1. Critical practical aspects in the application of liquid chromatography-mass spectrometric studies for the characterization of impurities and degradation products
Mallikarjun Narayanam, Tarun Handa, Parul Sharma, Shalu Jhajra, Praveen Kumar Muthe, Pavan Kumar Dappili, Ravi P Shah, Saranjit Singh J Pharm Biomed Anal. 2014 Jan;87:191-217. doi: 10.1016/j.jpba.2013.04.027. Epub 2013 Apr 28.
Liquid chromatography-mass spectrometry (LC-MS) is considered today as a mainstay tool for the structure characterization of minor components like impurities (IMPs) and degradation products (DPs) in drug substances and products. A multi-step systematic strategy for the purpose involves high resolution mass and multi-stage mass studies on both the drug and IMPs/DPs, followed by comparison of their fragmentation profiles. Its successful application requires consideration of many practical aspects at each step. The same are critically discussed in this review.
2. Evaluation of the Local Anesthetic Activity, Acute Toxicity, and Structure-Toxicity Relationship in Series of Synthesized 1-Aryltetrahydroisoquinoline Alkaloid Derivatives In Vivo and In Silico
Azizbek A Azamatov, et al. Molecules. 2023 Jan 4;28(2):477. doi: 10.3390/molecules28020477.
Isoquinoline alkaloids constitute one of the most common classes of alkaloids that have shown a pronounced role in curing various diseases. Finding ways to reduce the toxicity of these molecules and to increase their therapeutic margin is an urgent matter. Here, a one-step method for the synthesis of a series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines was performed in 85-98% yield by the Pictet-Spengler reaction. This was accomplished using the reaction between 3,4-dimethoxyphenylethylamine and substituted benzaldehydes boiling in trifluoroacetic acid. Furthermore, 1-(3'-amino-, 4'-aminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines were obtained in 94% and 97% yield by reduction in 1-(3'-nitro-, 4'-nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines with SnCl2 × 2H2O. The structures of the substances obtained were confirmed by infrared (IR) and nuclear magnetic resonance (1H and 13C NMR) spectra. ADMET/TOPKAT in silico study concluded that the synthesized compounds exhibited acceptable pharmacodynamic and pharmacokinetic properties without carcinogenic or mutagenic potential but with variable hepatotoxicity. The acute toxicity and structure-toxicity relationship (STR) in the series of 20 derivatives of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (3a-r, 4a, b) was studied via determination of acute toxicity and resorptive action in white mice employing intragastric step-by-step administration. The first compound, 1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3a), showed the highest toxicity with LD50 of 280 mg/kg in contrast to 1-(3'-bromo -4'-hydroxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3e) which proved to be the safest of the compounds studied. Its toxicity was 13.75 times lower than that of the parent compound 3a. All compounds investigated showed high local anesthetic activity on rabbit eyes in the concentrations studied. Only 3r, 3n, and 4a caused eye irritation and redness. All investigated derivatives (except 4b) in 1% concentration were more active than lidocaine, providing longer duration of complete anesthesia. Therefore, based on the obtained results of in silico tests, local anesthesia, and acute toxicity, a conclusion can be drawn that the experimental compounds need further extensive future investigations and possible modifications so that they can act as promising drug candidates.
3. A new carbonic anhydrase identified in the Gram-negative bacterium (Chromohalobacter sp.) and the interaction of anions with the enzyme
Furkan Orhan, Murat Senturk, Mucip Genisel Comp Biochem Physiol C Toxicol Pharmacol. 2022 Apr;254:109290. doi: 10.1016/j.cbpc.2022.109290. Epub 2022 Jan 31.
In this study, the characterization and inhibition characteristic of α-class carbonic anhydrase from Chromohalobacter (ChCA) was documented for the first time. The carbonic anhydrase enzyme had 47.77% yield and 54.45-fold purity. The specific activity of the enzyme was determined as 318.52 U/mg proteins. Alternative substrate (4-nitrophenyl trifluoroacetate, 4-nitrophenyl phosphate, 4-nitrophenyl sulphate and 4-nitrophenyl acetate) were tested for the enzyme. KM and Vmax values for 4-nitrophenyl acetate were 4.57 mM and 4.29 EU/mL and for 4-nitrophenyl trifluoroacetate were 2.39 mM and 2.41 EU/mL. The anions, Cl-, NO2-, NO3-, Br-, ClO3-, ClO4-, I-, CO32- and SO42-, inhibited the ChCA hydratase activity. Among nine anions, the strongest inhibitor activities were obtained with micro molar concentrations of NO2-, NO3-, Br-, I-, CO32- (KI values of 160-255 μM). Other four anions tested (Cl-, ClO3-, ClO4- and SO42-) showed moderate inhibitory activities (KI values of 680-813.5 μM). The results obtained demonstrate that the anions we tested inhibit the Chromohalobacter CA (ChCA) enzyme as in other α-CAs in mammals; however, the susceptibility of ChCA resulted from anions differed significantly from that of other organism CAs.
