Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives.

A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a-3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k-3m. Thus, compounds 3k-3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB.

Sensitivity Enhanced Ecofriendly UV Spectrophotometric Methods for Quality Control of Telmisartan and Benidipine Formulations: Comparison of Whiteness and Greenness with HPLC Methods.

The development of an environmentally friendly analytical technique for simultaneous measurement of medicines with large concentration differences is difficult yet critical for environmental protection. Hence, in this work, new manipulated UV-spectroscopic methods with high scaling factors were established for concurrent quantification of telmisartan (TEL) and benidipine (BEN) in fixed-dose combinations. Two different methods were developed and established by calculation of peak height at zero crossing point of second derivative and the ratio of first derivative spectra with a scaling factor of 200 and 100, respectively. The absorption difference between the peaks and troughs of the ratio spectra, as well as continuous subtraction from ratio spectra, were established as additional methods. In addition, new procedures were validated using ICH recommendations. The proposed methods' linearity curves were constructed in the range of 0.5-10 µg mL-1 and 1-30 µg mL-1 for BEN and TEL, respectively, under optimized conditions. Furthermore, both the detection (0.088-0.139 µg mL-1 for BEN and 0.256-0.288 µg mL-1 for TEL) and quantification limits (0.293-0.465 µg mL-1 for BEN and 0.801-0.962 µg mL-1 for TEL) were adequate for quantifying both analytes in the formulation ratios. The accuracy and precision were confirmed by the good recovery percent (98.37%-100.6%), with low percent relative error (0.67%-1.70%) and less than 2 percent relative standard deviation, respectively. The specificity of the methods was proven by accurate and precise outcomes from the standard addition method and analysis of laboratory mixed solutions with large differences in concentrations of both analytes. Finally, the BEN and TEL content of the formulations was determined simultaneously without prior separation using these first ever reported spectroscopic methods. Furthermore, developed UV derivative spectroscopic methods demonstrated high greenness and whiteness when compared to the reported HPLC methods. These findings show that the projected methods were effective, practical, and environmentally acceptable for quality control of BEN and TEL in multicomponent formulations.

An Experimental Design Approach to Quantitative Expression for Quality Control of a Multicomponent Antidiabetic Formulation by the HILIC Method.

A rapid and reproducible hydrophilic liquid chromatography (HILIC) process was established for concomitant determination of remogliflozin etabonate (RE), vildagliptin (VD), and metformin (MF) in a formulation. A face-centered central composite experimental design was employed to optimize and predict the chromatographic condition by statistically studying the surface response model and design space with desirability close to one. A HILIC column with a simple mobile phase of acetonitrile (65% v/v) and 20 mM phosphate buffer (35% v/v, pH 6, controlled with orthophosphoric acid) was used to separate RE, VD, and MF. RE, VD, and MF were separated in 3.6 min using an isocratic mode mobile phase flow at a flow rate of 1.4 mL at room temperature, and the analytes were examined by recording the absorption at 210 nm. The developed HILIC method was thoroughly validated for all parameters recommended by ICH, and linearity was observed in the ranges 20−150 µg/mL, 10−75 µg/mL, and 50−750 µg/mL for RE, VD, and MF, respectively, along with excellent regression coefficients (r2 > 0.999). The calculated percentage relative deviation and relative error ascertained the precision and accuracy of the method. The selectivity and accuracy were further confirmed by the high percentage recovery of added standard drugs to the formulation using the standard addition technique. The robustness of the HILIC processes was confirmed by developing a half-normal probability plot and Pareto chart, as the slight variation of a single factor had no significant influence on the assay outcomes. Utilization of the optimized HILIC procedure for concurrent quantification of RE, VD, and MF in solid dosage forms showed accurate and reproducible results. Hence, the fast HILIC method can be regularly employed for the quality assurance of pharmaceutical preparations comprising RE, VD, and MF.

Environmental sustainable mathematically processed UV spectroscopic methods for quality control analysis of remogliflozin and teneligliptin: Evaluation of greenness and whiteness.

Environmental sustainable analytical methods were developed by mathematical modification of UV absorption spectra for quality control study of multicomponent formulations consisting of remogliflozin (REM) and teneligliptin (TEN), with good sensitivity and selectivity. Then analytes were quantified by measuring the peak amplitude of the first derivative spectra at zero crossing points at 230.2 nm and 213.8 nm for REG and TEN in the first derivative method. The second method involves the formation of ratio spectra and taking the absorption difference at two selected wavelengths of peak and trough of a spectrum. In the ratio first derivative method peak amplitudes were measured at 235.2 nm and 259.1 nm for simultaneous quantification of REM and TEN respectively. The fourth method was based on the measurement of the peak amplitude of zero-order spectra of analytes generated from the mixture spectrum by subtraction of a constant from the ratio spectrum followed by multiplication with divisor spectrum, Further, the proposed methods were validated systematically to confirm the linearity, precession, accuracy, sensitivity, and selectivity. Finally, validated UV spectroscopic methods were applied for simultaneous quantification of REM and TEN from formulation, and laboratory mixed solutions and statistically compared with the reported HPLC method. Further, recently developed AGREE, Hexagonal greenness and white analytical chemistry, a whiteness evaluation tools were applied to the proposed UV spectroscopic methods and found to be safer analytical methods, compared to the reported expensive, time-consuming and toxic HPLC method. Hence, proposed UV spectroscopic methods could be used for routine quality control of formulations containing REM and TEN.