Discovery Chemists Research Articles

One pot facile synthesis of flavanoidal oxadiazinanones: In vitro antibacterial activity, docking and MD simulation using DNA gyrase

Flavanones are commonly spread in nature because they are essential intermediates in the biosynthetic flavonoid pathway1 and are of therapeutic significance because of their broad variety of biological activities such as hypertensive, antifungal, antibacterial, and antitumor activities2. Therefore, the field of flavanones is of numerous attentions to medicinal chemists for drug discovery. Flavanones have a 2,3- dihydro skeleton in the C6-C3-C6 structure of the flavonoid and do not have a double bond between C2 and C3, (Fig. 1) which renders them chiral in the C2 position3 hence two stereoisomeric forms of each flavanone are possible4. The chirality means that the B-ring is distorted compared to the A-C rings and is not planar. Such a disparity in molecular orientation is of considerable importance as it may influence how flavonoids engage with biological receptors and their bioactive properties5,6.

IBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.

IBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System.

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.

Scaffold hopping by net photochemical carbon deletion of azaarenes.

Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can rarely be conducted in a manner matching their thought process. This is because many of the necessary chemical transformations required to modify compound cores in a straightforward fashion are not applicable in complex contexts. We report a method that addresses one facet of this problem by allowing chemists to hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show that selective photolysis of quinoline N-oxides with 390-nanometer light followed by acid-promoted rearrangement affords N-acylindoles while showing broad compatibility with medicinally relevant functionality. Applications to late-stage skeletal modification of compounds of pharmaceutical interest and more complex transformations involving serial single-atom changes are demonstrated.

Novel Niacin Receptor Agonists: A Promising Strategy for the Treatment of Dyslipidemia

Background: Hyperlipidemia is characterized by high level of cholesterol and triglycerides in blood. Various classes of drugs like statins, fibrates, niacin etc. are used for treatment of hyperlipidaemia. Objective: Niacin, which is one of the beneficial anti-hyperlipidemic agents, helps to lower LDL cholesterol by 20 to 40% and causes increase of HDL cholesterol by 20 to 35%. However cutaneous flushing, loss of glucose tolerance, liver toxicity are the reported side effects of niacin therapy responsible for decreased patient compliance. Very recently, the G protein coupled receptor (GPCR); GPR109A located on the adipocytes has been identified as the receptor for activation of niacin. Method: In-vitro studies have demonstrated that GPR109A receptor having high affinity for niacin. The present review attempts to provide a systematic presentation of the various chemical classes of compounds that have been reported as novel niacin receptor agonists including pyrazole-3-carboxylic acids, urea derivatives, anthranilic acids, biaryl anthranilides, tetrahydro anthranilic acid, xanthines, barbituric acid, bicyclic pyrazole carboxylic acids, pyrido pyrimidinones, pyrazolyl propionyl cyclohexenamides, pyrazole acids etc. Results: As the design of GPR109A receptor agonists offers a promising solution for treatment of dyslipidemia, this review will be beneficial for medicinal and drug discovery chemists to expediate the process of discovery of new class of antihyperlipidemic agent with favorable lipid lowering profile with increase in HDL levels. Conclusion: This review explains about novel GPR109A receptor agonist for the treatment of dyslipidemia.

Cartridge-based Automated Synthesis – A New Tool for the Synthetic Chemist

Despite recent advances in reaction methodologies, organic synthesis remains complex and challenging. Many of the fundamental processes in use have not changed in over 100 years, with a large proportion of the work being carried out manually, using lengthy procedures and difficult or hazardous reaction conditions. As such, organic synthesis still presents a bottle-neck in discovery research. Endeavours to automate synthesis in discovery, through robotic platforms, have so far not been widely successful because the highly complex nature of such machines, and the level of skill required for their operation, presents a barrier too great for most discov- ery chemists. Synple Chem has developed a safe, easy to use, efficiency-enhancing automated technology for the acceleration of discovery research. The automated flow-batch hybrid system utilises a range of innovative pre-packed reagent cartridges for different reaction classes, along with pre-programmed, highly optimised but editable reaction protocols. The combination of these three key elements, provides users with a convenient, easy to use, time-saving technology that makes the synthesis of molecules far simpler, faster and more efficient. The described technology offers all discovery chemists access to real synthesis automation without any of the barriers that have previously restricted its utility.

DeepScreening: a deep learning-based screening web server for accelerating drug discovery.

Deep learning contributes significantly to researches in biological sciences and drug discovery. Previous studies suggested that deep learning techniques have shown superior performance to other machine learning algorithms in virtual screening, which is a critical step to accelerate the drug discovery. However, the application of deep learning techniques in drug discovery and chemical biology are hindered due to the data availability, data further processing and lacking of the user-friendly deep learning tools and interface. Therefore, we developed a user-friendly web server with integration of the state of art deep learning algorithm, which utilizes either the public or user-provided dataset to help biologists or chemists perform virtual screening either the chemical probes or drugs for a specific target of interest. With DeepScreening, user could conveniently construct a deep learning model and generate the target-focused de novo libraries. The constructed classification and regression models could be subsequently used for virtual screening against the generated de novo libraries, or diverse chemical libraries in stock. From deep models training to virtual screening, and target focused de novo library generation, all those tasks could be finished with DeepScreening. We believe this deep learning-based web server will benefit to both biologists and chemists for probes or drugs discovery.

Nano-SnCl4.SiO2, an efficient catalyst for synthesis of benzimidazole drivatives as antifungal and cytotoxic agents.

The concept of green chemistry has made significant impact on many frontages including the use of green solvents or sustainable catalyst materials. Benzimidazole ring is an important nitrogen-containing heterocyclic, which exhibits a broad spectrum of bioactivities and are widely utilized by the medicinal chemists for drug discovery. A simple and efficient method was developed for the synthesis of some benzimidazole derivatives via reaction of o-phenylenediamine and substituted aldehydes in the presence of nano-SnCl4/SiO2 as a mild catalyst. Ten 2-substituted benzimidazole compounds (J1-J10) were synthesized. All compounds were evaluated against different species of yeasts and filament fungi using broth micro dilution method as recommended by clinical and laboratory standard institute. Among these compounds, the active ones were chosen for their cytotoxic activities evaluation against MCF-7 and A549 cell lines using MTT method. Compound J2 showed the best antifungal activity against all tested species. Compounds J5-J7 had also desirable antifungal activities. Our cytotoxic results were also similar to the antifungal activities except for J7 which had no cytotoxic activity.

No Denying It: Medicinal Chemistry Training Is in Big Trouble.

There has been little consensus between the pharmaceutical industry and academic communities concerning the best approach to train medicinal chemists for drug discovery. For decades the pharmaceutical industry has shown preference for synthetic organic graduates over candidates with degrees from medicinal chemistry programs on the assumption that medicinal chemistry expertise will be acquired on the job. However, ongoing changes to pharmaceutical drug discovery organizations and practices threaten to undermine this training model. There is a compelling argument to be made for establishment of a strong industry-academic partnership to train new candidates with sophisticated knowledge of contemporary drug design concepts and techniques to ensure that the future needs of both industry and academic drug discovery research can be served.

Scope and relevance of a pulmonary biopharmaceutical classification system AAPS/FDA/USP Workshop March 16-17th, 2015 in Baltimore, MD

The Biopharmaceutics Classification System (BCS), developed in the 1990s for oral immediate release drugs, is utilized by RD specifically a dose number, dissolution number, and absorption number. Interest in applying similar principles to pulmonary drug products is increasing. To date the focus has been on dissolution of drugs in the lung. A workshop co-sponsored by the AAPS, FDA, and USP was held in March 2015 in Baltimore to evaluate if a systematic framework to classify pulmonary drugs could be established, and the scope and relevance of such a classification scheme. The focus of the workshop was to address factors influencing drug delivery and action in the lungs rather than the development of a specific model or system. Presentations included: the history and evolution of the oral BCS (described as the “giBCS” by Gordon Amidon), lung physiology and the fate of inhaled drugs, regional aerosol deposition and dose, macroscopic clearance mechanisms, particle dissolution, drug permeability, absorption and their interplay with pharmacokinetics and pharmacodynamics. Background discussions were followed by three separate breakout sessions each focused on the BCS concepts of dose, dissolution, and absorption numbers as they would apply to pulmonary drug delivery. The workshop concluded that a classification system, if fully developed, would be a useful tool for formulators and discovery chemists. The scope of such a system, at this point in time, would not include aspects relevant to regulatory relief. The goals of the workshop were met by identifying an opportunity to develop a model to classify pulmonary drugs based on physicochemical attributes specific to lung physiology and drug delivery.

Systematic conformational bias in small-molecule crystal structures is rare and explicable

Analysis of the Cambridge Structural Database, together with DFT and crystal structure prediction calculations, show that the observation of higher-energy planar conformers of biphenyl (BP) and cyclobutane (CB) is possible because of improved intermolecular interactions in their crystal structures. Such intermolecular/intramolecular energy compensation almost always occurs when crystallographic and molecular symmetry elements coincide. For BP and CB, almost exclusively, a crystallographic inversion centre coincides with a centre of symmetry in a Ci-symmetric molecule. We conclude that the observation of higher energy conformers (with the compensation of conformational energies up to ≈8–10 kJ.mol.−1 above the global minimum) together with this symmetry coincidence is rare. The work shows that concerns, expressed by some drug discovery chemists and other scientists, that conformations observed in crystal structures are systematically biased due to ‘crystal packing effects’ is overstated: only 16% of BP and CB fragments are exactly planar in small-molecule crystal structures, while the remaining conformations are close to their gas-phase energy minima. Thus, crystal structure conformations are good guides to conformational preferences in other phases and in other applications, e.g. in conformer generation or in the study of protein–ligand binding.

A Perspective on Synthetic and Solid-Form Enablement of Inhalation Candidates

The administration of compounds by a dry-powder inhaler presents significant challenges to the development and discovery chemist, owing to the stringent requirements placed upon the physical characteristics of the active pharmaceutical ingredient and the high complexity of the molecules concerned. The current state of synthetic chemistry technology is such that commercial syntheses of these compounds are demanding but achievable. While synthetic chemistry will remain a major component of the development of inhaled therapies, the main challenge facing practitioners in this area is the early identification of a suitable solid form. Further advances in the prediction of solid-form properties would significantly enable this field and may allow triage of molecules to be carried out at the design stage of projects.

Creation and implementation of a customized patent information training program for chemists in a global company

To address a broad company wide education initiative to train non-patent associates on intellectual property related issues, a customized patent information training program targeting discovery chemists was created and implemented. An electronic survey was designed to identify training needs for specific skills pertaining to patents and the patenting process, searching and retrieving patent information, and interpreting search results. From the results of the survey, a training program consisting of several modules was developed and marketed globally through the corporate intranet and by using targeted emails. The modules were a series of classroom based training classes that covered the topics of most interest: a) understanding patent families and legal status, b) differences between different types of patent searches, and c) strengths and attributes of different patent databases. The success of the program was clearly evident based on the high response rate, the positive feedback received and by it stimulating communication and collaboration between patent analysts and discovery chemists. Key determining factors in ensuring the success of the program were the support of the training effort by management, face-to-face communication and making the attendees feel that they were contributing to the long term success of the training program.

Assessment of Cytochrome P450 Enzyme Inhibition and Inactivation in Drug Discovery and Development

Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the 'victim' drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk.

STUDIES IN DRUG ALBUMIN BINDING USING HSA AND RSA AFFINITY METHODS

A HPLC gradient methodology using immobilized human serum albumin (HSA) and rat serum albumin (RSA) has been used as a tool to investigate the protein binding trends of novel discovery compounds. These methods have been set up to support a high throughput approach and have been shown to be complementary to one another. Significant binding differences have been observed with some compounds when both methods have been employed. Discovery chemists are now also able to rank order molecules using these quick “trend analysis” albumin binding screens by submitting a 20 μl sample from the 10 mM stock solution from the inhouse compound archive. Additionally, chemists have the opportunity to predict trends in albumin binding by use of an internal QSAR model based upon a diverse 1200 compound result set, which had been previously analyzed with the HSA methodology.

Busting the Black Box Myth: Designing Out Unwanted ADMET Properties with Machine Learning Approaches

Drug design is usually understood as “an inventive process of finding new medications based on the knowledge of the biological target” – according to the Wikipedia definition – where “drug” is usually defined as a relatively small organic ligand binding to a biomolecule to either inhibit or promote its activity. [1] Methods of thus-defined drug design are well established in the early stages of drug discovery and focus mainly on identifying new chemical entities (NCEs) – molecules with desired biological activity. Along with activity, however, drugs must possess acceptable ADMET (Absorption, Distribution, Metabolism, Elimination, and Toxicity) properties. Although a few recent trends push ADMET optimization into drug design, these properties are still largely neglected until the lead optimization phase occurring later in drug discovery when the available chemical space is already narrowed by affinity and selectivity concerns. Usually one group of drug discovery researchers hands out lead molecules to a separate group of drug development scientists: “Our job is done, here are the active molecules. Now you worry about their other properties.” This separation could, and often does, lead to frustrating failures where all the lead compounds may, for example, turn out to be insoluble in water, impermeable via the intended route of administration, unacceptably metabolized by enzymes common to co-medications, or produce unacceptable adverse effects. All the effort and cost of discovering them would then be wasted. Authors of this article strongly believe in “ADMET design” – a paradigm where ADMET properties are included in the earliest stages of drug discovery and treated on equal footing with biological efficacy. This multidimensional search and optimization should be a normal function of the team of discovery chemists and other pharmaceutical scientists. The difficulty is that humans are not well-adapted to thinking in more than a few dimensions at once. In silico approaches are the solution as they facilitate integration of multiple variables and the most efficient use of experimental data. In the following sections we focus on machine learning approaches, such as Artificial Neural Networks (ANN) [2] or Support Vector Machines (SVM) [3], to QSAR/QSPR modeling [4] of ADMET properties. In QSAR/QSPR, chemical structures are encoded by calculated values of molecular descriptors serving as inputs to mathematical predictive models. ANN models, in particular, have been determined to be superior predictors over other methods. [5] Training several ANN or SVM and taking an arithmetic average of their outputs as the final answer usually enhances accuracy of prediction and is known as ANN Ensemble (ANNE) or SVM Ensemble (SVME) approaches. [6] Some researchers regard these techniques as “black boxes” meaning that although ANNE or SVME models can produce numerical outputs, their internal complexity precludes any descriptive interpretation of these results. Contrary to these stereotypical beliefs, predictive mathematical models of this type are quite interpretable and thus amenable to a direct use in drug design. We demonstrate this claim on specific examples.

Chloracne in seven organic chemists exposed to novel polycyclic halogenated chemical compounds (triazoloquinoxalines)

Chloracne is an acneiform eruption caused though poisoning by aromatic compounds (usually halogenated) showing a specific molecular configuration. We describe an outbreak of chloracne among seven discovery chemists who synthesized novel polycyclic halogenated chemical compounds which were classified as triazoloquinoxalines, not known to be chloracnegenic. The diagnosis of chloracne, made clinically, elicited a thorough risk assessment and monitoring programme by the occupational health department. The chemists were investigated by serum excretion rates, skin sampling for Propionibacterium acnes, skin biopsy and laboratory blood investigations. Sebum excretion was normal in five cases, raised in one case and severely reduced in another. Skin levels of P. acnes were normal in all patients except for the one subject who had low sebum excretion, in whom they were undetectable. One subject had a slightly raised serum level of alanine aminotransferase. There were no other signs of systemic toxicity. Two subjects were treated with an oral antibiotic, two received topical therapy only and three required no treatment at all. The patients have had thorough health surveillance at 6-monthly and yearly intervals. In each case the chloracne mostly resolved within 18-24 months although on examination about 3 years later, five of the seven still showed minor changes of chloracne. This outbreak emphasizes the need for vigilance in discovery science. The triazoloquinoxalines were not previously recognized as being chloracnegens although their chemical characteristics were subsequently identified as being in keeping with other chemicals that can cause chloracne. Chloracne can be a difficult diagnosis to make when it occurs in a novel setting: occupational physicians and dermatologists need to be vigilant when dealing with unusual eruptions in discovery chemists.

Development of the commercial process for Zoloft®/sertraline

Sertraline represented Pfizer's first product with stereocenters not derived from natural sources, as was the case with azithromycin and beta-lactam products. Discovery chemists employed chromatography and classical resolution to secure the active agent's two stereocenters. Investigations to identify a commercial route comprised a number of synthetic approaches, including enantioselective ketone reduction, SN2 displacement of an activated alcohol to transfer chirality, and continuous chromatography. The challenges of adopting new technology in the pharmaceutical industry are discussed in the context of sertraline's development. The successful outcome employed continuous chromatography, and the potential for this technology to shift the development paradigm for any development candidate or commercial product is described.

Phloem mobility of crop protection products

Phloem mobility of a crop protectant is an attribute that contributes positively to its efficacy. Herbicides, insecticides and fungicides, generally organic molecules of small molecular weight, are applied foliarly and often must move to remote plant parts (such as meristems, emerging leaves, roots and fruits) via the phloem to achieve economically useful activity. In addition, insecticides must move within the phloem to be effective against piercing and sucking insects. Conversely, phloem mobility of crop protectants and their metabolites can also contribute to detectable residues in raw agricultural commodities. This is especially true of compounds that are biologically stable and applied during fruit development or seed set. Thus, the knowledge of phloem mobility allows an understanding of potential benefits (efficacy) and potential risks (dietary exposure) of a crop protection chemical. The customers for this knowledge range from the discovery chemist and biologist (who participate in the design of the chemical), through to the regulatory official (who grants permission to sell) and the farmer, the ultimate beneficiary of the technology. One can estimate or predict phloem mobility (based on physical/chemical properties and molecular structure) using a number of models, or measure it directly (in whole plants or explants) with a variety of techniques. In the future, crop protection and crop production technology will increasingly rely on effective transport of macro-molecules, such as protein toxins for insect control and mRNA for signal initiation and coordination of growth and development processes. Phloem mobility will be equally important for these macromolecules and for the small molecules that currently control pests and influence plant growth and development. Understanding the processes that control macromolecular transport in the phloem will lay the foundation for effective use of this technology in the decades to come.