Software-assisted automated detection and identification of "unknown" fentanyl analogues.

Fentanyl and its non-pharmaceutical analogues (NPFs) are potent synthetic opioids, traditionally used for pain management, with ever-increasing illicit uses. Tightening the regulation for known fentanyls leads to new synthetic analogues in the opioid market. Furthermore, the Organization for the Prohibition of Chemical Weapons (OPCW) has recently issued a decision regarding aerosolized use of central nervous system (CNS)-acting agents, such as fentanyl and its analogues, under the concern that these materials could be misused for terror or war purposes. The ever-increasing development of new fentanyl analogues makes the task of detection and identification of these new, unknown analogues crucial. In this work, we introduce an automated tool for the detection and putative identification of "unknown" fentanyl analogues, using liquid chromatography-mass spectrometry (LC-MS) (high-resolution mass spectrometry [HRMS]) analysis, subsequently followed by data processing using the "Compound Discoverer" software. This software, in our modified use, enabled the automatic detection of various fentanyl analogues, by "digging" out components and comparing them to pre-calculated theoretical molecular ions of possible modifications or transformations on the fentanyl backbone structure (no library or database used). Subsequently, structural elucidation for the proposed component of interest is carried out by automated MS/MS data interpretation, as performed by the software. This method was explored on 12 fentanyl-based "unknown" analogues used as model examples, including chemical modifications such as fluorination and methylation. In all tested compounds, automatic detection and identification were achieved, even at concentrations as low as 1 ng/mL in an environmental soil matrix extract.

Addressing the Opioids Lipophilicity Challenge via a Straightforward and Simultaneous 1H NMR-Based logP/D Determination, Both Separately and in Mixtures.

A systematic study of trends in the lipophilicity of prominent representatives of the opioid family, including natural, semisynthetic, synthetic, and endogenous neuropeptide opioids, is described. This was enabled by a straightforward 1H NMR-based logP/D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous logD determination of opioid mixtures, overcoming the high sensitivity of this family to the measurement conditions, which is critical when a determination of the exact ΔlogD values of matched pairs is required. Interpretation of the experimental ΔlogD7.4 values of selected matched pairs, focusing inter alia on the 3-OMe and 14-OMe motifs in morphinan opioids, is suggested with the aid of DFT calculations and may be useful for the discovery of new opioid therapeutics.

CF2H, a Functional Group-Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH3?

The effects of the CF2H moiety on H-bond (HB) acidity and lipophilicity of various compounds, when attached directly to an aromatic ring or to other functions like alkyls, ethers/thioethers, or electron-withdrawing groups, are discussed. It was found that the CF2H group acts as a HB donor with a strong dependence on the attached functional group ( A = 0.035-0.165). Regarding lipophilicity, the CF2H group may act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH3, respectively, when attached to Ar or alkyl. In addition, the lipophilicity of ethers, sulfoxides, and sulfones is dramatically increased upon CH3/CF2H exchange at the α position. Interestingly, this exchange significantly affects not only the polarity and the volume of the solutes but also their HB-accepting ability, the main factors influencing log Poct. Accordingly, this study may be helpful in the rational design of drugs containing this moiety.

Difluoromethyl Bioisostere: Examining the "Lipophilic Hydrogen Bond Donor" Concept.

There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute 1H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.

Auroside, a xylosyl-sterol, and patusterol A and B, two hydroxylated sterols, from two soft corals Eleutherobia aurea and Lobophytum patulum.

A new sterol glycoside, auroside (1) and two new hydroxylated sterols, patusterol A and B (2, 3) have been isolated from the South African soft coral Eleutherobia aurea and from the Kenyan soft coral Lobophytum patulum. The structure elucidation was achieved from extensive 1D- and 2D- NMR and MS data, and in the case of auroside also by chemical reactions. In addition, from Lobophytum patulum, was also isolated a known nitrogen containing compound (Z)-N-[2-(4-hydroxyphenyl)ethyl]-3-methyldodec-2-enamide, and from Eleutherobia aurea several, earlier reported, diterpenoids. Compound 2 was found to be toxic to brine shrimp embryos with an LC50 value of 2.30 microM.

Nardosinanols A-I and lemnafricanol, sesquiterpenes from several soft corals, Lemnalia sp., Paralemnalia clavata, Lemnalia africana, and Rhytisma fulvum fulvum.

Ten new sesquiterpenes, nardosinanols A-I ( 1- 9) and lemnafricanol ( 10), have been isolated from several Kenyan soft corals, i.e., from Lemnalia sp., Paralemnalia clavata, Lemnalia africana, and Rhytisma fulvum fulvum. The structures and relative stereochemistry of these compounds were elucidated by interpretation of MS, COSY ( (1)H- (1)H correlations), HSQC, HMBC, and NOESY NMR spectroscopic experiments and in the case of 5 also by chemical transformation to compounds 11 and 12. Nine compounds ( 1- 9) are based on the nardosinane skeleton ( 1- 6 are nardosinanes and 7- 9 nornardosinanes). Lemnafricanol ( 10) possesses a novel tricyclic skeleton. Compounds 3, 7, and 10 were found to be toxic to brine shrimp with LC 50 values of 4.0, 0.35, and 0.32 microM, respectively.