A direct alkylation of various heteroaryls using stoichiometric potassium alkyl and alkoxymethyltrifluoroborates has been developed. This method leads to the synthesis of complex substituted heterocycles, which have been obtained with yields up to 89%.Heteroaryl moieties are important components in natural products and pharmaceutical drugs.

Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 reverse transcriptase (RT) used for the treatment of AIDS. RT is a heterodimer composed of p66 and p51 subunits; p51 is produced from p66 by C-terminal truncation by HIV protease. The monomers can form p66/p66 and p51/p51 homodimers as well as p66/p51 heterodimer. Dimerization and efavirenz binding are coupled processes. In the crystal structure of the p66/p51—EFV complex, the drug is bound to the p66 subunit. The binding of efavirenz to wild-type and dimerization-defective RT proteins was studied by equilibrium dialysis, tryptophan fluorescence and native gel electrophoresis. A 1:1 binding stoichiometry was determined for both monomers and homodimers. Equilibrium dissociation constants are ~2.5 μM for both p66— and p51—EFV complexes, 250 nM for p66/p66—EFV complex, and 7 nM for p51/p51—EFV complex. An equilibrium dissociation constant of 92 nM for p66/p51—EFV complex was calculated from the thermodynamic linkage between dimerization and inhibitor binding. Binding and unbinding kinetics monitored by fluorescence were slow. Progress curve analyses revealed a one-step, direct binding mechanism with association rate constants k1 ~13.5 M–1 s–1 for monomers and heterodimer and dissociation rate constants k–1 ~1 × 10–4 s–1 for monomers. A conformational selection mechanism is proposed to account for the slow association rate. These results show that efavirenz is a slow, tight-binding inhibitor capable of binding all forms of RT and suggest that the NNRTI binding site in monomers and dimers is similar.

Background Among older adults, malnutrition is common, often missed by healthcare providers, and influences recovery from illness or injury. Objective To identify modifiable risk factors associated with malnutrition in older patients. Design Prospective cross-sectional multicenter study Setting 3 EDs in the South, Northeast, and Midwest Participants Non-critically ill, English-speaking adults aged ≥65 years Measurements Random time block sampling was used to enroll patients. The ED interview assessed malnutrition using the Mini Nutritional Assessment Short-Form. Food insecurity and poor oral health were assessed using validated measures. Other risk factors examined included depressive symptoms, limited mobility, lack of transportation, loneliness, and medication side effects, qualified by whether the patient reported the risk factor affected their diet. The population attributable risk proportion (PARP) for malnutrition was estimated for each risk factor. Results In our sample (n=252), the prevalence of malnutrition was 12%. Patient characteristics associated with malnutrition included not having a college degree, being admitted to the hospital, and residence in an assisted living facility. Of the risk factors examined, the PARPs for malnutrition were highest for poor oral health (54%; 95% CI 16%, 78%), food insecurity (14%; 95% CI 3%, 31%), and lack of transportation affecting diet (12%; 95% CI 3%, 28%). Conclusion Results of this observational study identify multiple modifiable factors associated with the problem of malnutrition in older adults.

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The biologically active form of HIV-1 reverse transcriptase is the p66/p51 heterodimer. The process of maturation of the heterodimer from precursor proteins is poorly understood. Previous studies indicated that association of p66 and p51 is very slow. Three techniques, a pre-steady-state activity assay, intrinsic tryptophan fluorescence, and a FRET assay, were used to monitor the dimerization kinetics of RT. Kinetic experiments were carried out with purified p66 and p51 proteins in aqueous buffer. All three techniques gave essentially the same results. The dissociation kinetics of p66/p51 were first-order with rate constants kdiss of ~ 4 × 10−6 s−1 (t1/2 = 48 h). The association kinetics of p66 and p51 were concentration dependent with second-order rate constants kass of ~ 1.7 M−1s−1 for the simple bimolecular association reaction. The implications of slow dimerization of p66/p51 for the maturation process are discussed. A reaction-controlled model invoking conformational selection is proposed to explain the slow protein-protein association kinetics.