Small molecule inhibitors of anthrax lethal factor toxin

Abstract

This manuscript describes the preparation of new small molecule inhibitors of Bacillus anthracis lethal factor. Our starting point was the symmetrical, bis-quinolinyl compound 1 (NSC 12155). Optimization of one half of this molecule led to new LF inhibitors that were desymmetrized to afford more drug-like compounds.

One-Pot Approach to N-Quinolyl 3′/4′-Biaryl Carboxamides by Microwave-Assisted Suzuki–Miyaura Coupling and N-Boc Deprotection

“…The biaryl carboxamides play important roles as vital building blocks in the synthesis of a diversity of drugs such as anticancer, − anti-inflammatory, , anxiolytic, Alzheimer’s, and anemia therapeutic agents . Among these biaryl carboxamides, N -quinolyl (Q) 3′/4′-biaryl carboxamide is a unique substructure in medicinal chemistry that has shown the potential to antagonize bacteria, promote weight loss, promote differentiation of adult human cardiac progenitor cells, and activate TRPV1 (transient receptor potential vanilloid type 1) ion channel. , …”

Design, synthesis, and evaluation of novel heteroaryldihydropyrimidine derivatives as non‐nucleoside hepatitis B virus inhibitors by exploring the solvent‐exposed region

“…The key intermediate 2 , prepared from the commercially available 2‐thiazolecarboxamidine hydrochloride ( 1 ), 2‐bromo‐4‐fluorobenzaldehyde, and ethyl acetoacetate by classic “Biginelli reaction,” was converted to intermediate 3 with NBS and CCl 4 by free radical reaction. Using acetone as solvent, the intermediate 3 was reacted with NaN 3 to give intermediate 4 by nucleophilic substitution reaction (He et al., ), which was further reduced to intermediate 5 via one‐step “Staudinger reaction.”(Williams et al., ) Finally, target compounds I‐(1–18) were obtained from intermediate 5 by easy condensation reaction with DCM, Et 3 N, and different substituted sulfonyl chloride as raw materials (Scheme 1), and target compounds II‐(1–10) were obtained from intermediate 4 by CuAAC reaction (Scheme 2).…”

Chemical Strategies To Target Bacterial Virulence

“…This highlights the importance of overall charge, solubility, and lipophilicity of the inhibitor in designing a potential drug lead. Using NSC 12155 as the starting compound, a medicinal chemistry study was performed by Williams et al, identifying more drug-like compounds with similar in vitro potency and improved selectivity over other metalloproteases such as BoNT A and human matrix metalloproteases (MMPs) . In a high-throughput screen of 10 000 drug-like molecules, Schepetkin et al sought to identify LF inhibitors with distinct chemical structures from previously identified small-molecule inhibitors of LF .…”

“…Using NSC 12155 as the starting compound, a medicinal chemistry study was performed by Williams et al, identifying more drug-like compounds with similar in vitro potency and improved selectivity over other metalloproteases such as BoNT A and human matrix metalloproteases (MMPs). 165 In a highthroughput screen of 10 000 drug-like molecules, Schepetkin et al sought to identify LF inhibitors with distinct chemical structures from previously identified small-molecule inhibitors of LF. 166 These efforts resulted in four lead compounds possessing novel fragments such as 2-phenylfuran, N-phenyldihydropyrazole, N,N-diphenylurea-sulfonamide, and a carboxylic N-phenylpyrrole, with nanomolar K i values in vitro (see pyrimidinthiazole, Figure 7).…”