Fluoroquinolone Compounds Research Articles

Варианты генов Mycobacterium tuberculosis, ассоциированные с лекарственной устойчивостью к фторхинолонам (обзор литературы)

Background: The spread of M. tuberculosis drug resistance to fluoroquinolones poses a threat to their long-term clinical efficacy. Understanding the mechanisms of formation of drug resistance to fluoroquinolones, based on information on genes associated with drug resistance of M. tuberculosis, is important for optimizing TB chemotherapy regimens. The aim of the study: To study the available literature data on the most significant variants of M. tuberculosis genes associated with drug resistance to fluoroquinolones. Materials and methods: To achieve this goal, the task was to analyze the sources of domestic and foreign literature on this priority issue over the past 5 years. The databases of scientific electronic libraries PubMed, Elibriary were used. Results: Mycobacterial resistance to fluoroquinolones is associated with mutations in the gyrA and gyrB genes, encoding the GyrA and GyrB subunits of DNA gyrase, the main target of fluoroquinolones. In the fluoroquinolone-binding pocket of the “DNA-gyrase + DNA” catalytic center, the fluoroquinolone molecule is supported by the gyrA and gyrB regions, which determine resistance to fluoroquinolones (QRDR-A and QRDR-B). Modification of any of the constituent fragments of these regions affects the level of resistance to fluoroquinolones. Small quinolone molecules (nalidixic acid) have a high MIC against Mtb and other bacteria, while larger PC molecules (sparfloxacin, sitafloxacin, gatifloxacin, levofloxacin and moxifloxacin) are tightly adjacent to the fluoroquinolone-binding pocket and have a lower MIC. Modification of the DNA structure can change the spatial structure of the pocket itself, which leads to destabilization of the fluoroquinolone inside it. Thus, the presence of heteroresistance of the tuberculosis pathogen to fluoroquinolones indicates the active development of its resistance to this group of drugs in modern conditions. Conclusion: Analysis of modern studies shows the dependence of drug resistance of mycobacteria on fluoroquinolone compounds, while most often resistance to a decrease in the concentration of fluoroquinolones is associated with substitutions in the gyrB gene, as well as mutations in the gyrA gene. It has also been established that in addition to the main studied regions of the gyrA and gyrB genes associated with phenotypic drug resistance to fluoroquinols, there are regions that have not been sufficiently studied so far. These areas cannot be diagnosed in the clinical work of bacteriological laboratories of anti-tuberculosis institutions.

Exploring the Biochemical Mechanisms of Fluoroquinolone Compounds against Tuberculosis by Utilizing Molecular Docking and Quantitative Structure-amino Acid Relationship

Background: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). It is one of the leading causes of death of 1.5 million people each year. TB can be treated by directly observed treatment short course (DOTS), but due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, consequences can be devastating if the single DOTS dose is missed by the patient. MDR and XDR-TB require much more attention and time to control the infection. The longer period of tuberculosis treatment has side effects and it is expensive. Objectives: This alarming condition demands the development of novel processes to diagnose the disease in its early stage as well as to produce more promising antimicrobial chemotherapeutics. The current study aimed to explore molecular mechanisms involving docking simulation-based quantitative structureamino acid relationship (QSAAR) in order to have a better understanding of the interactions between the fluoroquinolones and Mtb DNA gyrase. Methods: In this study, 24 fluoroquinolone (FQ) compounds present in the literature were selected and docked against the Mtb DNA gyrase. Further, the relationship between the minimum inhibitory concentration of the compounds and interacting amino acids was assessed using QSAAR. Results: The study has established a novel method of formulating a quantitative structure-amino acid relationship. A significant correlation (R-value=0.829) between biological activity and the docked amino acid residues responsible for producing anti-tubercular activities has been obtained. Conclusion: The predicted residues captured in the developed model have been explored to report the Mtb virulence.

Usefulness of medicine screening tools in the frame of pharmaceutical post-marketing surveillance.

The negative consequences of Substandard and falsified (SF) medicines are widely documented nowadays and there is still an urgent need to find them in more efficient ways. Several screening tools have been developed for this purpose recently. In this study, three screening tools were used on 292 samples of ciprofloxacin and metronidazole collected in Cameroon. Each sample was then analyzed by HPLC and disintegration tests. Seven additional samples from the nitro-imidazole (secnidazole, ornidazole, tinidazole) and the fluoroquinolone (levofloxacin, ofloxacin, norfloxacin, moxifloxacin) families were analyzed to mimic falsified medicines. Placebo samples that contained only inert excipients were also tested to mimic falsified samples without active pharmaceutical ingredient (API). The three screening tools implemented were: a simplified visual inspection checklist, a low-cost handheld near infrared (NIR) spectrophotometer and paper analytical devices (PADs). Overall, 61.1% of the samples that failed disintegration and assay tests also failed the visual inspection checklist test. For the handheld NIR, one-class classifier models were built to detect the presence of ciprofloxacin and metronidazole, respectively. The APIs were correctly identified in all the samples with sensitivities and specificities of 100%. However, the importance of a representative and up-to-date spectral database was underlined by comparing models built with different calibration set spanning different variability spaces. The PADs were used only on ciprofloxacin samples and detected the API in all samples in which the presence of ciprofloxacin was confirmed by HPLC. However, these PADs were not specific to ciprofloxacin since they reacted like ciprofloxacin to other fluoroquinolone compounds. The advantages and drawbacks of each screening tool were highlighted. They are promising means in the frame of early detection of SF medicines and they can increase the speed of decision about SF medicines in the context of pharmaceutical post-marketing surveillance.

Metal Chelators as Anticancer Approach: Part I; Novel 7-Anisidine Derivatives with Multidentate at 7-8 Carbons of Fluoroquinolone Scaffold as Potential Chelator Anticancer and Antilipolytic Candidates

Background: Cancer is one of the greatest troubling maladies currently. It is believed that it is the second reason for death following cardiovascular maladies. Owing to the multiplicity of its types, stages and genetic basis, there is no existing drug to cure all types of cancer. Resistance to present drugs and severe adverse effects are other challenges in the struggle against cancer. In such pursuit, fluoroquinolones (FQs) have the potential as antiproliferative compounds due to safety, low cost, and absence of resistance.
 Aims: In this study, we aim to synthesize biologically active compounds that have dual anticancer and anti-lipase potential. Sixteen compounds were prepared, fully characterized, and studied through identification of IC50 values against the highly susceptible cancer cell lines.
 Methods: In this work we are concerned with synthesizing biologically active compounds that belong to fluoroquinolones (FQs) with dual anti-colorectal cancer and anti-lipase activity, owing to association between cancer and obesity, conduct titration and docking experiments to validate our hypothesis.
 Results: In vitro findings indicated that these compounds demonstrated promising anticancer activity against tested cell lines in micromolar range with a potency comparable to cisplatin. Compound 11 exhibited approximately doubled potency compared to cisplatin against SW620 colorectal cancer cell line with IC50 3.2 μM which proposes FQs as potent antiproliferative agents. The synthesized Fluoroquinolone (FQ) compounds were further screened for their in vitro anti-lipase potential. The findings demonstrated that all the screened compounds have demonstrated remarkable anti-lipase activity, as compared to control molecule orlistat. Compound 9 exhibited comparable activity to orlistat against pancreatic lipase with IC50 0.4 μM which proposes FQs as potent pancreatic lipase inhibitors.
 Conclusions: The anticancer potential of these derivatives is referred to their ability to inhibit Topo II which indicates that chelation is the mechanism of inhibition of Topo II emphasized with titration and docking experiments.

Synthesis and Sonodynamic Antibacterial Activity Evaluation of Three Novel Fluoroquinolone Compounds

Three ciprofloxacin derivatives (CPDs) were synthesized. Also, their sonodynamic antibacterial activities and possible mechanism under ultrasound (US) irradiation were preliminarily investigated. Staphylococcus aureus and Escherichia coli were selected as the research objects. The sonodynamic antibacterial effects of three CPDs and their structure-effective relationship were explored by the inhibition rate. The reactive oxygen species (ROS) produced under US irradiation were detected by oxidative extraction spectrophotometry and used to analyze the sonodynamic antibacterial mechanism of three CPDs. Research indicated that three CPDs, named compound 1 (C1), compound 2 (C2) and compound 3 (C3), separately all had strong sonodynamic antibacterial activities. In addition, C3 had the strongest effect relative to the other CPDs. The study also found that CPDs' concentration, US irradiation time, US solution temperature and US medium could disturb their sonodynamic antimicrobial effects. Moreover, 1O2 and ·OH were the main types of ROS produced by C1 and C3; the ROS produced by C2 included 1O2, among other types. Results showed that all three CPDs could be activated to produce ROS after US irradiation. Among them, C3 displayed the highest ROS production and the utmost activity, which may be related to the introduction of the electron-giving group at the C-3 position of the quinoline backbone.

Evaluation of Gold Nanoparticles on the Expression of NorA and NorB Efflux Pumps in Ciprofloxacin-resistant Staphylococcus aureus Isolated from Burn Patients

Background: In the development of multidrug resistance, efflux pumps effectively pump drug compounds out of cells, which results in reduced membrane permeability to drug compounds. This study evaluated the effect of gold nanoparticles on the inhibition of norA and norB efflux pumps in ciprofloxacin-resistant Staphylococcus aureus isolated from burn patients in Qom province, Iran. Methods: In this cross-sectional study, S. aureus strains were isolated from burn patients in Qom hospital, Iran. After gold nanoparticles were synthesized using chemical reduction and characterized by spectrophotometry, transmission electron microscopy (TEM), and dynamic light scattering (DLS), ciprofloxacin resistance of S. aureus was screened by the disc diffusion method. The Minimum Inhibitory Concentration (MIC) of ciprofloxacin (CCCP), ciprofloxacin + gold nanoparticles (CCCP + gold nanoparticles), and ciprofloxacin + CCCP was determined. Moreover, norA and norB genes were evaluated by PCR using special primers. Real-time PCR was then performed for norA and norB genes. Results: Of 88 S. aureus strains tested, 50 (56.81%) were resistant to ciprofloxacin. From the 50 ciprofloxacin-resistant S. aureus strains, 12 isolates had active pumps. Real-time PCR of 12 ciprofloxacin- resistant S. aureus and S. aureus ATCC 25923 before and after exposure to ciprofloxacin, gold nanoparticles, and gold nanoparticles with sub-MIC ciprofloxacin revealed significant differences in expression of norA and norB genes before exposure to the treatments compared to after exposure (p <0.05). Conclusion: Gold nanoparticles with ciprofloxacin could be used to prevent the expression of pump genes involved in resistance to fluoroquinolone compounds.

Synthesis and Antibacterial Evaluation of Ciprofloxacin Congeners with Spirocyclic Amine Periphery.

The synthesis of novel fluoroquinolones, congeners of ciprofloxacin, which was inspired by earlier work on spirocyclic ciprofloxacin, is described. An antibacterial evaluation of the 11 fluoroquinolone compounds synthesized against the ESKAPE panel of pathogens in comparison with ciprofloxacin revealed that the more compact spirocycles in the fluoroquinolone periphery resulted in active compounds, while larger congeners gave compounds that displayed no activity at all. In the active cohort, the level of potency was comparable to that of ciprofloxacin. However, the spectrum of antibacterial activity was quite different, as the new compounds showed no activity against Pseudomonas aeruginosa. Among the prepared and tested compounds, the broadest range of activity (five pathogens of the six in the ESKAPE panel) and the highest level of activity were demonstrated by 1-yclopropyl-7-[8-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)-6-azaspiro[3.4]oct-6-yl]-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the lead compound nominated for further characterization and development.

Sonocatalytic degradation of fluoroquinolone compounds of levofloxacin using titanium and zirconium oxides nanostructures supported on paper sludge/wheat husk-derived biochar

The present study aimed at treating a water medium containing pharmaceutical compounds such as levofloxacin (LEV). For this purpose, ultrasound (US)-based degradation of LEV was catalyzed by TiO2 and ZrO2 nano-catalysts supported on biochar (BC). BC was obtained from a precursor composite of paper sludge and wheat husk. The application of BC-ZrO2 led to a degradation efficiency of 54.65% within 60 min. When BC-TiO2 was used, a lower degradation efficiency of 49.62% was obtained at the same reaction time. However, increasing the time to 120 min improved the sonocatalytic degradation of LEV by BC-TiO2 (72.88%) compared to that of BC-ZrO2 (66.42%). In the presence of H2O2 and S2O82−, the LEV degradation efficiency of US/BC-TiO2 increased from 72.88% to 87.98% and 94.03%, respectively, and for the US/BC-ZrO2 process, it increased from 66.42% to 76.79% and 90.14%, respectively. The addition of isopropanol caused the most suppressive effect on the sonocatalytic degradation of LEV for both US/BC-TiO2 (decreasing from 72.88% to 13.99%) and US/BC-ZrO2 (decreasing from 66.42% to 16.43%) processes. The reusability test results showed an approximately 20% reduction in the sono-reactor performance within three consecutive experimental runs with no substantial change in the functional groups of the as-prepared sonocatalyst. Intermediates of LEV decomposed by the two sonocatalytic processes were also identified.

Antiproliferative Properties of 7,8-Ethylene Diamine Chelator-Lipophilic Fluoroquinolone Derivatives Against Colorectal Cancer Cell Lines.

Cancer is one of the most overwhelming diseases nowadays. It is considered the second cause of death after cardiovascular diseases. Due to the diversity of its types, stages and genetic origin, there is no available drug to treat all cancers. Serious side effects and resistance of existing drugs are other problems in the struggle against cancer. In such quest, fluoroquinolones (FQs) promising as antiproliferative compounds due to safety, low cost and lack of resistance. Therefore, this work aims at developing lipophilic FQs and screening their antiproliferative activity against colorectal cancer. Nine prepared FQs were investigated for antiproliferative activity utilizing in vitro SRB method. In comparison to the antiproliferative agent cisplatin; the assessment of antiproliferative activities of these novel FQs in a panel of Colorectal Cancer Cell (CRC) lines (HT29, HCT116, SW620, CACO2, SW480) and normal periodontal ligament fibroblasts for safety examination was performed. Antibacterial activity (MIC) was conducted against Staphylococcus aureus and Escherichia coli standard strains using the broth double dilution method. Antioxidant properties were suspected as the mechanism of antiproliferative activity; thus, a DPPH test was performed to analyze radical scavenging potency of FQs compared to ascorbic acid as reference agent. FQs compounds 3-5(a-c) were prepared, characterized and their structure was confirmed using spectroscopy techniques. All compounds manifested good to excellent antiproliferative activity on HT29, HCT116, and SW620 with high safety index. The reduced series 4a, 4b and 4c exerted excellent micro to nano -molar antiproliferative activities on HT29, HCT116, and SW620 which were stronger than the reference cisplatin against all cells. The reduced group of compounds 4(a-c) revealed higher potency vs. both nitro and triazolo groups. On cell lines HT29, HCT116, and SW620, reduced 4a with 7,8-ethylene diamine,the substitution revealed the highest antiproliferative efficacy (IC50 value) approaching nano molar affinity with higher safety vs. cisplatin. The most active compound, 4a, exhibited significant potency against HCT116, and SW620 with IC50 0.6 and 0.16 μM respectively. Novel FQs (4a, 4b and 4c) also showed strong radical scavenging activity with IC50 values (μM) 0.06, 23, and 7.99, respectively. Exquisitely 4a revealed a similar pattern of activity to doxorubicin, indicating a similar mechanism of action. Strong antiproliferative and weak antibacterial activities of series 4 endorse that their mechanism involves eukaryotic topoisomerase II inhibition. This work has revealed novel FQs with excellent anticancer activity against 5 colorectal cancer (HT29, HCT116, SW620, CACO2, SW480) cell lines with a potential chelation mechanism due to 7,8-ethylene diamine chelator bridge. The new FQs have confirmed that more lipophilic compounds could be more active as hypothesized. The p-halogenated aniline, N1-Butyl group in addition to 3-COOH, 8-NH2 are all essential requirements for strong antiproliferative FQ of our FQ scaffold. This work emphasizes the role of C-8 amino as part of ethylene diamine group as an essential requirement for antiproliferative FQs for the first time in the literature, entailing its role toward potential antineoplastic FQs.

Correlation of gyr Mutations with the Minimum Inhibitory Concentrations of Fluoroquinolones among Multidrug-Resistant Mycobacterium tuberculosis Isolates in Bangladesh.

Fluoroquinolone (FQ) compounds—moxifloxacin (MOX), levofloxacin (LEV), and ofloxacin (OFL)—are used to treat multidrug-resistant tuberculosis (MDR-TB) globally. In this study, we investigated the correlation of gyr mutations among Mtb isolates with the MICs of MOX, LEV, and OFL in Bangladesh. A total of 50 MDR-TB isolates with gyr mutations, detected by the GenoType MTBDRsl assay, were subjected to drug susceptibility testing to determine the MICs of the FQs. Spoligotyping was performed to correlate the genetic diversity of the gyr mutant isolates with different MIC distributions. Among the 50 isolates, 44 (88%) had mutations in the gyrA gene, one (2%) had a mutation in the gyrB gene, and five (10%) isolates had unidentified mutations. The substitutions in the gyrA region were at A90V (n = 19, 38%), D94G (n = 16, 32%), D94A (n = 4, 8%), D94N/D94Y (n = 4, 8%), and S91P (n = 1, 2%), compared to the gyrB gene at N538D (n = 1.2%). D94G mutations showed the highest MICs for MOX, LEV, and OFL, ranging between 4.0 and 8.0 μg/mL, 4.0 and 16.0 μg/mL, and 16.0 and 32.0 μg/mL, respectively; while the most common substitution of A90V showed the lowest ranges of MICs (1.0–4.0 μg/mL, 2.0–8.0 μg/mL, and 4.0–32.0 μg/mL, respectively). Spoligotyping lineages demonstrated no significant differences regarding the prevalence of different gyr mutations. In conclusion, the substitutions of codon A90V and D94G in the gyr genes were mostly responsible for the FQs’ resistance among Mtb isolates in Bangladesh. Low levels of resistance were associated with the substitutions of A90V, while the D94G substitutions were associated with a high level of resistance to all FQs.

Reusable and sustainable graphene oxide/metal–organic framework-74/Fe3O4/polytyramine nanocomposite for simultaneous trace level quantification of five fluoroquinolones in egg samples by high performance liquid chromatography

A nanohybrid material termed graphene oxide/metal-organic framework-74/Fe3O4/polytyramine (GO/MOF-74/Fe3O4­/PTy) was fabricated and applied in magnetic dispersive micro-solid phase extraction (MD-µ-SPE) coupled with high performance liquid chromatography (HPLC) for simultaneous determination of fluoroquinolones compounds including, ofloxacin, ciprofloxacin, lomefloxacin, enrofloxacin and sperfloxacin in egg samples. The GO/MOF-74/Fe3O4/PTy nanocomposite was fabricated through an in situ synthesis of MOF-74 in the presence of magnetic GO and followed with an oxidative polymerization of tyramine using horsedish peroxide (HRP) enzyme. The modifier agents improved the merits of the nanoporous sorbent. Extraction protocols based on GO/MOF nanocomposites have various benefit such as, the high stability, the tunable porosity, the fast mast transfer and reasonable enrichment factor. The fabricated material was characterized via energy dispersive x-ray analysis (EDX), the scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and the x-ray diffraction (XRD). The calibration curves revealed linearity (0.992 ≤ r2 ≤ 0.997) in the ranges of 1.0-475.0, 0.5-350.0, 0.5-350.0, 0.5-375.0 and 1.5-300.0 ng mL-1 with limit of detections (LODs, S/N=3) of 0.3, 0.1, 0.2, 0.1 and 0.4 ng mL-1 for ofloxacin, ciprofloxacin, lomefloxacin, enrofloxacin and sperfloxacin, respectively. The intra-assay (≤7.7%, n = 9) and inter-assay (≤7.0%, n = 9) precisions along with accuracy less than 9.0% were obtained.

The AcrAB-TolC Efflux Pump Impacts Persistence and Resistance Development in Stationary-Phase Escherichia coli following Delafloxacin Treatment.

Bacteria have a repertoire of strategies to overcome antibiotics in clinical use, complicating our ability to treat and cure infectious diseases. In addition to evolving resistance, bacteria within genetically clonal cultures can undergo transient phenotypic changes and tolerate high doses of antibiotics. These cells, termed persisters, exhibit heterogeneous phenotypes; the strategies that a bacterial population deploys to overcome one class of antibiotics can be distinct from those needed to survive treatment with drugs with another mode of action. It was previously reported that fluoroquinolones, which target DNA topoisomerases, retain the capacity to kill nongrowing bacteria that tolerate other classes of antibiotics. Here, we show that in Escherichia coli stationary-phase cultures and colony biofilms, persisters that survive treatment with the anionic fluoroquinolone delafloxacin depend on the AcrAB-TolC efflux pump. In contrast, we did not detect this dependence on AcrAB-TolC in E. coli persisters that survive treatment with three other fluoroquinolone compounds. We found that the loss of AcrAB-TolC activity via genetic mutations or chemical inhibition not only reduces delafloxacin persistence in nongrowing E. coli MG1655 or EDL933 (an E. coli O157:H7 strain), but it limits resistance development in progenies derived from delafloxacin persisters that were given the opportunity to recover in nutritive medium following antibiotic treatment. Our findings highlight the heterogeneity in defense mechanisms that persisters use to overcome different compounds within the same class of antibiotics. They further indicate that efflux pump inhibitors can potentiate the activity of delafloxacin against stationary-phase E. coli and block resistance development in delafloxacin persister progenies.

Distribution of fluoroquinolones in the two aqueous compartments of Escherichia coli

The double-layered cell envelope of Gram-negative bacteria and active drug efflux present a formidable barrier for antimicrobial compounds to penetrate. Fluoroquinolones are among the few classes of antimicrobials that are clinically useful in the treatment of Gram-negative bacterial infection. Previous studies on fluoroquinolone accumulation measured total bacteria associated compounds, rather than the cytoplasmic accumulation. Fluoroquinolones target the type II topoisomerases in the cytoplasm. Thus, the cytoplasmic accumulation is expected to be more relevant to the potency of the drugs. Here, we fractionated and measured the concentration of nine fluoroquinolone compounds in the periplasm and the cytoplasm of two strains of E. coli cells, a parent strain and its isogenic efflux-deficient tolC knockout strain. The potency of the drugs was determined using the minimum inhibitory concentration (MIC) assay. We found that all fluoroquinolones tested accumulated at much higher concentrations in the periplasm than in the cytoplasm. The periplasmic concentrations were 2–15 folds higher than the cytoplasmic concentration, while the actual distribution ratio varies drastically among the compounds tested. Good correlation between the MIC and the cytoplasmic accumulation, but not whole cell accumulation, was observed using a pair of isogenic wild type and drug-efflux deficient strains.

Functionalised Flouroquinolones as a Potentially Novel Class of Anti-inflammatory and Anti-glycation Compounds; Synthesis and Pharmacological Appraisal

New synthetic 36 fluoroquinolones (FQs) have been developed. Their anti-inflammatory and 2,2-diphenyl-1-picrylhydrazyl (DPPH)- and nitric oxide (NO)- radicals scavenging propensities were delineated in vitro. The anti-inflammation related NO radical scavenging bioactivities of new FQs compounds against lipopolysaccharide (LPS)-prompted NO production in RAW 264.7 macrophages were examined using the Griess assay. Selectively nitro FQ compound 2-AnisCEtA exerted an exceedingly superior anti-inflammatory effects (p<0.001 vs. indomethacin IC50 value of 103.35±4.4 μM) while 7 nitro FQs, 10 reduced FQs and 9 triazolo FQs were moderately more efficacious than indomethacin. The remaining 9 Compounds could display appreciable anti-inflammatory capacity. Unequivocally their DPPH radical scavenging effects were of substantially lesser efficacy than ascorbic acid. Using 400 μM methylglyoxal as the choice glucotoxicity concentration in RAW264.7 macrophages; it was shown that 18 out of 36 FQs could exhibit an exceedingly more superior than or significantly comparable cytoprotection against methylglyoxal-induced carbonyl toxicity to antiglycation aminoguanidine. Suggestively dual modulation of glycation-inflammation can be linked with FQs lipophilicity-chelating properties. FQs can serve as scaffolds for the development and designing of new druggable deglycation and antiglycation therapeutic candidates via duality of antiglycation-antiinflammatory capacities.

Evaluation of the 1-octanol/water partition coefficient of quinolones and quinolones compounds via free energy estimated in quantum chemical calculations

A rapid screening assay for the measurement of octanol-water partition coefficients (logP) of pharmaceuticals such as quinolines, quinolones and fluoroquinolones compounds were developed by using quantum chemical calculations. In this paper, we report the logP of the pharmaceutical derivatives compounds that determined by the calculation of the difference in the solvation free energies in water-octanol using the thermodynamic integration method. The logP values calculated in this method are closer to the experimental values compared to other ab initio methods. Solvation free energy in water and octanol, free energy of cavity formation in water and Henry’s constants, and some other parameters are determined at the density functional theory (DFT) and Hartree-Fock (HF) level with 6-31++G** basis set. Moreover, surface area, mass, refractivity, volume, polarizability have been calculated for some of the compounds with the same levels.

Study on the Influence of Saturated Aliphatic Dicarboxylic Acids on the Solubility of Their Norfloxacin Salts

The crystallization of norfloxacin, an antibacterial fluoroquinolone compound, with different saturated aliphatic dicarboxylic acids yields five novel pharmaceutical salts via molecular recognition. In particular, a new norfloxacin-glutaric acid salt was obtained, which was characterized by infrared spectroscopy and powder X-ray diffraction. The effect of pKa on the solubility and dissolution profile of drug salts are investigated in pure water. After the formation of salts, the solubility increases at near neutral pH in all cases. Glutaric acid shows evidence of a good candidate to enhance the solubility of fluoroquinolone drugs for the solubility of 1 is approximately 27.7 times as large as that of norfloxacin in pure water.

Functionalised Triazoloquinolones as a Potentially Novel Class of Antidiabesity and Antiproliferative compounds: Synthesis and Pharmacological Appraisal

Nine newly prepared triazoloquinolones (TQs) and their precursor’s fluoroquinolones (FQs) are investigated for pancreatic lipase (PL) inhibitory activity utilizing in vitro spectrophotometric method. Registered antiobesity orlistat was the reference agent for potency and efficacy determinations. In comparison to the antiproliferative agent cisplatin; the assessment of antineoplastic activities of these novel TQs/ FQs in a panel of colorectal carcinoma (CRC) cell lines (HT29, HCT116, SW620, CACO2, SW480) and normal periodontal ligament fibroblasts for safety examination was performed. DPPH radical scavenging capacity of TQs/ FQs as antiproliferative action mechanism was analyzed in comparison to ascorbic acid as reference agent. Unlike orlistat (0.2 μM) antilipolytic properties, TQs/ FQs compounds 3a and 5a manifested moderate PL inhibition (IC50 value (μM): 39.15 and 34.19 respectively). The nitro-groups of compounds revealed higher potency vs. triazolo- and reduced groups. The ortho substituted compounds were more potent vs. meta- and para-substituted TQs/ FQs. On cell line HT29; TQ 5a, revealed significantly higher antiproliferative efficacy (IC50 value 4.09 μM) with appreciable safety vs. cisplatin (6.9 μM). Compounds 4a, 4b and 4c exerted excellent antiproliferative activities on SW620, CACO2 and SW480 with high safety index. The most active compound, 4b, exhibited significant potency against SW620, CACO2 and SW480 with IC50 0.42 μM, 1.12 μM and 1.69 μM respectively. Novel FQs (4a, 4b and 4c) also showed strong radical scavenging activity with IC50 values (μM) (90.5, 22.4, and 31 respectively). In effect the proven antilipolytic activity coupled to the antioxidative-chemopreventive efficacies of these novel TQs/ FQs are delineated.

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.

Fabrication of CQDs/Bi5Nb3O15 nanocomposites for photocatalytic degradation of veterinary pharmaceutical sarafloxacin

Abstract The unabated release of fluoroquinolone compounds into surface water led to environmental problems. In this contribution, the heterogeneous photocatalytic technology was employed utilizing carbon quantum dot CQDs/Bi5Nb3O15 nanocomposites for degrading the veterinary pharmaceutical sarafloxacin as a model pollutant. A simple hydrothermal method was used to synthesize CQDs/Bi5Nb3O15 nanocomposites with different CQDs amount (1–4 wt%). X-ray diffraction and Fourier transform infrared spectra revealed the formation of CQDs/Bi5Nb3O15 nanocomposites. UV–vis spectra of CQDs/Bi5Nb3O15 nanocomposites displayed a marked absorption enhancement in the range of 400–700 nm. Transmission electron microscopy images demonstrated the as-prepared CQDs having small particle size were successfully coupled with Bi5Nb3O15. X-ray photoelectron spectra indicated the presence of C, O, Bi and Nb in CQDs/Bi5Nb3O15 nanocomposites. Brunauer-Emmett-Teller measurements confirmed that the surface area of 3 wt% CQDs/Bi5Nb3O15 nanocomposites was higher than that of Bi5Nb3O15. The photocatalytic decomposition of sarafloxacin was investigated using these novel nanocomposites under irradiation of 250 W Xe lamp. The prepared 3 wt% CQDs/Bi5Nb3O15 nanocomposites exhibited better degradation efficiency than pure Bi5Nb3O15 nanoparticles. In addition, the degradation products were identified by UHPLC/MS/MS and possible degradation pathways were proposed. Four new intermediates were found, featuring a series of steps including cleavage of piperazine ring and oxidation.

Solid Forms of Ciprofloxacin Salicylate: Polymorphism, Formation Pathways, and Thermodynamic Stability

The crystallization of ciprofloxacin—an antibacterial fluoroquinolone compound—with salicylic acid resulted in the isolation of five distinct solid forms of the drug, namely, an anhydrous salt, two...