In vitro metabolism of tetrazole aminoquinolines and derivatives of metergoline and fusidic acid

Includes bibliographical references.Drug metabolism is recognised as a key component of the drug discovery and development process. It exerts an influence on the action, duration of action and toxicity of a drug in vivo. The integration of drug metabolism studies is therefore crucial to compound progression through the various stages of the development process. This work details the in vitro metabolism work conducted during the early development of aminoquinoline tetrazoles, and derivatives of metergoline and fusidic acid as potential antiplasmodial and/or antimycobacterial agents

Synthesis and In Vitro Antiprotozoan Evaluation of 4-/8-Aminoquinoline-based Lactams and Tetrazoles

A second generation of 4-aminoquinoline- and 8-aminoquinoline-based tetrazoles and lactams were synthesized via the Staudinger and Ugi multicomponent reactions. These compounds were subsequently evaluated in vitro for their potential antiplasmodium activity against a multidrug-resistant K1 strain and for their antitrypanosomal activity against a cultured T. b. rhodesiense STIB900 strain. Several of these compounds (4a–g) displayed good antiplasmodium activities (IC50 = 0.20–0.62 µM) that were comparable to the reference drugs, while their antitrypanosomal activity was moderate (200 µM) at pH 7

Synthesis and biological characterisation of ester and amide derivatives of fusidic acid as antiplasmodial agents

A series of novel fusidic acid (FA) derivatives was synthesized by replacing the carboxylic acid group with various ester and amide groups and evaluated in vitro for their antiplasmodial activity against the chloroquine-sensitive NF54 and multidrug-resistant K1 strains of the malarial parasite Plasmodium falciparum. Most of these derivatives showed a 4-49 and 5-17-fold increase in activity against NF54 and KI strains, respectively, as compared to FA and had a good selectivity index. These derivatives are stable over the incubation period and do not appear to be prodrugs of fusidic acid

Antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains inhibit microtubule and hemozoin formation : structure–activity relationship and in vivo oral efficacy studies

A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure–activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.The University of Cape Town, South African Medical Research Council and South African Research Chairs Initiative of the Department of Science and Innovation, administered through the South African National Research Foundation (NRF) and a NRF Community of Practice on ‘Evaluating Malaria Control Interventions’.http://pubs.acs.org/loi/jmcmar2022-04-12hj2021BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC

Defining the clinical and cognitive phenotype of child savants with autism spectrum disorder

Objective: Whilst savant syndrome is most commonly observed in individuals with Autism Spectrum Disorder (ASD), it has historically been associated with intellectual impairment, and little is known about the clinical and cognitive characteristics of intellectually able individuals with ASD and savant skills. Methods: Participants with ASD and validated savant skills were compared with age and intelligence matched non-savants with ASD using a range of diagnostic and standardised tests. Results: Although the analysis of the clinical data revealed few differences between the groups, striking differences emerged during cognitive testing. Children with savant skills exhibited highly superior working memory and their scores on tests of analytic skills were also superior to those of non-savants. Conclusion: We propose that obsessionality, focused attention, superior working memory and analytic skills facilitate veridical mapping and pattern perception abilities characteristic in savant syndrome

UCT943, a next generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria

The 2-aminopyridine MMV048 was the first drug candidate inhibiting; Plasmodium; phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant; Plasmodium falciparum; and; Plasmodium vivax; clinical isolates. Excellent; in vitro; antiplasmodial activity translated into high efficacy in; Plasmodium berghei; and humanized; P. falciparum; NOD-; scid IL-2R; γ; null; mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate; in vivo; intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation; Plasmodium; PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria

Opto-Electrical Properties of Chemical bath Deposited Cu4SnS4 Thin Films

Thin films could be explained as a very thin layer of a substance deposited onto various substrates. Nowadays, a variety of binary, ternary, quaternary and pent nary films have been produced by using different deposition techniques. A comprehensive study of the effects of deposition temperature on the optical and electrical properties of chemical bath deposited copper tin sulphide (Cu4SnS4) thin films is reported. The Cu4SnS4 thin films were prepared, characterized, and optimized for solar light trapping. Optical properties of the films namely, reflectance and transmittance were measured using UV-VIS NIR 3700 spectrophotometer. Transmittance and band gap of the optimized Cu4SnS4 thin films were found to be below 25 % and 1.46 eV respectively (films deposited at 70 oC). Further, these films showed a peak average absorbance of 62.95 %. The films were characterized using a four-point probe to determine their surface sheet resistivity. The resistivity decreases from 19.28 Ω-cm to 8.38 Ω-cm with an increase in the deposition temperature (40°C to 70°C). The obtained optical and electrical results showed the optimum deposition temperature (70°C) for the formation of Cu4SnS4 thin films, could be used as an absorber layer for solar cell applications. The optimized Cu4SnS4 films had the lowest transmittance and reflectance, highest absorbance, minimum band gap, and lowest resistivity, all positive qualities of potential material for use as an absorber layer for photovoltaic applications

Antimalarial benzoheterocyclic 4-aminoquinolines : structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively

Antimalarial pyrido[1,2-a]benzimidazole derivatives with mannich base side chains: synthesis, pharmacological evaluation and reactive metabolite trapping studies

A novel series of pyrido[1,2- a]benzimidazoles bearing Mannich base side chains and their metabolites were synthesized and evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post-treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent in vitro antiplasmodium activity against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum ( P. falciparum) strains. Rapid metabolism was observed for all the analogues with <40% of parent compound remaining after 30 min of incubation in liver microsomes. RM trapping studies detected glutathione adducts only in derivatives bearing 4-aminophenol moiety, with fragmentation signatures showing that this conjugation occurred on the phenyl ring of the Mannich base side chain. As with amodiaquine (AQ), interchanging the positions of the 4-hydroxyl and Mannich base side group or substituting the 4-hydroxyl with fluorine appeared to block bioactivation of the AQ-like derivatives though at the expense of antiplasmodium activity, which was significantly lowered