjected to QSCR analysis. Next, cross-validation of the generated QSCR models was performed along with the external test set prediction. Finally, the data was analyzed and contour plots were developed to deduce the cytotoxicity-inducing structural parameters among these congeners using Minitab® software. The validated QSCR model exhibited a statistically significant predictive value of 92.27 percent. Our QSCR model revealed a direct proportionality between hydrogen counts and cytotoxicity, and exclusion of sulphur and nitrogen with lesser crowding of cyclopropyl rings in future potential 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin-4(1H)-one analogues. Based on the QSCR model predictions and contour plot analysis, the de novo REPUBLIC1986 molecule provided the best hit with predicted IC50 (μM) of 0.45 against CHO cell line and is amenable to salt formation crucial for anti-ovarian cancer activity. These findings suggest the relevancy of the developed QSCR model in designing novel, potent, and safer anti-cancer drugs with 6-Fluoro-3-(4H-1,2,4-triazol-3-yl)quinolin- 4(1H)-ones as seed compounds.

Development and Validation of a RP-HPLC Method for Simultaneous Determination of Levofloxacin and Moxifloxacin in Pharmaceutical Dosage Forms

A simple, fast and economic reversed phase high performance liquid chromatographic (HPLC) method has been successfully developed and validated for simultaneous determination of fluoroquinolone analogs namely levofloxacin and moxifloxacin in both pure form (as API) and in pharmaceutical dosage forms. The method was validated according to the guidelines of ICH, FDA and USP with respect to accuracy, precision and linearity. For method development a C-18 bonded silica column (250 x 4.6 mm, 5μ, Phenomenex, Inc) was used with a mobile phase comprising of 10% aqueous solution of acetic acid and acetonitrile in a ratio of 80:20 v/v. The flow rate was 0.5 mL/min and effluents were monitored at 300 nm and the retention times were found to be at 7.0±0.1 min and 10.59±0.1 min for levofloxacin and moxifloxacin, respectively. The recovery was found to be more than 99% for each spiked samples of levofloxacin and moxifloxacin, demonstrating the accuracy of the protocol. Intra-day and inter-day precisions of the new method were less than the maximum allowable limit (RSD% £ 2.0) according to FDA. The method showed linear response with correlation coefficient value of 0.9975 in both the cases.
 Therefore, the developed method was found to be simpler, accurate, reproducible, efficient and less time consuming and can be successfully applied for the simultaneous assay of levofloxacin and moxifloxacin formulations.HPLC, method development, validation, levofloxacin, moxifloxacin.

Design and Synthesis of Fluoroquinolone Derivatives as Potent α‐Glucosidase Inhibitors: In Vitro Inhibitory Screening with In Silico Docking Studies

AbstractFluoroquinolones are extensively used in clinical applications as a crucial class of antibacterial medicine and have shown high potential for the treatment of several other diseases. This study is based on synthesis, structure elucidation and biological evaluation of various fluoroquinolone (enoxacin) analogues with electrophilic substitution of aromatic amine moiety of central enoxacin nucleus by benzyl halides. The synthesized derivatives were characterized on the basis of different chemical and physical measurements and structures were elucidated by various spectroscopic techniques (NMR, EI‐MS), including elemental (CHN), and X‐ray diffraction analysis. Furthermore these compounds were investigated for their potential α‐glucosidase inhibition activities and all synthesized analogues of fluoroquinolones were found to exhibit promising inhibition potential of 45.8±0.2 to 74.5±0.2 μM in comparison to IC50 value of 425.6±1.3 μM for standard inhibitor of α‐glucosidase1‐deoxynojirimycin. Further, docking of synthetic compounds were carried out by using α‐glucosidase I enzyme of Saccharomyces cerevisiaeas a target. The study provided an insight of the molecular interactions of fluoroquinolone derivatives with the enzyme that are in good agreement with the inhibitory activity of synthesized compounds and can be considered as a valuable tool for designing new drugs.

Cheminformatics Analysis of Fluoroquinolones and their Inhibition Potency Against Four Pathogens.

Drug-resistant bacteria are a worldwide public health concern. As the prevalence of multi-drug resistant pathogens outpaces the discovery of new antibacterials, it is of importance to explore the structure-activity relationships for series of known bactericides with proven scaffolds. Herein, we assembled a set of 507 fluoroquinolone analogues all experimentally tested for their inhibition potency against four pathogens: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. We relied on cheminformatics techniques to characterize and cluster them based on their structural similarity and analyzed the structure-activity relationships identified for each cluster of fluoroquinolones. Then, we utilized machine learning techniques to develop and validate predictive QSAR models for computing the inhibition potencies (pMIC) of analogues for each pathogen. These QSAR models afforded reasonable external prediction performances (R2≥0.6, MAE∼0.4). This study confirmed that (i) there are both global and local inter-pathogen concordance regarding the antibacterial potency of fluoroquinolones, (ii) small clusters of fluoroquinolone analogues are characterized by unique patterns of strain selectivity and potency, the latter being potentially useful to design new analogues with enhanced potency and/or selectivity towards a given pathogen, and (iii) robust QSAR models were obtained allowing for future design of new bioactive fluoroquinolones.

Design, synthesis, molecular docking study, and antibacterial evaluation of some new fluoroquinolone analogues bearing a quinazolinone moiety.

Increasing bacterial resistance to quinolones is concerning. Hence, the development of novel quinolones by chemical modifications to overcome quinolone resistance is an attractive perspective in this context. In this study, it is aimed to design and synthesize a novel series of functionalized fluoroquinolones using ciprofloxacin and sarafloxacin cores by hybridization of quinazolinone derivatives. This objective was tested by a comprehensive set of in vitro antibacterial assays in addition to SAR (structure-activity relationship) characterisation studies. A nucleophilic reaction of ciprofloxacin and sarafloxacin with 2-(chloromethyl)quinazolin-4(3H)-one in the presence of NaHCO3 in dimethylformamide (DMF) was performed to obtain the desired compounds 5a-j. Novel compounds were characterised by 1H, 13C- NMR and IR spectroscopy, MS and elemental analysis. In silico pharmacokinetics prediction assays and molecular docking studies were performed to explore the binding characteristics and interactions. Antibacterial activities of the novel compounds were evaluated by Broth microdilution, well diffusion and disc diffusion assays against three gram-positive (Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus and Enterococcus faecalis) and three gram-negative bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli). The compounds exhibited moderate to good activities against gram-positive bacteria and weak to moderate activities against gram-negative bacteria. Amongst all ciprofloxacin-derivatives, compound 5d was the most potent agent with high antibacterial activity against gram-positive bacteria, including MRSA and S. aureus ((minimum inhibitory concentration (MIC) = 16nM for both), that is 60 times more potent than ciprofloxacin as parent drug. Compound 5i from sarafloxacin-derivatives was the most potent compound against MRSA and S. aureus (MIC = 0.125μM). Well diffusion and disk diffusion assay results demonstrated confirmatory outcomes for the quantitative broth microdilution assay. Molecular docking study results were in accordance with the results of antibacterial activity assays. The results of the current study demonstrated that the novel ciprofloxacin and sarafloxacin derivatives synthesized here have promising antibacterial activities. Particularly, compounds 5d and 5i have potential for wider antibacterial applications following further analysis.

Sensitive immunoassays based on a monoclonal antibody for detection of marbofloxacin in milk

Marbofloxacin (MBF) is a key class of synthetic fluoroquinolone antibiotic that is commonly used as a veterinary drug. However, excess residue of MBF in animal-derived food samples, such as milk, is harmful to consumers. In this study, 4 mAb against MBF, namely, M4E3, M7A6, M3C7, and M5C6, were produced. Indirect competitive (ic) ELISA revealed that the M4E3 exhibited the highest sensitivity with a half-maximal inhibitory concentration (IC50) of 0.07 ng/mL and a limit of detection of 0.01 ng/mL for detection of MBF. The results of the cross-reactivity experiment revealed that the M4E3 could detect lomefloxacin, ofloxacin, fleroxacin, pefloxacin, danofloxacin, and enrofloxacin sensitively with IC50 of 0.02, 0.07, 0.18, 0.27, 0.30, and 0.32 ng/mL, respectively. Meanwhile, a cross-reactivity experiment showed that the M4E3 had a crossover rate of more than 20% with these fluoroquinolone analogs. A weak crossover rate below 1.11% was observed with 14 other fluoroquinolone analogs. The recovery rate of MBF in milk ranged from 72.28% to 129.19%, which showed that the developed indirect competitive ELISA was effective in detecting MBF in milk. Furthermore, a visual colloidal gold-based immunochromatographic assay was developed for detecting MBF with a cut-off value of 1 ng/mL in both phosphate-buffered saline and a milk sample by using this mAb. Given this sensitive mAb, both indirect competitive ELISA and colloidal gold-based immunochromatographic assay could be effective screening tools for detection of MBF in milk.

Synthesis and In vitro Antibacterial, Antitubercular Studies of Novel Fluoroquinolones Analogs Containing 4-substituted Sec Amine

Background: Tuberculosis is a contagious, air borne disease and second leading cause of death among infectious diseases worldwide. Fluoroquinolones are well-known antibacterial agents and they were recommended as second-line of antitubercular drugs. Method: A series of novel fluoroquinolone analogs 6-24 was effectively synthesized. An attempt was made by tagging the substituted pyrazole on to fluoroquinolones for the first time at C-7 position. The newly synthesized compounds were characterized by FTIR, 1HNMR, ESI-MS, HR-MS and elemental analysis. The in vitro antibacterial activity of all the title compounds was investigated against various gram positive, gram negative bacterial organisms and in vitro antitubercular activity against Mycobacterium Tuberculosis H37Rv strain. Result: Most of the synthesized compounds showed comparable activity against the entire gram positive and gram negative bacterial organisms. Fluoroquinolone 16 showed enhanced activity against both type of bacterial strains and compound 11showed promising activity against MTB-H37Rv strain. Conclusion: Some of the novel fluoroquinolone analogs (11, 16) showed potent antibacterial, antitubercular activity.

The synthesis and biological evaluation of virtually designed fluoroquinolone analogs against fluoroquinolone-resistantEscherichia coliintended for UTI treatment

Synthesis and evaluvate the supercoiling activity of the virtually screened novel fluoroquinolone analogs against fluoroquinolone-resistantEscherichia colifor the treatment of urinary tract infections (UTIs).

New fluoroquinolone compounds with endo-nortropine derivatives at C-7 position show antibacterial activity against fluoroquinolone-resistant strains of Staphylococcus aureus.

A series of new fluoroquinolone analogs (3-18) were prepared, in three steps, by substituting chloro esters and esters with cyclic amines on the C-7 endo-nortropine derivatives of difluoroquinolone acid. All the synthesized compounds displayed good MIC against the Staphylococcus aureus when initially screened for Escherichia coli, S.aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. The molecules were further evaluated for their antibacterial activity against fluoroquinolone-resistant strains of S.aureus and for cytotoxic assay. Based on the results, five of the sixteen compounds displayed the potential to be developed further for treatment against fluoroquinolone-resistant strains of S.aureus.

Probing structural requirements for human topoisomerase I inhibition by a novel N1-Biphenyl fluoroquinolone

Fluoroquinolones substituted with N-1 biphenyl and napthyl groups were discovered to act as catalytically inhibitors of human topoisomerases I and II, and to possess anti-proliferative activity in vivo. Structural requirements for these novel quinolones to inhibit catalytic activity of human topoisomerase I have not been explored. In this work novel derivatives of the N-1 biphenyl fluoroquinolone were designed, synthesized and evaluated to understand structural requirements of the C-3 carboxylic acid, C-6 fluorine, C-7 aminomethylpyrrolidine, C-8 methoxy, and the N-1 biphenyl functional groups for hTopoI inhibition. Characterization of each analog for inhibition of hTopoI catalytic inhibition reveals critical insight into structural requirements of these novel quinolones for activity. Additionally, results of DNA binding and modeling studies suggest that N-1 biphenyl fluoroquinolones intercalate between the DNA base pairs with the N-1 biphenyl functional group, rather than the quinolone core, and that this mode of DNA intercalation contributes to inhibition of hTopoI by these novel structures. The results presented here support further development and evaluation of N-1 biphenyl fluoroquinolone analogs as a novel class of anti-cancer agents that act through catalytic inhibition of hTopoI.

Design and virtual screening of novel fluoroquinolone analogs as effective mutant DNA GyrA inhibitors against urinary tract infection-causing fluoroquinolone resistant Escherichia coli.

Fluoroquinolones (FQs) belong to the class of quinolone drugs that are used to treat Urinary tract infections (UTIs) through inhibition of E. coli DNA gyrase. Resistance to FQs poses a serious problem in the treatment against resistant strains of E. coli which are associated with Ser83 to Leu and Asp87 to Asn mutations at the quinolone resistance determining region (QRDR) of the GyrA subunit of DNA gyrase. Mutant DNA GyrA (mtDNA GyrA) is deemed to be a significant target for the development of novel FQ drugs. Due to resistance to FQ drugs, discovery or development of novel FQs is crucial to inhibit the mtDNA GyrA. Hence, the present study attempts to design and develop novel FQs that are efficient against resistant E. coli strains. A three-dimensional structure of the mtDNA GyrA protein was developed by homology modeling, following which 204 novel FQ analogs were designed using target based SAR. The designed ligands were then screened using molecular docking studies, through which the pattern of interaction between the ligands and the target protein was studied. As expected, the results of the docking study revealed that the molecules FQ-147, FQ-151 and FQ-37 formed hydrogen bonding and Van der Waals interactions with Leu83 and Asn87 (mutated residues), respectively. Further, the wild-type (WT), mtDNA GyrA and docking complex were studied by molecular dynamics (MD) simulations. Subsequently, all the screened compounds were subjected to a structure and ligand based pharmacophore study followed by ADMET and toxicity (TOPKAT) prediction. Finally, eighteen hit FQ analogs which showed good results for the following properties, viz., best binding score, estimated activity (MIC value) and calculated drug-like properties, and least toxicity, were shortlisted and identified as potential leads to treat UTI caused by FQ resistant E. coli. Apart from development of novel drug candidates for inhibition of mtDNA GyrA, the present study also contributes towards a superior comprehension of the interaction pattern of ligands in the target protein. To a more extensive degree, the present work will be useful for the rational design of novel and potent drugs for UTIs.

Development of an icELISA and immunochromatographic strip for detection of norfloxacin and its analogs in milk

ABSTRACTWe developed a monoclonal antibody (mAb) to detect norfloxacin (NOR) using a novel hapten by introducing an amino group via amido linkage into the piperazine ring of NOR. The sensitivity of an indirect competitive enzyme-linked immunosorbent assay (icELISA) based on this mAb showed an improved IC50 value from 1.18 to 0.12 ng/mL and the limit of detection from 0.37 to 0.05 ng/mL by using a heterologous coating (pazufloxacin coupled to ovalbumin). The recovery rate for NOR in milk ranged from 77.3% to 117.8%. Cross-reactivity (CR) experiments showed good CR with nine common fluoroquinolone analogs: pefloxacin, lomfloxacin, ciprofloxacin, enrofloxacin, dafloxacin, sparfloxacin, ofloxacin, marbofloxacin and flumequine. Furthermore, based on this antigen–antibody combination, an immunochromatographic strip with cut-off value of 1 ng/mL was developed. Given their good sensitivity and CR, the developed icELISA and immunochromatographic strip could be useful for detection of NOR and its analogs in milk.

SYNTHESIS OF NOVEL FLUOROQUINOLONE-TRIAZOLE HYBRID COMPOUNDS AS ANTIMICROBIAL AGENTS

Abstract: The hydrazide compound ( 2 ) was synthesized starting from 1-(2-fluorophenyl)piperazine via two stage. The reaction of compound ( 2 ) with different alkyl(aryl)isothiocyanates afforded the corresponding compounds ( 3a-c ) . 1,3-Thiazolidine derivatives ( 4a-c ) were synthesized from the treatment of ( 3a-c ) with ethyl bromoacetate. Mannich bases ( 6a-d ) were yielded the treayment of ( 5a-c) with various suitable amines in the exictence of formaldehyde. Compound ( 3 ) derivatives were converted to 1,2,4-triazole as the starting material of fluoroquinolone analogues ( 11a-c ). Finally synthesized compounds were examined their biological properties and some of these showed potent activity.

Diversity of chemiluminescence from fluoroquinolones in the presence of peroxynitrous acid

Abstract In this article, eight fluoroquinolone analogs showed intriguing chemiluminescence (CL) diversity in the presence of peroxynitrous acid. Compared to current literature, these studied fluoroquinolones exhibit many novel characteristics on CL spectra, CL quantum yield and reaction routes. Furthermore, when the distribution of CL was comparable to its fluorescence, a diversity of differences between the analogs were observed. These results indicate that the hydroxyl radical OH and excited state peroxynitrous acid may account for these observations. This discovery could deepen the understanding of mechanisms in CL systems and change the traditional theories about CL phenomena.

The importance of efflux systems in antibiotic resistance and efflux pump inhibitors in the management of resistance

The process of active efflux, the last described resistance mechanism in bacteria, is one of the important factors of acquired antibiotic resistance. Efflux systems which consist of membrane-located pump proteins that exist in all eukaryotic and prokaryotic cells, are responsible for extrusion of the various exogenous and endogenous substances. Bacterial pump proteins, namely ATP Binding Cassette (ABC), Major Facilitator (MFS), Small Multidrug Resistance (SMR), Multidrug and Toxic Compound Extrusion (MATE) and Resistance - Nodulation - Division (RND) are grouped in five super families. Efflux pumps play a role in intrinsic resistance against antibiotics among some pathogens. Besides, pumps give rise to acquired resistance by over-expression and contribute to other resistance mechanisms. Furthermore, pumps can directly or indirectly intensify the virulence properties of bacteria. Thus, for inhibition of efflux-mediated resistance or conversion of resistant bacteria to the susceptible phenotype, potential pump inhibitors combined with traditional antibiotics is one of the research areas of interest in the fight against resistance. There are some compounds known to inhibit bacterial pump systems, such as phenyl-arginine beta naphthylamide (PAβN), INF271, INF55, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), reserpine, 1-(1-naphthylmethyl)-piperazine (NMP), biricodar, timcodar, verapamil, milbemycin, chlorpromazine, paroxetine and omeprazole. However, particularly due to the toxicity problems, there has been no clinical use of a pump inhibitor yet. Nevertheless, in the upcoming period, derivatives of efflux pump inhibitor compounds with acceptable level of toxicity and efficacy may be included in antibacterial formulations. Additionally, a number of natural and synthetic compounds with pump inhibition activity are reported by many researchers in industrial and academic areas. In this context, various antibiotic derivatives (tetracycline, fluoroquinolone and aminoglycoside analogs) or non-antibiotic compounds (indole, urea, aromatic acid, piperidine-carboxylic acid, quinoline derivatives and peptidomimetics), some of which already have patent applications, are often studied. Pump inhibitors are shown to reduce the minimum inhibitory concentration (MIC) values of various antibiotics in some studies. In this review article, the structure and functions of bacterial efflux pumps have been summarized and the efflux pump inhibitors with natural and synthetic origins have been evaluated.

In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model.

BackgroundEmergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. Current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (ACT).MethodsFluoroquinolone analogues, compounds 10, 12 and 18 were investigated for their anti-malarial interaction in combination with artemisinin in vitro, against Plasmodium falciparum 3D7 strain, employing fixed-ratio combination isobologram method. In addition, the efficacy of these compounds was evaluated intraperitoneally in BALB/c mice infected with chloroquine-resistant Plasmodium berghei ANKA strain in the Peters’ four-day suppressive test.ResultsPromising results were obtained in the form of synergistic or additive interactions. Compounds 10 and 12 were found to have highly synergistic interactions with artemisinin. Antiplasmodial effect was further verified by the convincing ED50 values of these compounds, which ranged between 2.31 and 3.09 (mg/kg BW).ConclusionsIn vivo studies substantiated the potential of the fluoroquinolone derivatives to be developed as synergistic partners for anti-malarial drug combinations.