Persistent bacteria, including persister cells within surface-attached biofilms and slow-growing pathogens lead to chronic infections that are tolerant to antibiotics. Here, we describe the structure-activity relationships of a series of halogenated phenazines (HP) inspired by 2-bromo-1-hydroxyphenazine 1. Using multiple synthetic pathways, we probed diverse substitutions of the HP scaffold in the 2-, 4-, 7-, and 8-positions, providing critical information regarding their antibacterial and bacterial eradication profiles. Halogenated phenazine 14 proved to be the most potent biofilm-eradicating agent (≥99.9% persister cell killing) against MRSA (MBEC < 10 μM), MRSE (MBEC = 2.35 μM), and VRE (MBEC = 0.20 μM) biofilms while 11 and 12 demonstrated excellent antibacterial activity against M. tuberculosis (MIC = 3.13 μM). Unlike antimicrobial peptide mimics that eradicate biofilms through the general lysing of membranes, HPs do not lyse red blood cells. HPs are promising agents that effectively target persistent bacteria while demonstrating negligible toxicity against mammalian cells.

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C–H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.

High-throughput screening (HTS) is the primary driver to current drug discovery efforts. New therapeutic agents that enter the market are a direct reflection of the structurally simple compounds that make up screening libraries. Unlike medically relevant natural products (e.g., morphine), small molecules currently being screened have low fraction sp3 character and few, if any, stereogenic centers. Although simple compounds have been useful in drugging certain biological targets (e.g., protein kinases), more sophisticated targets (e.g., transcription factors) have largely evaded the discovery of new clinical agents from screening collections. Here, we describe a tryptoline ring distortion strategy that enabled the rapid synthesis of 70 complex and diverse compounds from yohimbine 1, an indole alkaloid. The compounds that were synthesized had architecturally complex and unique scaffolds, unlike 1 and other scaffolds. These compounds were subjected to phenotypic screens and reporter gene assays leading to the identification of new compounds that possess various biological activities, including: antiproliferative activities against cancer cells with functional hypoxia inducible factors, nitric oxide inhibition, inhibition and activation of the antioxidant response element (ARE). This tryptoline ring distortion strategy can begin to address diversity problems in our screening libraries while occupying biologically relevant chemical space in areas critical to human health.

Indole‐containing compounds demonstrate an array of biological activities relevant to numerous human diseases. The biological activities of diverse indole‐based agents are driven by molecular interactions between indole agent and critical therapeutic target. The chemical inventory of medicinally useful or promising indole compounds spans the entire structural spectrum, from simple synthetic indoles to highly complex indole alkaloids. In an analogous fashion, the chemistry behind the indole heterocycle is unique and provides rich opportunities for extensive synthetic chemistry, enabling the construction and development of novel indole compounds to explore chemical space. This review will present heterocyclic chemistry of the indole nucleus, indole compounds of clinical use, complex indole alkaloids and indole‐inspired discovery efforts by multiple research groups interested in using novel indole‐containing small molecules to drive discoveries in human biology and medicine.

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