The search for the "next" euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning.

PURPOSE: A detailed review on the chemistry and pharmacology of non-fentanil novel synthetic opioid receptor agonists, particularly N-substituted benzamides and acetamides (known colloquially as U-drugs) and 4-aminocyclohexanols, developed at the Upjohn Company in the 1970s and 1980s is presented. METHOD: Peer-reviewed literature, patents, professional literature, data from international early warning systems and drug user fora discussion threads have been used to track their emergence as substances of abuse. RESULTS: In terms of impact on drug markets, prevalence and harm, the most significant compound of this class to date has been U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide), reported by users to give short-lasting euphoric effects and a desire to re-dose. Since U-47700 was internationally controlled in 2017, a range of related compounds with similar chemical structures, adapted from the original patented compounds, have appeared on the illicit drugs market. Interest in a structurally unrelated opioid developed by the Upjohn Company and now known as BDPC/bromadol appears to be increasing and should be closely monitored. CONCLUSIONS: International early warning systems are an essential part of tracking emerging psychoactive substances and allow responsive action to be taken to facilitate the gathering of relevant data for detailed risk assessments. Pre-emptive research on the most likely compounds to emerge next, so providing drug metabolism and pharmacokinetic data to ensure that new substances are detected early in toxicological samples is recommended. As these compounds are chiral compounds and stereochemistry has a large effect on their potency, it is recommended that detection methods consider the determination of configuration.

Direct observation of the rise of delayed fluorescence in dithienylbenzothiadiazole and its role in the excited state dynamics of a donor-acceptor-donor molecule.

Dithienylbenzothiadiazole (DTBT) is used as a building block in several molecules having application in organic light emitting devices (OLED) and organic photovoltaic (OPV) devices. Delayed fluorescence (DF) is the preferred design principle employed currently in OLED research. DTBT has excellent delayed fluorescence properties which makes this moiety a potentially viable OLED material. Here, the dynamics of intersystem crossing (ISC) and reverse intersystem crossing (RISC) have been explored using fluorescence, phosphorescence, fluorescence lifetime and transient absorption measurements. Experimentally it is demonstrated that singlet and triplet states of DTBT are close lying or degenerate and after a certain time the molecules can stay in the singlet or the triplet state forming an equilibrium between the two states which hinders the identification of these two states that could be characterized by routine steady state fluorescence and phosphorescence studies. Similarly in OPV material research, DTBT is coupled with strong donors to form push-pull molecules to produce a prolonged charge separated state. In this study DTBT appended with carbazole at both ends (CDTBT) was used to study the dynamics of DTBT within a donor-acceptor-donor system. The study reveals similar kinds of ISC and RISC in CDTBT along with a competitive deactivation pathway of the singlet state and it was concluded to be through the formation of a charge separated species in CDTBT.

Pyrene-Oxadiazoles for Organic Light-Emitting Diodes: Triplet to Singlet Energy Transfer and Role of Hole-Injection/Hole-Blocking Materials.

Three pyrene-oxadiazole derivatives were synthesized and characterized by optical, electrochemical, thermal, and theoretical investigations to obtain efficient multifunctional organic light emitting diode (OLED) materials. Synthesized molecules were used as emitters and electron transporters in three different device configurations, involving hole-injection/hole-blocking materials that showed good current and power efficiencies. To understand the underlying mechanisms involved in the application of these molecules as emitters and transporters, a detailed photophysical characterization of molecules 4-6 was carried out. The absorption, steady-state fluorescence, phosphorescence, fluorescence lifetime, and phosphorescence lifetime measurements were carried out. The high quantum yield and efficient reverse intersystem crossing leading to delayed fluorescence emission makes the molecule a good emitter, and the charge delocalization properties leading to excimer formation make them efficient electron transporters. Isoenergetic singlet and triplet states of the molecules make the reverse intersystem crossing feasible at room temperature even in the absence of thermal activation.

A novel FRET 'off-on' fluorescent probe for the selective detection of Fe³âº, Al³âº and Cr³âº ions: its ultrafast energy transfer kinetics and application in live cell imaging.

A rhodamine-naphthalimide dyad probe, 1, that selectively responds to the addition of trivalent metal ions (Fe(3+) or Al(3+) or Cr(3+)) via ultrafast Förster resonance energy transfer (FRET) from naphthalimide to rhodamine is designed and synthesized. 1 is highly selective to the trivalent metal ions and the presence of other monovalent or divalent metal ions do not affect its detection ability. The probe is highly sensitive and it can respond to the presence of trivalent metal ions even at sub-micromolar levels. 1 is stable over a broad range of pH, non-toxic under experimental conditions and suitable to the fluorescence bio-imaging of live cells exposed to trivalent metal ions. The trivalent metal ion induced ultrafast energy transfer kinetics of 1 is explored using time resolved fluorescence experiments.

A naphthalimide based PET probe with Fe3+ selective detection ability: theoretical and experimental study.

A naphthalimide based fluorescent probe '1' that operates based on photoinduced electron transfer phenomenon is synthesized and its chemosensory application is explored. Among various metal ions, 1 selectively detects Fe(3+) with a detection limit of 3.0 × 10(-8) M. 1 is stable at physiological pH, nontoxic under experimental conditions and suitable for the detection of Fe(3+) ions present in aqueous samples and live cells.

A fluorescence study on the interaction of telmisartan in triblock polymers pluronic P123 and F127.

Telmisartan is a poorly soluble drug used in treatment of hypertension. There is a recent interest to use pluronic for improving the solubility and bioavailability of these drugs. In this study the interaction of telmisartan with P123 and F127 has been carried out using steady state and time dependent fluorescence study. Quenching of telmisartan fluorescence by potassium iodide is controlled by interactions arising from collisions and complex formation. A comparison of the fluorescence of telmisartan in pluronics with the well understood fluorescence of 8-anilino-1-naphthalene-sulfonic acid, a known fluorescent molecular probe, indicates that telmisartan is generally present in a relatively polar microenvironment with restricted diffusive motion.

Synthesis and biological evaluation of new epalrestat analogues as aldose reductase inhibitors (ARIs).

Baylis-Hillman chemistry derived four series of new epalrestat analogues were synthesized. Three structural changes are introduced in these 39 new epalrestat analogues synthesized. All compounds were evaluated for their in vitro aldose reductase inhibitory (ALR) activity. Biological activity data indicates that compounds 6, 16, 19, 28 and 29 are potent and the activity is in the range of reference drug, epalrestat. Molecular modelling studies were performed to understand the binding interactions of these active molecules with the ALR protein. Molecular docking data indicates the key interactions of epalrestat were retained in some of the active compounds whereas some new interactions were noticed for other molecules. The modifications introduced on epalrestat have impact for developing a new-type of ALR inhibitor.

Synthesis, crystal structure and antidiabetic activity of substituted (E)-3-(Benzo [d]thiazol-2-ylamino) phenylprop-2-en-1-one.

A novel series of substituted (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-onewere synthesized starting from 2-aminobenzothiazole and 1-aryl-3,3-bis- (methylsulfanyl)-2-propen-1-onesin the presence of a catalytic amount of sodium hydride in THF. The synthesised compounds' structures were confirmed by IR, Mass spectrometry, (1)H NMR, (13)C NMR and HRMS spectral data. These compounds were evaluated for their antidiabetic activity, and most of the derivatives of (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-one displayed significant antidiabetic activity.

Synthesis and glycosidase inhibitory activity of novel (2-phenyl-4H-benzopyrimedo[2,1-b]-thiazol-4-yliden)acetonitrile derivatives.

A series of (2-phenyl-4H-benzopyrimodo[2,1-b][1,3]thiazol-4-yliden-4-yliden)acetonitrile derivatives have been prepared by ring transformation reaction of 4-(methylthio)-2-oxo-6-aryl-2H-pyrane-3-carbonitriles. The yield of ring transformation product is moderate to good. Furthermore the glycosidase inhibitory activities were tested by using α-amylase and α-glucosidase pancreatic, intestinal and liver enzymes, responsible for hyperglycemia in type II diabetes. The results revealed that all compounds exhibit significant glycosidase inhibitory activity.

Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase3 (PDE3): a target for heart failure and platelet aggregation.

Twenty-six 2-pyridone derivatives (8a-8z), which are structurally analogous to amrinone and milrinone two important cardiotonic drugs, are synthesized and characterized. The synthesis of 2-pyridone derivatives involves addition, followed by cyclization between Baylis-Hillman acetates (7a-7k) and enamino esters or nitriles (3a-3e). Thus synthesized pyridones were subjected to PDE3 inhibitory activity, 14 pyridones were found to be hits out of 26 pyridones synthesized and out of 14 hits, there are 5 pyridones found to be lead compounds having excellent PDE3 inhibitory activity. Further we have carried out computational analysis to understand protein/enzyme and 2-pyridone derivative interactions to identify amino acid residues involved in the vicinity of binding and compared with milrinone drug.

Synthesis of new praziquantel analogues: potential candidates for the treatment of schistosomiasis.

An efficient synthesis of antischistosomal drug praziquantel and analogues was achieved and the synthetic route designed was to afford structurally diverse analogues for better structure-activity relationship understanding. Total of nineteen PZQ analogues with structural variations at amide, piperazine and aromatic moieties have been synthesized and fully characterized. Among all the new analogues tested for antischistosomal activity, one dimethoxy tetrahydroisoquinoline analogue and two tetrahydro-ß-carboline analogues exhibited moderate activity against adult Schistosoma mansoni. Tetrahydro-ß-carboline analogues showed moderate activity whereas the presence of p-trifluoromethylbenzoyl and p-toluenesulphonyl moieties resulted in complete suppression of antischistosomal activity.

Photochemical dehydrogenation of 3,4-dihydro-2-pyridones.

Photochemical dehydrogenation of various substituted 3,4-dihydro-2-pyridones was achieved in a very efficient way by employing 10-15 mol% of photo-induced electron transfer sensitizers like 9-cyanoanthracene, 9-cyanophenanthrene and 1-cyanonaphthalene in presence of molecular oxygen, for the first time.

Concise synthesis of stagonolide-F by ring closing metathesis approach and its biological evaluation.

The first total synthesis of 9-membered macrolide, stagonolide-F (3), starting from commercially available 1,5-pentane diol is reported. A combination of Jacobsen's hydrolytic kinetic resolution (HKR) and Sharpless epoxidation is used for the creation of two stereogenic centers, while ring-closing metathesis (RCM) strategy was used for the construction of the lactone ring. The molecule synthesized exhibited potent antifungal, antibacterial and cytotoxic activities against all the tested strains.