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Background The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. Objectives A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). Methods Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. Results No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean T max range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean T max 3.87 h), a lower C max (−17.7%) and increased AUC0– t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both C max and AUC0–tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0–tau) compared with C max (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. Conclusions Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food. [ABSTRACT FROM AUTHOR]

The sensitivity of Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis, which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects. Boosting the action of a TB drug: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and is one of the leading causes of death from a single infectious agent. Ethionamide is a prodrug used to treat multidrug resistant TB. MymA is a mycobacterial oxidase that is responsible for the activation of ethionamide. The production of MymA is under the control of the transcriptional regulator VirS. Flipo et al. now report the discovery of the small-molecule SMARt751, a VirS ligand that up-regulates expression of the mymA operon. SMARt751 reversed resistance to ethionamide in mouse models of acute and chronic TB. [ABSTRACT FROM AUTHOR]

New treatments are needed for neglected tropical diseases (NTDs) such as Human African trypanosomiasis (HAT), Chagas disease, and schistosomiasis. Through a whole organism high-throughput screening campaign, we previously identified 797 human kinase inhibitors that grouped into 59 structural clusters and showed activity against T. brucei, the causative agent of HAT. We herein report the results of further investigation of one of these clusters consisting of substituted isatin derivatives, focusing on establishing structure-activity and -property relationship scope. We also describe their in vitro absorption, distribution, metabolism, and excretion (ADME) properties. For one isatin, NEU-4391, which offered the best activity-property profile, pharmacokinetic parameters were measured in mice. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection. [ABSTRACT FROM AUTHOR]