Search

Tenofovir (TFV) is the cornerstone nucleotide reverse transcriptase inhibitor (NtRTI) in many combination antiretroviral therapies prescribed to patients living with HIV/AIDS. Due to poor cell permeability and oral bioavailability, TFV is administered as one of two FDA-approved prodrugs, both of which metabolize prematurely in the liver and/or plasma. This premature prodrug processing depletes significant fractions of each oral dose and causes toxicity in kidney, bone, and liver with chronic administration. Although TFV exalidex (TXL), a phospholipid-derived prodrug of TFV, was designed to address this issue, clinical pharmacokinetic studies indicated substantial hepatic extraction, redirecting clinical development of TXL toward HBV. To circumvent this metabolic liability, we synthesized and evaluated ω-functionalized TXL analogues with dramatically improved hepatic stability. This effort led to the identification of compounds 21 and 23, which exhibited substantially longer t1/2 values than TXL in human liver microsomes, potent anti-HIV activity in vitro, and enhanced pharmacokinetic properties in vivo.

A series of five benzimidazole-based compounds were identified using a machine learning algorithm as potential inhibitors of the respiratory syncytial virus (RSV) fusion protein. These compounds were synthesized, and compound 2 in particular exhibited excellent in vitro potency with an EC(50) value of 5 nM. This new scaffold was then further refined leading to the identification of compound 44, which exhibited a 10-fold improvement in activity with an EC(50) value of 0.5 nM.

Phthalate diesters are used in personal care products, plastics, and pesticides, resulting in widespread human and wildlife exposure. Phthalate diesters leach out of these products and ultimately enter biological systems where they are quickly metabolized to phthalate monoesters and glucuronides. As such, phthalate monoesters can serve as indicators of anthropogenic activity in wilderness areas. The Okavango Delta, an inland seasonal wetland covering 5000–12,000 km2 in Botswana, provides fresh water to many species of birds, fish, reptiles, and large mammals. Water samples (N = 46) were taken from across the Okavango water system, extracted, and analyzed for eight different phthalate monoesters using liquid chromatography and isotope dilution mass spectrometry. Seven of eight phthalate monoesters were detected from the low ng/L to low µg/L levels. Phthalate monoesters were found in samples from all five sampling regions. Sources of these contaminants are unknown, but their presence indicates encroachment of human activity on the Okavango Delta.