Predicting Autoxidation of Sulfides in Drug-like Molecules Using Quantum Mechanical/Density Functional Theory Methods.

Autoxidation of drugs and drug-like molecules is a major concern in the development of safe and effective therapeutics. Because active pharmaceutical ingredients (APIs) that contain sulfur atoms can form sulfoxides under oxidative stress, predicting oxidative susceptibilities within an organic molecule can have a major impact in accelerating the compound's stability assessment. For investigation of a sulfur atom's oxidative stability, density functional theory (DFT) methods were applied to accurately predict S-O estimated bond dissociation enthalpies (BDEs) of sulfoxides. Our process employed B3LYP/6-31+G(d) for geometry optimization and frequency calculation, and we employed B3P86/6-311++G(2df,2p) to obtain electronic energies from single-point energy calculations. A total of 84 drug-like molecules containing 50 different sulfide scaffolds were used to develop a risk scale. Our results showed that when S-O BDE is less than 69 kcal/mol, the sulfur atom has low oxidative susceptibility. High oxidation risk occurs when the S-O BDE is greater than 75 kcal/mol. The risk scale was successful in predicting the relative propensities of sulfide oxidation among the small organic molecules and commercial drugs examined.

N-oxidation Regioselectivity and Risk Prediction Using DFT-ALIE Calculations.

INTRODUCTION: The formation of N-oxide degradants is a major concern in development of new drugs due to potential effects on a compound's pharmacological activity. Such effects include but are not limited to solubility, stability, toxicity, and efficacy. In addition, these chemical transformations can impact physicochemical properties that affect drug manufacturability. Hence identification and control of N-oxide transformations is of critical importance in the development of new therapeutics. OBJECTIVE: This study describes the development of an in-silico approach to identify N-oxide formation in APIs with respect to autoxidation. METHODS: Average Local Ionization Energy (ALIE) calculations were carried out using molecular modeling techniques and application of Density Functional Theory (DFT) at the B3LYP/6-31G(d,p) level of theory. A total of 257 nitrogen atoms and 15 different oxidizable nitrogen types were used in developing this method. RESULTS: The results show that ALIE could be reliably used to predict the most susceptible nitrogen for N-oxide formation. A risk scale was developed that rapidly categorizes nitrogen's oxidative vulnerabilities as small, medium, or high. CONCLUSIONS: The developed process presents a powerful tool to identify structural susceptibilities for N-oxidation as well as enabling rapid structure elucidation in resolving potential experimental ambiguities.

Data Mining for Terahertz Generation Crystals.

A data mining approach to discover and develop new organic nonlinear optical crystals that produce intense pulses of terahertz radiation is demonstrated. The Cambridge Structural Database is mined for non-centrosymmetric materials and these structural data are used in tandem with density functional theory calculations to predict new materials that efficiently generate terahertz radiation. This enables us to (in a relatively short time) discover, synthesize, and grow large, high-quality crystals of four promising materials and characterize them for intense terahertz generation. In a direct comparison to the current state-of-the-art organic terahertz generation crystals, these new materials excel. The discovery and characterization of these novel terahertz generators validate the approach of combining data mining with density functional theory calculations to predict properties of high-performance organic materials, potentially for a host of exciting applications.

Enabling high-power, broadband THz generation with 800-nm pump wavelength.

The organic terahertz (THz) generation crystal BNA has recently gained traction as a source for producing broadband THz pulses. When pumped with 100 fs pulses, the thin BNA crystals can produce relatively high electric fields with frequency components out to 5 THz. However, the THz output with 800-nm pump wavelength is limited by the damage threshold of the material, particularly when using a 1 kHz or higher repetition rate laser. Here, we report that the damage threshold of BNA THz generation crystals can be significantly improved by bonding BNA to a high-thermal conductivity sapphire window. When pumped with 800-nm light from an amplified Ti:sapphire laser system, this higher damage threshold enables generation of 2.5× higher electric field strengths compared to bare BNA crystals. We characterize the average damage threshold for bare BNA and BNA-sapphire, measure peak-to-peak electric field strengths and THz waveforms, and determine the nonlinear transmission in BNA. Pumping BNA bonded to sapphire with 3 mJ 800-nm pulses results in peak-to-peak electric fields exceeding 1 MV/cm, with broadband frequency components >3 THz. This high-field, broadband THz source is a promising alternative to tilted pulse front LiNbO3 THz sources, enabling many research groups without optical parametric amplifiers to perform high-field, broadband THz spectroscopy.

Heterogeneous layered structures for improved terahertz generation.

One of the most effective ways of generating terahertz (THz) radiation involves the conversion of short-pulsed IR or visible laser light into THz pulses at significantly lower frequencies. This conversion can be accomplished using organic crystals with nonlinear optical crystal (NLO) properties for IR to THz conversion through optical rectification. Due to the high refractive indices of organic crystals, pump laser light as well as generated THz radiation is lost from reflections at crystal surfaces. Here we report a structure composed of a layered series of materials with intermediate refractive indices designed to reduce reflective losses and improve the THz generation from organic crystals. This structure increases the transmission coefficients for both infrared pump input and THz output. We combine simple theoretical calculations with experimental data to show that a structure composed of materials with intermediate refractive indices can be used to increase generated THz intensity by nearly 50%.

Boron-Templated Dimerization of Allylic Alcohols To Form Protected 1,3-Diols via Acid Catalysis.

We report an unprecedented boron-templated dimerization of allylic alcohols that generates a 1,3-diol product with two stereogenic centers in high yield and diastereoselectivity. This acid-catalyzed reaction is achieved via in situ formation of a boronic ester intermediate that facilitates selective cyclization and formation of a cyclic boronic ester product. High yields are observed with a variety of allylic alcohols, and mechanistic studies confirm the role of boron as a template for the reaction.

Terahertz generation and optical characteristics of P-BI.

We present the structural and THz generation characteristics of the molecular salt crystal (E)-2-(4-(dimethylamino)styryl)-1,1,3-trimethyl-1H-benzo[e]indol-3-ium iodide (P-BI) using optical rectification with IR pump wavelengths. P-BI shows a peak-to-peak field ∼6 times greater than inorganic crystal GaP, and a broader THz spectrum. Data were obtained from 0-6 THz showing a significant dip in generation at 1.8 THz, similar to what has been observed with the THz generation crystal DAST at 1 THz. We characterized the power dependence of P-BI at different IR wavelengths, with optimal THz generation at the 1550-nm pump wavelength. To model THz generation as a function of P-BI crystal thickness, we measured the THz complex refractive index and the IR group index; modeling shows that imperfect phase matching leads to spectral narrowing centered at ∼2.5 THz as the crystal thickness is increased. P-BI could provide a useful alternative to inorganic THz generation crystals such a GaP.

Synthesis and characterization of ethyl benzotriazolyl acrylate-based D-π-A fluorophores for live cell-based imaging applications.

A series of eight new ethyl (Z)-benzotriazolyl acrylates 6a-d and 7a-d have been synthesized by conventional heating and microwave irradiation from ethyl benzotriazolyl acetates 3 and 4 with the corresponding aromatic aldehydes. This work reports the synthetic approach and spectroscopic characterization (1H, 13C-NMR, HRMS) of all the synthesized compounds. X-ray diffraction analyses were performed for molecules 6a, 7a and 7d. Photophysical properties of compounds were evaluated. Finally, compound 6a was tested in a human cell line and showed low to no cytotoxicity at relevant concentrations. Initial testing demonstrates its potential use as a fluid-phase fluorescent marker for live cell imaging.