Pyrido-Dibemequine Metabolites Exhibit Improved Druglike Features, Inhibit Hemozoin Formation in , and Synergize with Clinical Antimalarials.

Structural modification of existing chemical scaffolds to afford new molecules able to circumvent drug resistance constitutes one of the rational approaches to antimalarial drug discovery. Previously synthesized compounds based on the 4-aminoquinoline core hybridized with a chemosensitizing dibenzylmethylamine side group showed efficacy in -infected mice despite low microsomal metabolic stability, suggesting a contribution from their pharmacologically active metabolites. Here, we report on a series of these dibemequine (DBQ) metabolites with low resistance indices against chloroquine-resistant parasites and improved metabolic stability in liver microsomes.

Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity and Efficacy in a Mouse Malaria Infection Model.

Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue (NF54 IC = 0.012 μM; K1 IC = 0.040 μM) displaying high microsomal metabolic stability (HLM CL < 11.

Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against In Vitro.

In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds , , and displayed high activities against asexual blood stage parasites (NF54 IC = 0.025-0.

New Amidated 3,6-Diphenylated Imidazopyridazines with Potent Antiplasmodium Activity Are Dual Inhibitors of Phosphatidylinositol-4-kinase and cGMP-Dependent Protein Kinase.

Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive activity and efficacy in mouse models of malaria infection. Herein, we report the synthesis and antiplasmodium evaluation of a new series of amidated analogues and demonstrate that these compounds potently inhibit phosphatidylinositol-4-kinase (PI4K) type IIIβ while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) activity . Using docking, we predict key binding interactions for these analogues within the adenosine triphosphate (ATP)-binding site of PI4K and PKG, paving the way for structure-based optimization of imidazopyridazines targeting both PI4K and PKG.

Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action.

A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated.

Reversed isoniazids: Design, synthesis and evaluation against Mycobacterium tuberculosis.

Novel reversed isoniazid (RINH) agents were synthesized by covalently linking isoniazid with various efflux pump inhibitor (EPI) cores and their structural motifs. These RINH agents were then evaluated for anti-mycobacterial activity against sensitive, isoniazid mono-resistant and MDR clinical isolates of M. tuberculosis and a selected number of compounds were also tested ex vivo for intracellular activity as well as in the ethidium bromide (EB) assay for efflux pump inhibition efficacy.

Design, Synthesis, and Evaluation of Novel Hybrid Efflux Pump Inhibitors for Use against Mycobacterium tuberculosis.

Efflux pumps are considered a major potential contributor to the development of various forms of resistance in Mycobacterium tuberculosis leading to the emergence of multidrug-resistant tuberculosis (TB). Verapamil (VER) and tricyclic chemosensitizers such as the phenothiazines are known to possess efflux pump inhibition properties and have demonstrated significant efficacy in various TB disease models. Novel hybrid molecules based on fusion of the VER substructure with various tricyclic, as well as nontricyclic, chemosensitizer cores or their structural motifs are described.

New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells.

There is a growing interest in repurposing mycobacterial efflux pump inhibitors, such as verapamil, for tuberculosis (TB) treatment. To aid in the design of better analogs, we studied the effects of verapamil on macrophages and Mycobacterium tuberculosis-specific T cells. Macrophage activation was evaluated by measuring levels of nitric oxide, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and gamma interferon (IFN-γ).

Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c.

New verapamil analogues were synthesized and their inhibitory activities against Mycobacterium tuberculosis H37Rv determined in vitro alone and in combination with rifampicin (RIF). Some analogues showed comparable activity to verapamil and exhibited better synergies with RIF. Molecular docking studies of the binding sites of Rv1258c, a M.

Synthesis, docking and in vitro antimalarial evaluation of bifunctional hybrids derived from β-lactams and 7-chloroquinoline using click chemistry.

1,2,3-Triazole tethered β-lactam and 7-chloroquinoline bifunctional hybrids were synthesized and evaluated as potential antimalarial agents. Activity against cultured Plasmodium falciparum was dependent on the N-substituent of the β-lactam ring as well as the presence of bis-triazole at the C-3 position. The observed activity profiles were further substantiated by docking studies via inhibition of P.