New anthranilic acid-incorporating N-benzenesulfonamidophthalimides as potent inhibitors of carbonic anhydrases I, II, IX, and XII: Synthesis, in vitro testing, and in silico assessment.

The carbonic anhydrase (CA) inhibitory activity of newly synthesized compounds 4-21 against the human CA (hCA) isoforms I, II, IX, and XII was measured and compared to that of standard sulfonamide inhibitors, acetazolamide (AAZ) and SLC-0111. Among this series; benzensulfonamides 6-11 gave the best potent hCA inhibitors with inhibition constants (KIs) ranging from 81.9 to 456.6 nM (AAZ and SLC-0111: KIs, 250.0 and 5080 nM, respectively). Compounds 6-11 proved to be effective hCA II inhibitors (KIs, 8.9-51.5 nM); they were almost equally potent to AAZ (KI, 12.0 nM) and had superior potency to SLC-0111 (KI, 960.0 nM). For hCA IX inhibition, compounds 6-11 proved to be potent inhibitors, with KI values of 3.9-36.0 nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (KIs, 25.0 and 45.0 nM, respectively). For hCA XII inhibitory activity, compounds 6-11 displayed effective inhibition with KI values ranging from 4.6 to 86.3 nM and were therefore comparable to AAZ and SLC-0111 (KIs, 5.7 and 4.5 nM, respectively). Molecular docking studies of compounds 6, 7, 10, and 11 were conducted using the crystal structures of hCA isozymes I, II, IX, and XII to study their binding interactions for further lead optimization.

Neurotoxicity assessment of selected organic solvents based on spontaneous and evoked cortical and hippocampal activity in rats.

In a series of acute experiments on rats the potential of toluene, mesitylene, hemimellitene and pseudocumene to affect the CNS function was assessed following an analysis of spontaneous and evoked hippocampal and cortical activity. The electrophysiological examinations were performed on rats with recording electrodes chronically implanted into selected brain structures. Solvent concentration in peripheral blood was determined by gas chromatography combined with the head space technique in rats with no surgical treatment. The experiments revealed significant quantitative differences between hippocampal and cortical EEG after i.p. injections of equimolar doses of the solvents. A relationship was found between the changes in spontaneous EEG and blood concentration of the solvents. Hemimellitene, with the lowest recorded blood level was found to have the highest potential for inducing the CNS effects.

Report of the Association of British Pharmaceutical Industries Collaborative Study Group. Collaborative study to evaluate the inter/intra laboratory reproducibility and phenotypic stability of Salmonella typhimurium TA97a and TA102.

A collaborative trial was carried out to determine the intra/interlaboratory variability of Salmonella typhimurium strains TA102 and TA97a with regard to spontaneous revertant frequency and in response to four model mutagens (cumene hydroperoxide and bleomycin for strain TA102, and 4-nitrophenylenediamine and 4-aminoantipyrine for strain TA97a). A secondary objective of the trial was to monitor the stability of the strains after storage for up to 8 months and identify any technical problems associated with their use. Thirteen different laboratories participated in the trial, all receiving identical stock cultures of the bacterial strains and samples from the same batch of mutagenic compound. A standard protocol was followed and two independent experiments were carried out within 1 month of receipt of the strains/compounds (phase I), and again after a period of 6-8 months (phase II). Comparative studies with the standard strain TA100 after treatment with 4-nitrophenylenediamine were carried out as part of phase II. Overall, both strains gave acceptably consistent results in different laboratories and are considered useful for screening purposes when used under standardized conditions. One major source of interlaboratory variability identified for TA102 appears to be the sensitivity of different types of automatic colony counter for detecting the micro-colony revertants that this strain produces.

Laboratory assessment of the antimycotic drug clotrimazole.

Laboratory studies on clotrimazole showed that it had marked activity in vitro against all the Candida spp. and Cryptococcus spp. tested, against almost all strains of dermatophytes, and against Aspergillus spp and other fungal genera responsible for systemic mycoses; it had limited activity towards Gram-positive bacteria. The majority of Candida strains required MICs below 1 mug/ml and MCCs below 2 mug/ml.Serum, urine, and faecal assays of clotrimazole were made by microbiological methods on five children who received 100 mg/kg/day clotrimazole for several weeks. In-vitro sensitivity tests and biological fluid drug assays are also reported on specimens from 18 patients in other hospitals receiving clotrimazole for severe candidosis; several were renal transplant cases. Similar investigations are reported on specimens from 18 patients with pulmonary aspergilloses. The significance of low levels of the drug in body fluids, even after prolonged therapy, is discussed, and it is suggested that clotrimazole may be the first of a long series of imidazole derivatives with varying pharmacological and therapeutic properties.