In this research the sequential generation and cyclization of N-alkoxyaminyl radicals to produce 1-azaspiro[4.4]nonane systems was studied. Competition experiments in benzene at 80°C with brominated oxime ethers using Bu3SnH as...

Subsystem density functional theory (DFT) is emerging as a powerful electronic structure method for large-scale simulations of molecular condensed phases and interfaces. Key to its computational efficiency is the use of approximate nonadditive noninteracting kinetic energy functionals. Unfortunately, currently available nonadditive functionals lead to inaccurate results when the subsystems interact strongly such as when they engage in chemical reactions. This work disrupts the status quo by devising a workflow that extends subsystem DFT’s applicability also to strongly interacting subsystems. This is achieved by implementing a fully automated adaptive definition of subsystems which is realized during geometry optimizations or ab initio molecular dynamics simulations. The new method prescribes subsystem merging and splitting events redistributing the resources (both for work and data) in an efficient way making use of modern parallelization strategies and object-oriented programming. We showcase the method with examples probing from moderate-to-strong inter-subsystem interactions, opening the door to using subsystem DFT for modeling chemical reactions in molecular condensed phases with a black box computational tool.

Background: Chagas disease is a potentially fatal disease caused by the parasite Trypanosoma cruzi. There is growing scientific interest in finding new and better therapeutic alternatives for this disease’s treatment. Methods: A total of 81 terpene compounds with potential trypanocidal activity were screened and found to have potential T. cruzi cysteine synthase (TcCS) inhibition using molecular docking, molecular dynamics, ADME and PAIN property analyses and in vitro susceptibility assays. Results: Molecular docking analyses revealed energy ranges from −10.5 to −4.9 kcal/mol in the 81 tested compounds, where pentacyclic triterpenes were the best. Six compounds were selected to assess the stability of the TcCS–ligand complexes, of which lupeol acetate (ACLUPE) and α-amyrin (AMIR) exhibited the highest stability during 200 ns of molecular dynamics analysis. Such stability was primarily due to their hydrophobic interactions with the amino acids located in the enzyme’s active site. In addition, ACLUPE and AMIR exhibited lipophilic characteristics, low intestinal absorption and no structural interferences or toxicity. Finally, selective index for ACLUPE was >5.94, with moderate potency in the trypomastigote stage (EC50 = 15.82 ± 3.7 μg/mL). AMIR’s selective index was >9.36 and it was moderately potent in the amastigote stage (IC50 = 9.08 ± 23.85 μg/mL). Conclusions: The present study proposes a rational approach for exploring lupeol acetate and α-amyrin terpene compounds to design new drugs candidates for Chagas disease.