Antibacterial and Pharmacological Evaluation of Fluoroquinolones: A Chemoinformatics Approach

Fluoroquinolone (FQ) antibiotics are an important class of synthetic antibacterial agents. These are the most extensively used drugs for treating bacterial infections in the field of both human and veterinary medicine. Herein, the antibacterial and pharmacological properties of four fluoroquinolones: lomefloxacin, norfloxacin, ciprofloxacin, and ofloxacin have been studied. The objective of this study was to analyze the antibacterial characteristics of the different fluoroquinolones. Also, the pharmacological properties of the compounds including the Lipinski rule of five, absorption, distribution, metabolism, and excretion, LD50, drug likeliness, and toxicity were evaluated. We found that among all four FQ molecules, ofloxacin showed the highest antibacterial activity through in silico assays with a strong interaction (−38.52 kJ/mol) with the antibacterial target protein (topoisomerase-II DNA gyrase enzyme). The pharmacological and pharmacokinetic analysis also showed that the compounds ciprofloxacin, ofloxacin, lomefloxacin and norfloxacin have good pharmacological properties. Notably, ofloxacin was found to possess an IGC50 (concentration needed to inhibit 50% growth) value of 0.286 μg/L against the Tetrahymena pyriformis protozoa. It also tested negative for the Ames toxicity test, showing its non-carcinogenic character.

Prediction of the aquatic toxicity of phenols to tetrahymena pyriformis from molecular descriptors

The purpose of this work is to develop robust and interpretable quantitative structure "activity relationship [QSAR] odels for assessing the aquatic toxicity of phenols using a combined set of descriptors encompassing the logP and recently developed variables [Monconn-Z variables]. The used dataset consists of 250 chemicals with toxicity data to the ciliate Tetrahymena pyriformis. For each compound, a total of 197 physico-chemical descriptors including logP and Molconn-Z descriptors were calculated. Multiple linear regression [LR] and Partial least squares [PLS] were used to obtain QSARs and the predictive performance of the proposed models were verified using external statistical validations. The results of stepwise-MLR analysis reveal that the AlogP, MlogP and ClogP models were not successful for the prediction of aquatic toxicity for all the compounds. And by using the logP [AlogP and MlogP] with Molconn-Z descriptors, the obtained QSARs were not successful enough until removal of some outliers. Two optimal QSARs were built with R[2] of 0.71 and 0.70 for the training sets and the external validation Q[2] of 0.69 and 0.68 respectively. All these selected descriptors in the best models account for the hydrophobic [AlogP, MlogP] and other electrotopological properties like SHCsatu, Scarboxylicacid, SHBa, gmax and nelem. PLS produces a good model using all the calculated descriptors with R[2] of 0.78 and Q[2] of 0.64, and hydrophobic and electrotopological descriptors show importance for the prediction of phenolic toxicity

In vitro toxicity of melamine against Tetrahymena pyriformis cells

This study assessed the toxicity of melamine against the unicellular eukaryotic system of Tetrahymena (T.) pyriformis exposed to 0, 0.05, 0.25, 0.5, 2.5, and 5 mg/mL of melamine. Cell growth curves of different cultures, the half maximum inhibition concentration (IC50) value of melamine, and morphological changes in cells were obtained via optical and transmission electron microscopic observation. The effects of eleven melamine concentrations, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5 mg/mL, on protein expression levels of T. pyriformis were examined using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The results showed an obvious inhibitory effect of melamine on the growth of eukaryotic cells. Cell growth dynamics indicated that the IC50 value of melamine on T. pyriformis was 0.82 mg/mL. The cellular morphology was also affected in a concentration-dependent manner, with characteristics of atrophy or cell damage developing in the presence of melamine. The relative contents of the top four main proteins corresponding to peak mass-to-charge ratios (m/z) of 4466, m/z 6455, m/z 6514, and m/z 7772 in the MALDI-TOF-MS spectra were all found to be closely correlated with the melamine concentrations. In conclusion, exposure of eukaryotic cells to melamine could inhibit cell growth, cause changes in cytomorphology and even disturb the expression of proteins in a concentration-dependent manner. The described method of examining four sensitive proteins affected by melamine was also proposed to be used in a preliminary study to identify protein biomarkers in T. pyriformis.

Toxicity caused by para-substituted phenols on Tetrahymena pyriformis: the structure-activity relationships

The toxicity of thirty para-substituted phenols on Tetrahymena pyriformis was modelled using an original methodology that uses the complex structural information of the compounds. Two models were built. The methodology allows atomic properties to be assigned to toxicity based on the selection of pairs of descriptors from the entire family, which is called Molecular Descriptors Family (MDF). One model has two independent structural descriptors and the other has four. The model with four descriptors proved to have high estimated and predictive abilities (over 97 percent of toxicity could be explained by structural information). The partial charge distribution by bonds (molecular topology) and space (molecular geometry) interaction proved to be related with the toxicity of para-substituted phenols on Tetrahymena pyriformis. The predictive ability of the model was tested by using the following methods: the cross-validation leave-one-out and the training versus test experiments. The comparisons among the models were performed using the correlated correlations method. The embedding of the complex information from the structure using MDF methodology can lead to further investigations of the mechanism of chemicals toxicity on Tetrahymena pyriformis.

new biological screening system for local anesthetics by inhibition mobility of tetrahymena pyriformis

An alternative in vitro approach to drug screening has been the use of human cell cultures for antiviral agents and microbial cell cultures for the assessment of the carcinogenic potential of selected compounds. A number of protozoan species have been also used as drug screens for anti-protozoal agents. The ciliated protozoan Tetrahymena pyriformis species has been widely utilised as a drug screen for a variety of pharmacologically active agents. Accordingly, it was decided to investigate whether T. pyriformis could be used as a preliminary drug screen for evaluation of the local anaesthetic activity and duration of action of certain commercially available local anaesthetics. In this communication, the results of this new in vitro biological drug screen are reported. It is based on the complete protozoan cell immobilization by the anaesthetic solution. A positive inverse correlation was observed between the lowest concentration [minimum inhibitory concentration =MIC] that wholly inhibits the mobility of all cells of T. pyriformis and the duration of action of the test compounds. Generally, MIC was high for the short-acting anaesthetics and low for the long-acting ones. The results suggest the suitability of this new microbiological assay system for the evaluation of local anaesthetic activity and duration of action and possibly irritancy and toxicity of other local anaesthetics as well as potentially active therapeutic agents which possess surface activity