Quinones represent a class of toxicological intermediates, which can create a variety of hazardous effects in vivo including, acute cytotoxicity, immunotoxicity, and carcinogenesis. In contrast, quinones can induce cytoprotection through the induction of detoxification enzymes, anti-inflammatory activities, and modification of redox status. The mechanisms by which quinones cause these effects can be quite complex. The various biological targets of quinones depend on their rate and site of formation and their reactivity. Quinones are formed through a variety of mechanisms from simple oxidation of catechols/hydroquinones catalyzed by a variety of oxidative enzymes and metal ions to more complex mechanisms involving initial P450-catalyzed hydroxylation reactions followed by two-electron oxidation. Quinones are Michael acceptors, and modification of cellular processes could occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active molecules which can red...

http://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.6b00256

Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects

Despite the burgeoning interest in three-dimensional (3D) printing for the manufacture of customizable oral dosage formulations, a U.S. Food and Drug Administration–approved tablet notwithstanding, the full potential of 3D printing in pharmaceutical sciences has not been realized. In particular, 3D-printed drug-eluting devices offer the possibility for personalization in terms of shape, size, and architecture, but their clinical applications have remained relatively unexplored. We used 3D printing to manufacture a tailored oral drug delivery device with customizable design and tunable release rates in the form of a mouthguard and, subsequently, evaluated the performance of this system in the native setting in a first-in-human study. Our proof-of-concept work demonstrates the immense potential of 3D printing as a platform for the development and translation of next-generation drug delivery devices for personalized therapy.

3D printing of a wearable personalized oral delivery device: A first-in-human study

The practices and tactics employed in successful optimizations are examined, judged from the trajectories of ligand efficiency and property evolution. A wide range of targets is analyzed, encompassing a variety of hit finding methods (HTS, fragments, encoded library technology) and types of molecules, including those beyond the rule of five. The wider employment of efficiency metrics and lipophilicity control is evident in contemporary practice and the impact on quality demonstrable. What is clear is that while targets are different, successful molecules are almost invariably among the most efficient for their target, even at the extremes. Trajectory mapping, based on principles rather than rules, is useful in assessing quality and progress in optimizations while benchmarking against competitors and assessing property-dependent risks.

Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations

Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2–5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer’s disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI > 196; 5t, IC50 = 0.067 μM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood–brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally d...

Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents

Mental disorders are neuropsychiatric conditions that are marked by unusual or irregular thinking, feelings, or behavior, and lead to distress and/or impaired functions. Major psychiatric conditions are depression, anxiety, and psychoses of various types. Their etiopathogeneses, of a primary or secondary origin, are associated with genetic and environmental factors. They are commonly treated with psychoactive drugs (also known as psychotropics), which target serotonin, dopamine, norepinephrine, glutamate, and nuclear receptors (NRs), including retinoic acid receptor-related orphan receptors (RORs) and other receptors in the central nervous system (CNS). Herein we present a diverse array of isoxazole derivatives, among which are some prominent marketed drugs. Some of the derivatives and forms, including N-oxides, are under either (pre)clinical evaluation or patent protection as new generation of psychotropics, and a few have effective blood-brain barrier (BBB) permeability. Various drug-like isoxazol(in)es and their structural features and efficiency, modified through scaffold hopping, are described and discussed in the context of treating neuropsychiatric conditions.

The Isoxazole Ring and Its N-Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics

The chemical structure of a drug determines its physicochemical properties, further determines its ADME/Tox properties, and ultimately affects its pharmacological activity. Medicinal chemists can regulate the pharmacological activity of drug molecules by modifying their structure. Ring systems and functional groups are important components of a drug. The proportion of non-hydrocarbon atoms among non-hydrogen atoms reflects the heavy atoms proportion of a drug. The three factors have considerable potential for the assessment of the drug-like properties of organic molecules. However, to the best of our knowledge, there have been no studies to systematically analyze the simultaneous effects of the number of aromatic and non-aromatic rings, the number of some special functional groups and the proportion of heavy atoms on the drug-like properties of an organic molecule. To this end, the numbers of aromatic and non-aromatic rings, the numbers of some special functional groups and the heavy atoms proportion of 6891 global approved small drugs have been comprehensively analyzed. We first uncovered three important structure-related criteria closely related to drug-likeness, namely: (1) the best numbers of aromatic and non-aromatic rings are 2 and 1, respectively; (2) the best functional groups of candidate drugs are usually -OH, -COOR and -COOH in turn, but not -CONHOH, -SH, -CHO and -SO3H. In addition, the -F functional group is beneficial to CNS drugs, and -NH2 functional group is beneficial to anti-infective drugs and anti-cancer drugs; (3) the best R value intervals of candidate drugs are in the range of 0.05-0.50 (preferably 0.10-0.35), and R value of the candidate CNS drugs should be as small as possible in this interval. We envision that the three chemical structure-related criteria may be applicable in a prospective manner for the identification of novel candidate drugs and will provide a theoretical foundation for designing new chemical entities with good drug-like properties.

https://www.mdpi.com/1420-3049/21/1/75/pdf

Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs.

The melting point (MP), an easily accessible physical parameter, has considerable potential for the judgment of drug-like properties. However, to the best of our knowledge, there are no useful guidelines for understanding the relationship between the MP and drug-like properties. To this end, we have constructed the largest MP database (experimental value) of globally approved drugs (3164 organic small-molecule drugs) and discontinued drugs (417 organic small-molecule drugs) and subsequently extracted six subdatabases from the whole approved database and two subdatabases from the discontinued database. The MP distribution statistics and analysis of approved drugs reveal five noteworthy observations; moreover, the MP distribution statistics and analysis of discontinued drugs further supplement these criteria. In addition, the comparison of molecular weight (MW) versus MP and Clog P versus MP distributions of different classes of approved drugs indicated that the MWs and Clog P values of most drugs in the optimal MP range were not more than 500 and 5, respectively, implying the MP distribution criterion was in accordance with Lipinski's rule of five.

Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery

Xiang Xu

Papers

Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs.

Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery