Frontiers in Medicinal Chemistry 2015: Meet the Experts of MedChem near the Cradle of Medicinal and Pharmaceutical Chemistry.

Pioneering inspiration: Right next to the former laboratories of Johannes Hartmann, the first so-called "Professor of Chymiatrie", the 2015 Frontiers in Medicinal Chemistry meeting was held last March at Philipps University in Marburg, Germany. Herein we give readers an idea of what it was like to attend the conference, which was organized jointly by the DPhG, GDCh, and SCS. Along with the lectures, we also describe the poster sessions, social program, and awards.

N-acyl derivatives of 4-phenoxyaniline as neuroprotective agents.

Neuronal cell death is the main cause behind the progressive loss of brain function in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Despite the differing etiologies of these neurological diseases, the underlying neuronal damage is triggered by common mechanisms such as oxidative stress, impaired calcium homeostasis, and disrupted mitochondrial integrity and function. In particular, mitochondrial fragmentation, mitochondrial membrane permeability, and the release of death-promoting factors into the cytosol have been revealed as the "point of no return" in programmed cell death in neurons. Recent studies revealed a pivotal role for the pro-apoptotic Bcl-2-family protein Bid in models of neuronal cell death, which confirmed Bid as a potential drug target. Herein, we present N-acyl-substituted derivatives of 4-phenoxyaniline that were screened for their potential to attenuate Bid-mediated neurotoxicity. These compounds provided significant protection against glutamate- and Bid-induced toxicity in cultured neurons. Substitution of the amino group in the 4-phenoxyaniline scaffold with 4-piperidine carboxylic acid and N-hydroxyethyl-4-piperidine carboxylic acid yielded compounds that displayed significant neuroprotective activity at concentrations as low as 1 µM. Furthermore, findings of a tBid-overexpression assay and real-time measurements of cell impedance support the hypothesis that these compounds indeed address the Bid protein.

Novel N-phenyl-substituted thiazolidinediones protect neural cells against glutamate- and tBid-induced toxicity.

Mitochondrial demise is a key feature of progressive neuronal death contributing to acute and chronic neurological disorders. Recent studies identified a pivotal role for the BH3-only protein B-cell lymphoma-2 interacting domain death antagonist (Bid) for such mitochondrial damage and delayed neuronal death after oxygen-glucose deprivation, glutamate-induced excitotoxicity, or oxidative stress in vitro and after cerebral ischemia in vivo. Therefore, we developed new N-phenyl-substituted thiazolidine-2,4-dione derivatives as potent inhibitors of Bid-dependent neurotoxicity. The new compounds 6, 7, and 16 were identified as highly protective by extensive screening in a model of glutamate toxicity in immortalized mouse hippocampal neurons (HT-22 cells). These compounds significantly prevent truncated Bid-induced toxicity in the neuronal cell line, providing strong evidence that inhibition of Bid was the underlying mechanism of the observed protective effects. Furthermore, Bid-dependent hallmarks of mitochondrial dysfunction, such as loss of mitochondrial membrane potential, ATP depletion, as well as impairments in mitochondrial respiration, are significantly prevented by compounds 6, 7, and 16. Therefore, the present study identifies a class of N-phenyl thiazolidinediones as novel Bid-inhibiting neuroprotective agents that provide promising therapeutic perspectives for neurodegenerative diseases, in which Bid-mediated mitochondrial damage and associated intrinsic death pathways contribute to the underlying progressive loss of neurons.

Congeneric but still distinct: how closely related trypsin ligands exhibit different thermodynamic and structural properties.

A congeneric series of benzamidine-type ligands with a central proline moiety and a terminal cycloalkyl group--linked by a secondary amine, ether, or methylene bridge--was synthesized as trypsin inhibitors. This series of inhibitors was investigated by isothermal titration calorimetry, crystal structure analysis in two crystal forms, and molecular dynamics simulations. Even though all of these congeneric ligands exhibited essentially the same affinity for trypsin, their binding profiles at the structural, dynamic, and thermodynamic levels are very distinct. The ligands display a pronounced enthalpy/entropy compensation that results in a nearly unchanged free energy of binding, even though individual enthalpy and entropy terms change significantly across the series. Crystal structures revealed that the secondary amine-linked analogs scatter over two distinct conformational families of binding modes that occupy either the inside or of the outside the protein's S3/S4 specificity pocket. In contrast, the ether-linked and methylene-linked ligands preferentially occupy the hydrophobic specificity pocket. This also explains why the latter ligands could only be crystallized in the conformationally restricting closed crystal form whereas the derivative with the highest residual mobility in the series escaped our attempts to crystallize it in the closed form; instead, a well-resolved structure could only be achieved in the open form with the ligand in disordered orientation. These distinct binding modes are supported by molecular dynamics simulations and correlate with the shifting enthalpic/entropic signatures of ligand binding. The examples demonstrate that, at the molecular level, binding modes and thermodynamic binding signatures can be very different even for closely related ligands. However, deviating binding profiles provide the opportunity to optimally address a given target.

Proteases of Plasmodium falciparum as potential drug targets and inhibitors thereof.

Malaria, caused by protozoa of the genus Plasmodium, remains one of the most dreadful infectious diseases worldwide killing more than 1 million people per year. The emergence of multidrug-resistant parasites highly demands a steadfast and continuous search not only for new targets but also for new anti-infectives addressing the known ones. As proteases in general have been proven to be excellent drug targets and the development of inhibitors has frequently resulted in approved drugs, this review will only focus on the proteases of Plasmodium falciparum as drug targets. The completion of the sequencing of the Plasmodium falciparum genome in 2002 lead to the discovery of nearly 100 putative proteases encoded therein. Within this review, only those proteases and inhibitors thereof will be discussed in more detail, in which their biological function has been determined undoubtedly or in those cases, in which the development of specific inhibitors has significantly contributed to the understanding of the underlying biological role of the respective protease thus validating the role as promising drug target.