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Hydrogen bonding equilibrium constants have been measured for a large and varied selection of proton donors against a common acceptor (N-methylpyrrolidinone) and of proton acceptors against a common donor (4-nitrophenol). Together these have been used to create the log Kalpha and log Kbeta scales of proton donor and acceptor ability which are explicitly targeted to the needs of the medicinal chemist in the context of potential drug-receptor interactions. To this end they have been measured in 1,1,1-trichloroethane, a solvent never before used for hydrogen bonding studies but whose high dipolarity is considered a much better model for real biological membranes than the very non-polar solvents that have previously been employed. It is shown that this solvent imposes significant ranking changes on the solutes, since the charge transfer element in hydrogen bonding is reinforced at the expense of the purely electrostatic component. Nevertheless it is possible to scale previous data in such a way that over 80 functional group log Kalpha and log Kbeta values become available to the medicinal chemist (Table 4). In addition, data are given for a large number of parent heterocycles, most of which have never before been studied. We note that heterocycles are uniquely able to ‘fine-tune’ these scales, so providing at least one justification for their special interest to the medicinal chemist. In addition to equilibrium constants we have measured the spectroscopic quantities deltanuc=0 (for donors) and betasm (for acceptors). On various lines of evidence we suggest that these are enthalpy-related quantities and, following previous arguments, may function as alternative parameters suitable for use by the medicinal chemist under conditions of severe steric constraint. Cross-comparisons of these data allow conclusions to be drawn which considerably illuminate the factors that influence hydrogen bond strength, and some of which have no precedent. A selection follows. Where a level comparison can be made, the donor order is OH > NH > CH and the acceptor order is N > 0 > S. However, within each category there are various sorts of family relationship. For example, phenols and alkanols lie on separate lines of log Kalpha vs pKa and a similar separation for log Kbeta is shown by 5- and 6-membered ring heterocycles. By contrast, OH and NH donors show a single relation between log Kalpha and deltanuc=0, negative deviations from which are satisfactorily accounted for in terms of steric and stereoelectronic factors. The most important of the latter is lone-pair repulsion: ‘alpha-effect’ heterocycles are anomalously strong acceptors, whereas certain classes of donor, notably sulphonamides and carboxylic acids, are much weaker than would be expected from their pKa values. More subtle anomalies attach, inter alia, to heterocycles as donors, CH donors generally, and amines and sulphonamides as acceptors; all however can be rationalised. The extremes of both scales are charted. Alkyl thiols and amines are negligible as proton donors; correspondingly, Pie-donor hetero-atoms as e.g. in esters and amides are negligible acceptors. At the opposite extreme, heterocycles such as tetrazole and 4-quinolone figure prominently. Based on these results, some structural criteria are suggested that might lead to the synthesis of stronger proton acceptors than any so far known.

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One main focus of the review (Part 2) is spectral and physicochemical properties of both N-unsubstituted methides and anhydrobases, including tautomerism and stability. In the sections on chemical reactivity, reactions upon the alpha-position as well as ring formation and transformation are dominant. Finally, recently published applications are reviewed.

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The UV photodissociation of isoxazole (c-C3H3NO) is studied in this work by chirped-pulse Fourier transform mm-wave spectroscopy in a pulsed uniform Laval flow. This approach offers a number of advantages over traditional spectroscopic detection methods due to its broadband, sub-MHz resolution, and fast-acquisition capabilities. In coupling this technique with a quasi-uniform Laval flow, we are able to obtain product branching fractions in the 193 nm photodissociation of isoxazole. Five dissociation channels are explored through direct detection of seven different photoproducts. These species and their respective branching fractions (%) include the following: HCN (53.8 ± 1.7), CH3CN (23.4 ± 6.8), HCO (9.5 ± 2.3), CH2CN (7.8 ± 2.9), CH2CO (3.8 ± 0.9), HCCCN (0.9 ± 0.2), and HNC (0.8 ± 0.2). Guided by previous electronic structure and dynamics simulations, we are able to elucidate the dissociation dynamics that govern the final product branching fractions observed in this work, which differ significantly from previous reports on the thermal decomposition of isoxazole. Interestingly, both direct and indirect dynamics contribute to its dissociation, and clear signatures of both are manifested in the relative branching ratios obtained. Consistent with previous studies on the unimolecular dissociation of isoxazole, our findings also suggest the importance of the open-shell singlet diradicaloid species vinylnitrene in the dissociation dynamics, regardless of the initially populated excited state. This work, taken together with previous investigations, provides a global picture of the complex dissociation pathways involved in the photodissociation of isoxazole.

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[Figure not available: see fulltext.] 1,2,4-Oxadiazoles are heterocycles characterized by low aromaticity and the presence of a weak O?N bond and are widely studied due to their tendency to rearrange into more stable heterocyclic compounds. This review covers literature from the last fifteen years, highlighting the general features of 1,2,4-oxadiazoles and their applications. Regarding the reactivity, the development of classical reactions (thermal and photochemical rearrangements) is presented in terms of synthetic utility and mechanistic insight. Among the relevant rearrangement reactions, the Boulton?Katritzky Rearrangement (BKR), Migration ? Nucleophilic Attack ? Cyclization (MNAC), and Addition of the Nucleophile, Ring Opening, and Ring Closure (ANRORC) reactions are discussed, together with recent noteworthy syntheses and applications of the 1,2,4-oxadiazole ring.

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This paper reports the development of a successful anti-solvent method that incorporates colloidal nano scale graphene oxide (nGO) directly into hydrophobic drug crystals. The nGO dispersed in solution acted as nucleating sites for crystallization and were embedded into the drug crystals without altering its structure or physical properties such as melting point. Several composites of drugs Sulfamethoxazole and Griseofulvin were synthesized with nGO concentration ranging between 0.2 and 1.0 %. The presence of nGO dramatically enhanced the dissolution rate. The time needed to reach a 50 % release (T50) reduced from 42?14 min with the integration of 0.8 % nGO in SMZ, while in GF the reduction was from 44?27 min with 0.5 % nGO. Increased release rates are attributed to the presence of the hydrophilic nGO which hydrogen bond more so with the aqueous mediums. Therefore, the incorporation of nGO into poorly soluble drugs is an effective approach towards drug delivery and bioavailability improvement and opens a new approach to high performance drug delivery.

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Lamellarins are marine alkaloids containing fused 14-phenyl-6H-[1]benzopyrano[4?,3?:4,5]pyrrolo[2,1-a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems. To date, more than 50 lamellarins have been isolated from a variety of marine organisms, such as mollusks, tunicates, and sponges. Many of them, especially fused type I lamellarins, exhibit impressive biological activity, such as potent cytotoxicity, topoisomerase I inhibition, protein kinases inhibition, and anti-HIV-1 activity. Due to their useful biological activity and limited availability from natural sources, a number of synthetic methods have been developed. In this chapter, we present an updated and comprehensive review on lamellarin alkaloids summarizing their isolation, synthesis, and biological activity.

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alpha-Damascone is widely used in perfumes. However, the manufacture of alpha-damascone remains challenging owing to the limitations of current production processes. Herein, alpha-damascone was successfully synthesized from alpha-ionone using a new route involving only four steps, namely oximization, epoxidation, dehydration, and reduction. The total yield was 54.9% with a final chemical purity of 97% (by GC). Only water, cyclohexane, and ethanol were used in the reactions except in the purification step, and all solvents could be recycled. The structures of the intermediates and target compound were identified by 1H NMR and 13C NMR analyses and MS experiments. This route is a simple and successful method for the industrial preparation of alpha-damascone.

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Background: Chalcones holding arylic substitutions and pyrazolic chalcones were reported as potent antimicrobial and antioxidant agents. Prompted by the literature, it was considered of interest in the present work to develop the bioactive materials incorporating five, and six-membered ring heterocycles in a single molecular framework with above molecules. Methods: Synthesis of chalcone derivatives derived from condensation of 2-(3,5-dimethyl-pyrazol-1- yl)-1-phenyl-ethanone and aldehydes has been discussed. Sodium hydride was employed as catalyst to facilitate the reaction which proved to be a worthy catalyst over NaOH and KOH. This protocol offers advantages such as easy workup, shorter reaction time and promising yield for the synthesis of chalcones. Further, another aromatic ring was installed to the chalcones to obtain pyrimidine, isoxazole, and pyrazole derivatives. The structures of the prepared compounds were confirmed by FT-IR, 1H NMR, 13CNMR spectroscopy, Mass spectrometry and elemental analysis. The biological activity of the compounds against four bacterial strains namely Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and three fungal strains have been evaluated. Results: An improved process for biologically useful chalcone derivatives has been discussed providing overall good yield. The newly synthesized compounds were screened for in vitro antioxidant and antimicrobial activity. Based on the preliminary results, compounds 5c, 6c, 6d in this series showed significant activity against tested bacterial strains. Compounds 6b, 6c, 6d and 7b showed potent inhibitory activity against fungal growth. Among them, compound 6c displayed the most potent activity against Candida parapsilosis, Candida tropicalis, Candida albicans, which was comparable with standard drug fluconazole. Conclusion: Synthesis, characterization and biological evaluation of new heterocyclic pyrazole chalcones has been described. The method of preparation of these compounds is very straightforward and free of tedious work up as well quite time saving. All the compounds have shown moderate to good inhibitory activity against B. subtilis and exhibited mild to moderate antibacterial activities against the other tested organisms.

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The attractive biological activity profiles of many heterocyclic moieties put them in the category of compounds having a variety of pharmacological therapeutic activities. Although lots of heterocyclic moieties have been studied for their anti-cancer activity, the present review emphasizes on heterocyclic compounds having moieties like oxadiazole, quinoline, isoxazoles and nicotinonitrile containing Nitrogen, Oxygen, and Sulphur in the heterocyclic ring structures, together with the substituent groups of the core scaffold. Their practical application ranging from extensive clinical use to fields as diverse as medicine has perched them as the true cornerstone of medicinal chemistry and their prominence lies in their study about their strong impact on the physicochemical properties. But their most important role in cell physiology and as probable intermediates for numerous biological reactions leading to anticancer research and thus capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds has put them in the most significant category. In this current review, the recent advances made on the anticancer therapeutic potential of the above mentioned aromatic heterocyclic compounds effective against human tumor/ cancer cell lines has been discussed. Their structure-activity relationships, mechanism of action and suppression activity along with the importance of the substitution pattern has also been dealt with.

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Carbon monoxide represents the most important C1-building block for the chemical industry, both for the production of bulk and fine chemicals, but also for synthetic fuels. Yet its toxicity and subsequently its cautious handling have limited its applications in medicinal chemistry research and in particular for the synthesis of pharmaceutically relevant molecules. Recent years have nevertheless witnessed a considerable headway on the development of carbon monoxide surrogates and reactor systems, which provide an ideal setting for performing carbonylation chemistry with stoichiometric and substoichiometric carbon monoxide. Such setups are particularly ideal for the introduction of isotope labels such as carbon-11, carbon-13, and carbon-14 into bioactive compounds. This review summarizes this growing field and examines the large number of carbonylation reactions that can be exploited for the introduction of a carbon isotope.

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