Synthesis, physicochemical and biological evaluation of N-dealkylated metabolites of antimalarial pyrido[1,2-a]benzimidazoles and related compounds containing a Mannich base side-chain

Malaria is one of the leading causes of deaths worldwide. Despite strategic implementations aimed at decreasing mortality and morbidity rates in recent decades, this plasmodial disease continues to impact public health and the economies of developing countries. Furthermore, the emergence of resistance toward current antimalarial treatments increases the necessity for the development of novel antimalarials. The benzimidazole scaffold is an extensively researched privileged scaffold in medicinal chemistry because of its capacity to interact with numerous biological systems in various diseases, including malaria. Based on previous metabolite identification studies in liver microsomes, a new series of pyrido[1,2-a]benzimidazole (PBI) metabolites containing Mannich base side-chains were designed and synthesized. Their in vitro parasite (Plasmodium falciparum) growth and β-hematin formation inhibition activities, turbidimetric solubility, cytotoxicity, and microsomal metabolic stability in mouse liver microsomes were evaluated. To investigate structure activity relationships (SARs), the study was broadly diversified into two series (SAR-1 and SAR-2). Mannich base side-chains from SAR-1 were designed and synthesized as hypothesized N-dealkylated metabolites. In SAR-2, hypothesized N-dealkylated metabolites were compared with their respective parent compounds with a focus on modifications around the PBI core. The most potent analogues exhibited sub-micromolar activity (50% inhibitory concentration (IC50) < 1 µM) against the drug-sensitive NF54 strain of Plasmodium falciparum. Some compounds showed high activity against early- and late-stage gametocytes, the sexual stage transmissible forms of the parasite. Overall, compounds in this series were more active against early-stage gametocytes than latestage gametocytes, thus indicating stage-specificity. All but three of the analogues synthesized were potent inhibitors of β-hematin formation. Most compounds showed no cytotoxicity against HepG2 and Chinese hamster ovarian (CHO) cells. Inclusion of Mannich base side-chains influenced the in vitro microsomal metabolic stability of compounds. As expected, N-dealkylated (desethyl) metabolites showed greater metabolic stability relative to their equivalent parent compounds

Bithiophene-Cored, mono-, bis-, and tris-(Trimethylammonium)- Substituted, bis-Triarylborane Chromophores: Effect of the Number and Position of Charges on Cell Imaging and DNA/RNA Sensing

The synthesis, photophysical, and electrochemical properties of selectively mono-, bis- and tris-dimethylamino- and trimethylammonium-substituted bis-triarylborane bithiophene chromophores are presented along with the water solubility and singlet oxygen sensitizing efficiency of the cationic compounds Cat1+, Cat2+, Cat(i)2+, and Cat3+. Comparison with the mono- triarylboranes reveals the large influence of the bridging unit on the properties of the bistriarylboranes, especially those of the cationic compounds. Based on these preliminary investigations, the interactions of Cat1+, Cat2+, Cat(i)2+, and Cat3+ with DNA, RNA, and DNApore were investigated in buffered solutions. The same compounds were investigated for their ability to enter and localize within organelles of human lung carcinoma (A549) and normal lung (WI38) cells showing that not only the number of charges but also their distribution over the chromophore influences interactions and staining properties

Structure−activity relationship studies reveal new astemizole analogues active against Plasmodium falciparum in vitro

Please read abstract in the article.https://pubs.acs.org/journal/aidcbc2022-08-02hj2021BiochemistryGeneticsMicrobiology and Plant Patholog

Benzimidazole derivatives are potent against multiple life cycle stages of Plasmodium falciparum malaria parasites

The continued emergence of resistance to front-line antimalarial treatments is of great concern. Therefore, new compounds that potentially have a novel target in various developmental stages of Plasmodium parasites are needed to treat patients and halt the spread of malaria. Here, several benzimidazole derivatives were screened for activity against the symptom-causing intraerythrocytic asexual blood stages and the transmissible gametocyte stages of P. falciparum. Submicromolar activity was obtained for 54 compounds against asexual blood stage parasites with 6 potent at IC50 < 100 nM while not displaying any marked toxicity against mammalian cells. Nanomolar potency was also observed against gametocytes with two compounds active against early stage gametocytes and two compounds active against late-stage gametocytes. The transmission-blocking potential of the latter was confirmed as they could prevent male gamete exflagellation and the lead compound reduced transmission by 72% in an in vivo mosquito feeding model. These compounds therefore have activity against multiple stages of Plasmodium parasites with potential for differential targets.Supporting Information 1 : Figure S1: screening cascade; chemical and spectroscopic information on new compounds (PDF)Supporting Information 2 : Summary of all data for all in vitro experiments (XLSX)https://pubs.acs.org/journal/aidcbchj2021BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC

Proteolytic activation of proapoptotic kinase protein kinase Cδ by tumor necrosis factor α death receptor signaling in dopaminergic neurons during neuroinflammation

<p>Abstract</p> <p>Background</p> <p>The mechanisms of progressive dopaminergic neuronal loss in Parkinson’s disease (PD) remain poorly understood, largely due to the complex etiology and multifactorial nature of disease pathogenesis. Several lines of evidence from human studies and experimental models over the last decade have identified neuroinflammation as a potential pathophysiological mechanism contributing to disease progression. Tumor necrosis factor α (TNF) has recently emerged as the primary neuroinflammatory mediator that can elicit dopaminergic cell death in PD. However, the signaling pathways by which TNF mediates dopaminergic cell death have not been completely elucidated.</p> <p>Methods</p> <p>In this study we used a dopaminergic neuronal cell model and recombinant TNF to characterize intracellular signaling pathways activated during TNF-induced dopaminergic neurotoxicity. Etanercept and neutralizing antibodies to tumor necrosis factor receptor 1 (TNFR1) were used to block TNF signaling. We confirmed the results from our mechanistic studies in primary embryonic mesencephalic cultures and in vivo using the stereotaxic lipopolysaccharide (LPS) model of nigral dopaminergic degeneration.</p> <p>Results</p> <p>TNF signaling in dopaminergic neuronal cells triggered the activation of protein kinase Cδ (PKCδ), an isoform of the novel PKC family, by caspase-3 and caspase-8 dependent proteolytic cleavage. Both TNFR1 neutralizing antibodies and the soluble TNF receptor Etanercept blocked TNF-induced PKCδ proteolytic activation. Proteolytic activation of PKCδ was accompanied by translocation of the kinase to the nucleus. Notably, inhibition of PKCδ signaling by small interfering (si)RNA or overexpression of a PKCδ cleavage-resistant mutant protected against TNF-induced dopaminergic neuronal cell death. Further, primary dopaminergic neurons obtained from PKCδ knockout (−/−) mice were resistant to TNF toxicity. The proteolytic activation of PKCδ in the mouse substantia nigra in the neuroinflammatory LPS model was also observed.</p> <p>Conclusions</p> <p>Collectively, these results identify proteolytic activation of PKCδ proapoptotic signaling as a key downstream effector of dopaminergic cell death induced by TNF. These findings also provide a rationale for therapeutically targeting PKCδ to mitigate progressive dopaminergic degeneration resulting from chronic neuroinflammatory processes.</p