Physicochemical and Biological Evaluation of gem-Difluorinated Saturated Oxygen Heterocycles as Bioisosteres for Drug Discovery.

A comprehensive study on the physicochemical properties of gem-fluorinated O-heterocyclic substituents is reported. Systematic additive effects of introducing O- and gem-CF group introduction on acidic properties (pK) of the corresponding carboxylic acids/protonated primary amines were demonstrated. The impact of the O/CF moieties on lipophilicity (LogP) was found to be complex; significant mutual influence of the corresponding polar moieties governed the compound's overall properties in this case.

"Angular" Spirocyclic Azetidines: Synthesis, Characterization, and Evaluation in Drug Discovery.

The previously neglected "angular" spirocyclic azetidines have been synthesized, characterized, and validated in drug discovery. We have shown that these compounds could act as bioisosteres for common saturated six-membered heterocycles. Their incorporation into the structure of the anticancer drug Sonidegib (instead of morpholine), and Danofloxacine (instead of piperazine) provided novel patent-free analogs with similar physicochemical properties and high activity.

CF-Cyclobutanes: Synthesis, Properties, and Evaluation as a Unique -Butyl Group Analogue.

Isosteric replacement of functional groups is an emerging strategy for optimizing bioactive molecules in drug discovery. -Butyl group is a particularly important moiety, yet its isosteric replacement with 1-trifluoromethyl-cyclobutyl group has been rather neglected. To enable the advance of this molecular fragment in drug discovery programs, we report the synthesis of over 30 small-molecule building blocks featuring the trifluoromethyl-cyclobutyl fragment, achieved by reacting sulfur tetrafluoride with cyclobutylcarboxylic acids on a gram-to-multigram scale.

3,3-Difluorooxetane-A Versatile Functional Group for Bioisosteric Replacements in Drug Discovery.

Functional group (FG) is one of the cornerstone concepts in organic chemistry and related areas. The wide spread of bioisosterism ideas in medicinal chemistry and beyond caused a striking rise in demand for novel FGs with a defined impact on the developed compound properties. In this work, the evaluation of the 3,3-difluorooxetane unit (3,3-diFox) as a functional group for bioisosteric replacements is disclosed.

2-Oxabicyclo[2.1.1]hexanes: Synthesis, Properties, and Validation as Bioisosteres of ortho- and meta-Benzenes.

We have developed a general and practical approach towards 2-oxabicyclo[2.1.1]hexanes with two and three exit vectors via an iodocyclization reaction.

Spiro[3.3]heptane as a Saturated Benzene Bioisostere.

The spiro[3.3]heptane core, with the non-coplanar exit vectors, was shown to be a saturated benzene bioisostere. This scaffold was incorporated into the anticancer drug sonidegib (instead of the meta-benzene), the anticancer drug vorinostat (instead of the phenyl ring), and the anesthetic drug benzocaine (instead of the para-benzene).

Anticancer activity features of imidazole-based ionic liquids and lysosomotropic detergents: in silico and in vitro studies.

Long-chain imidazole-based ionic liquids (compounds 2, 4, 9) and lysosomotropic detergents (compounds 7, 3, 8) with potent anticancer activity were synthesized. Their inhibitory activities against neuroblastoma and leukaemia cell lines were predicted by the new in silico QSAR models. The cytotoxic activities of the synthesized imidazole derivatives were investigated on the SK-N-DZ (human neuroblastoma) and K-562 (human chronic myeloid leukaemia) cell lines.

Synthesis of methotrexate-betulonic acid hybrids and evaluation of their effect on artificial and Caco-2 cell membranes.

An efficient protocol for the synthesis of novel methotrexate-betulonic acid hybrids with a (tert-butoxycarbonylamino)-3,6-dioxa-8-octanamine (Boc-DOOA) linkage has been developed. Reaction of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-betulonamide with methotrexate resulted in a mixture of isomeric conjugates which were separated by column chromatography. Their structures and composition have been fully established by H NMR, C spectra, FAB mass spectrometry and elemental analysis.

In Vitro and In Vivo Evaluation of Photocontrolled Biologically Active Compounds - Potential Drug Candidates for Cancer Photopharmacology.

Photocontrolled, biologically active compounds are an emerging class of "smart" drug candidates. They provide additional safety in systemic chemotherapy due to their precise spatiotemporal activation by directing a benign, non-ionizable light to a specific location within the patient's body. This paper presents a set of methods to evaluate the in vitro potency and ex vivo efficiency of the photoactivation of photocontrolled, biologically active compounds as well as the in vivo efficacy at early stages of drug development.

2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring.

The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved physicochemical properties - 2-oxabicyclo[2.2.

AI-Powered Virtual Screening of Large Compound Libraries Leads to the Discovery of Novel Inhibitors of Sirtuin-1.

The discovery of new scaffolds and chemotypes via high-throughput screening is tedious and resource intensive. Yet, there are millions of small molecules commercially available, rendering comprehensive in vitro tests intractable. We show how smart algorithms reduce large screening collections to target-specific sets of just a few hundred small molecules, allowing for a much faster and more cost-effective hit discovery process.

2-Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho-substituted phenyl ring.

The ortho-substituted phenyl ring is a basic structural element in chemistry. It is found in more than three hundred drugs and agrochemicals. During the past decade, scientists have tried to replace the phenyl ring in bioactive compounds with saturated bioisosteres to obtain novel patentable structures.

In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes.

New models for ACE2 receptor binding, based on QSAR and docking algorithms were developed, using XRD structural data and ChEMBL 26 database hits as training sets. The selectivity of the potential ACE2-binding ligands towards Neprilysin (NEP) and ACE was evaluated. The Enamine screening collection (3.

Magnet for the Needle in Haystack: "Crystal Structure First" Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces.

Fragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and "undruggable" targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine's multibillion REAL Space was performed.

Anionic amphiphilic calixarenes for peptide assembly and delivery.

Shape-persistent macrocycles enable superior control on molecular self-assembly, allowing the preparation of well-defined nanostructures with new functions. Here, we report on anionic amphiphilic calixarenes of conic shape and their self-assembly behavior in aqueous media for application in intracellular delivery of peptides. Newly synthesized calixarenes bearing four phosphonate groups and two or four long alkyl chains were found to form micelles of ∼ 10 nm diameter, in contrast to an analogue with short alkyl chains.

Towards in vivo photomediated delivery of anticancer peptides: Insights from pharmacokinetic and -dynamic data.

An in vivo study of a photoswitchable cytotoxic peptide LMB040 has been undertaken on a chemically induced hepatocellular carcinoma model in immunocompetent rats. We analysed the pharmacokinetic profile of the less toxic photoform ("ring-closed" dithienylethene) of the compound in tumors, plasma, and healthy liver. Accordingly, the peptide can reach a tumor concentration sufficiently high to exert a cytotoxic effect upon photoconversion into the more active ("ring-open") photoform.

Effect of gem-Difluorination on the Key Physicochemical Properties Relevant to Medicinal Chemistry: The Case of Functionalized Cycloalkanes.

Physico-chemical properties important to drug discovery (pK , LogP, and aqueous solubility), as well as metabolic stability, were studied for a series of functionalized gem-difluorinated cycloalkanes and compared to those of non-fluorinated and acyclic counterparts to evaluate the impact of the fluorination. It was found that the influence of the CF moiety on the acidity/basicity of the corresponding carboxylic acids and amines was defined by inductive the effect of the fluorine atoms and was nearly the same for acyclic and cyclic aliphatic compounds. Lipophilicity and aqueous solubility followed more complex trends and were affected by the position of the fluorine atoms, ring size, and even the nature of the functional group present; also, significant differences were found for the acyclic and cyclic series.

Oxa-spirocycles: synthesis, properties and applications.

A general approach to a new generation of spirocyclic molecules - oxa-spirocycles - was developed. The key synthetic step was iodocyclization. More than 150 oxa-spirocyclic compounds were prepared.

Phosphine Oxides (-POMe) for Medicinal Chemistry: Synthesis, Properties, and Applications.

A general practical approach to hetero(aromatic) and aliphatic P(O)Me-substituted derivatives is elaborated. The key synthetic step was a [Pd]-mediated C-P coupling of (hetero)aryl bromides/iodides with HP(O)Me. The P(O)Me substituent was shown to dramatically increase solubility and decrease lipophilicity of organic compounds.

A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions.

Screening of benzenesulfonamide in combination with chemically diverse fragments against carbonic anhydrase by differential scanning fluorimetry.

The differential scanning fluorimetry (DSF) screening of 5.692 fragments in combination with benzenesulfonamide (BSA) against bovine carbonic anhydrase (CA) delivered >100 hits that either caused, on their own, a significant thermal shift (Δ, °C) in the protein melting temperature or significantly influenced the thermal shift observed for BSA alone. Three hits based on 1,2,3-triazole moiety represent the periphery of the recently reported potent inhibitors of CA II, IX and XII which were efficacious .

Further validation of strecker-type α-aminonitriles as a new class of potent human carbonic anhydrase II inhibitors: hit expansion within the public domain using differential scanning fluorimetry leads to chemotype refinement.

Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles (selected from publicly available Enamine Ltd. Screening Collection) in thermal shift assay against bovine carbonic anhydrase (CA) led to further validation of this new class of inhibitors and identification a new, refined chemotype represented by inhibitors with 10-improved potency. [Formula: see text].

SAR by Space: Enriching Hit Sets from the Chemical Space.

We introduce SAR-by-Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process.

Pros and cons of virtual screening based on public "Big Data": In silico mining for new bromodomain inhibitors.

The Virtual Screening (VS) study described herein aimed at detecting novel Bromodomain BRD4 binders and relied on knowledge from public databases (ChEMBL, REAXYS) to establish a battery of predictive models of BRD activity for in silico selection of putative ligands. Beyond the actual discovery of new BRD ligands, this represented an opportunity to practically estimate the actual usefulness of public domain "Big Data" for robust predictive model building. Obtained models were used to virtually screen a collection of 2 million compounds from the Enamine company collection.

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity.

A practical synthesis of 2,4-methanopyrrolidines was elaborated. The key synthetic step was an intramolecular photochemical [2 + 2]-cycloaddition of an acrylic acid derivative in flow. In spite of a higher molecular weight, 2,4-methanopyrrolidines were shown to have higher solubility in water and lower lipophilicity than pyrrolidines, important characteristics of bioactive molecules in drug design.