Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011–2020).     

The Chemistry of Acetylpyrazoles and Its Utility in Heterocyclic Synthesis

A literature survey revealed that a great deal of interest has been focused on the synthesis of functionalized pyrazole derivatives due to their synthetic and biological potentialities. The pharmacological activities that have been found for some pyrazole derivatives include selective enzyme inhibition, antiviral, estrogen receptor agonist, anti‐inflammatory, anticancer, antiobesity, and antitumor properties. Other activities such as potential inhibitors of HIV‐1, pesticides, fungicides, and antihypertensive agents were reported for other pyrazole derivatives. This review summarizes the synthetic methods and reactions of 3‐acetyl‐pyrazoles, 4‐acetyl‐pyrazoles, and 3,4‐di‐acetyl‐pyrazoles. Most reaction types have been successfully applied and used in the production of biologically active compounds. The aim of this review is to focus mainly on the utility of acetylpyrazole derivatives in the synthesis of heterocyclic compounds during the period 1990–2018.     

Towards the understanding of the activity of G9a inhibitors: an activity landscape and molecular modeling approach

In this work, we analyze the structure–activity relationships (SAR) of epigenetic inhibitors (lysine mimetics) against lysine methyltransferase (G9a or EHMT2) using a combined activity landscape, molecular docking and molecular dynamics approach. The study was based on a set of 251 G9a inhibitors with reported experimental activity. The activity landscape analysis rapidly led to the identification of activity cliffs, scaffolds hops and other active an inactive molecules with distinct SAR. Structure-based analysis of activity cliffs, scaffold hops and other selected active and inactive G9a inhibitors by means of docking followed by molecular dynamics simulations led to the identification of interactions with key residues involved in activity against G9a, for instance with ASP 1083, LEU 1086, ASP 1088, TYR 1154 and PHE 1158. The outcome of this work is expected to further advance the development of G9a inhibitors.

     

Versatile Synthetic Route to Cycloheximide and Analogues That Potently Inhibit Translation Elongation

Cycloheximide (CHX) is an inhibitor of eukaryotic translation elongation that has played an essential role in the study of protein synthesis. Despite its ubiquity, few studies have been directed towards accessing synthetic CHX derivatives, even though such efforts may lead to protein synthesis inhibitors with improved or alternate properties. Described here is the total synthesis of CHX and analogues, and the establishment of structure–activity relationships (SAR) responsible for translation inhibition. The SAR studies aided the design of more potent compounds, one of which irreversibly blocks ribosomal elongation, preserves polysome profiles, and may be a broadly useful tool for investigating protein synthesis.     

Outstanding effect of the conformational restriction of isoquinolines: hints for the development of optimized antimicrobial agents

Conformational restriction constitutes a useful strategy of molecular modification for the design of new potential drug candidates. Herein we present the planning, antimicrobial evaluation, and establishment of structure–activity relationship (SAR) data for some isoxazole (3a–k, 8a–c, and 9a–c) and pyrazole (5a–h) derivatives. These derivatives were structurally designed by conformational restriction followed by bioisosteric exchange of previously described antimicrobial isoquinolines (1a–c). Some of these more conformationally restricted derivatives present improved properties as new antibacterial drug candidates.     

One step synthesis of pyrido[1,2-a]benzimidazole derivatives of aryloxypyrazole and their antimicrobial evaluation

A new series of pyrido[1,2-α]benzimidazole derivatives bearing the aryloxypyrazole nucleus have been synthesized by base-catalyzed cyclocondensation reaction through multi-component reaction（MCR） approach.All the synthesized compounds were investigated against a representative panel of pathogenic strains using broth microdilution minimum inhibitory concentration（MIC） method for their in vitro antimicrobial activity.Reviewing the data,majority of the compounds were found to be active against employed pathogens.SAR study explores that antimicrobial activity is strongly depends on the nature of the substituents at the ether linked aryl ring attached to the pyrazole unit,together with the substituent present on the C₅ of the benzimidazole unit.     

Adapting the DeepSARM approach for dual-target ligand design

The structure–activity relationship (SAR) matrix (SARM) methodology and data structure was originally developed to extract structurally related compound series from data sets of any composition, organize these series in matrices reminiscent of R-group tables, and visualize SAR patterns. The SARM approach combines the identification of structural relationships between series of active compounds with analog design, which is facilitated by systematically exploring combinations of core structures and substituents that have not been synthesized. The SARM methodology was extended through the introduction of DeepSARM, which added deep learning and generative modeling to target-based analog design by taking compound information from related targets into account to further increase structural novelty. Herein, we present the foundations of the SARM methodology and discuss how DeepSARM modeling can be adapted for the design of compounds with dual-target activity. Generating dual-target compounds represents an equally attractive and challenging task for polypharmacology-oriented drug discovery. The DeepSARM-based approach is illustrated using a computational proof-of-concept application focusing on the design of candidate inhibitors for two prominent anti-cancer targets.

     

Insights on cytochrome p450 enzymes and inhibitors obtained through QSAR studies

The cytochrome P450 (CYP) superfamily of heme enzymes play an important role in the metabolism of a large number of endogenous and exogenous compounds, including most of the drugs currently on the market. Inhibitors of CYP enzymes have important roles in the treatment of several disease conditions such as numerous cancers and fungal infections in addition to their critical role in drug-drug interactions. Structure activity relationships (SAR), and three-dimensional quantitative structure activity relationships (3D-QSAR) represent important tools in understanding the interactions of the inhibitors with the active sites of the CYP enzymes. A comprehensive account of the QSAR studies on the major human CYPs 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and a few other CYPs are detailed in this review which will provide us with an insight into the individual/common characteristics of the active sites of these enzymes and the enzyme-inhibitor interactions.     

From bird’s eye views to molecular communities: two-layered visualization of structure–activity relationships in large compound data sets

The analysis of structure–activity relationships (SARs) becomes rather challenging when large and heterogeneous compound data sets are studied. In such cases, many different compounds and their activities need to be compared, which quickly goes beyond the capacity of subjective assessments. For a comprehensive large-scale exploration of SARs, computational analysis and visualization methods are required. Herein, we introduce a two-layered SAR visualization scheme specifically designed for increasingly large compound data sets. The approach combines a new compound pair-based variant of generative topographic mapping (GTM), a machine learning approach for nonlinear mapping, with chemical space networks (CSNs). The GTM component provides a global view of the activity landscapes of large compound data sets, in which informative local SAR environments are identified, augmented by a numerical SAR scoring scheme. Prioritized local SAR regions are then projected into CSNs that resolve these regions at the level of individual compounds and their relationships. Analysis of CSNs makes it possible to distinguish between regions having different SAR characteristics and select compound subsets that are rich in SAR information.     

A theoretical study on electronic structure and structure–activity properties of novel drug precursor 6‐acylbenzothiazolon derivatives

In this work, electronic properties and structure–activity relationship (SAR) parameters of 20 novel drug precursor 6‐acylbenzothiazolon derivatives with analgesic activity have been investigated theoretically by performing Austin Model‐1 (AM1) and DFT‐B3LYP/6‐31G (d) calculations with the aim to correlate the properties of each substance—particularly electronic properties and SAR parameters—with the biological interactions that are linked to their pharmacological effects. Their molecular properties were related to the biological activity of these drug precursor molecules. The relationship between octanol–water partition coefficient (log P) and each of the SAR parameters [E_LUMO–HOMO, molecular volume (V_m), ionization potential (IP), electron affinity, electronegativity (χ), chemical hardness (η), chemical softness (S), electrophilic index (ω), and molar refractivity] present linear correlation except for IP and χ. This result suggests that there are future prospects for designing or developing new drugs based on the correlation between the theoretically calculated parameters. According to AM1 calculation, the values of heat of formation of 6‐acylbenzothiazolon derivatives are negative (exothermic), which shows that these molecules are thermodynamically stable. E_LUMO–HOMO energy levels of the studied molecules are 4–5 eV, which also indicate that they are kinetically unstable. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Systematic Profiling and Evaluation of Structure-based Kinase–Inhibitor Interactome in Cervical Cancer by Integrating In Silico Analyses and In Vitro Assays at Molecular and Cellular Levels

Various protein kinases are implicated in the pathogenesis of human cervical cancer and many kinase inhibitors have been used to regulate the activity of protein kinases involved in the disease signaling networks. In the present study, a systematic kinase–inhibitor interactome is created for various small-molecule inhibitors across diverse cervical cancer-related kinases by using ontology enrichment, molecular docking, dynamics simulation and energetics analysis. The interactome profile is examined in detail with heatmap analysis and heuristic clustering to derive promising inhibitors that are highly potential to target the kinome of human cervical cancer in a multi-target manner. A number of hit and unhit inhibitors are selected and their cell-suppressing effects are tested against human cervical carcinoma HeLa, from which several inhibitor compounds with high cytotoxicity are successfully identified. A further kinase assay confirms that these inhibitors can generally target their noncognate kinases HER3 and BRaf in cervical cancer with a high or moderate activity; the activity profile are comparable with or even better than that of cognate kinases inhibitors, with IC₅₀ values ranging between 4.8 and 340.6 nM for HER3 and between 37.2 and 638.2 nM for BRaf. This work would help to identify those unexpected kinase–inhibitor interactions in human cervical cancer and to develop new and efficient therapeutic strategy combating the disease.     

Investigation of the differences in activity between hydroxycycloalkyl N1 substituted pyrazole derivatives as inhibitors of B-Raf kinase by using docking, molecular dynamics, QM/MM, and fragment-based de novo design: study of binding mode of diastereomer compounds

N1 substituted pyrazole derivatives show diverse B-Raf kinase inhibitory activities when different hydroxy-substituted cycloalkyl groups are placed at this position. Docking, molecular dynamics (MD) simulations, and hybrid calculation methods (Quantum Mechanics/Molecular Mechanics (QM/MM)) were performed on the complexes, in order to explain these differences. Docking of the inhibitors showed the same orientation that X-ray crystal structure of the analogous (1E)-5-[1-(4-piperidinyl)-3-(4-pyridinyl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime. MD simulations of the most active diastereomer compounds containing cis- and trans-3-hydroxycyclohexyl substituents showed stable interactions with residue Ile463 at the entrance of the B-Raf active site. On the other hand, the less active diastereomer compounds containing cis- and trans-2-hydroxycyclopentyl substituents showed interactions with inner residues Asn580 and Ser465. We found that the differences in activity can be explained by considering the dynamic interactions between the inhibitors and their surrounding residues within the B-Raf binding site. We also explained the activity trend by using a testing scoring function derived from more reliable QM/MM calculations. In addition, we search for new inhibitors from a virtual screening carried out by fragment-based de novo design. We generated a set of approximately 200 virtual compounds, which interact with Ile463 and fulfill druglikeness properties according to Lipinski, Veber, and Ghose rules.     

Strategies and Approaches for Discovery of Small Molecule Disruptors of Biofilm Physiology

Biofilms, the predominant growth mode of microorganisms, pose a significant risk to human health. The protective biofilm matrix, typically composed of exopolysaccharides, proteins, nucleic acids, and lipids, combined with biofilm-grown bacteria’s heterogenous physiology, leads to enhanced fitness and tolerance to traditional methods for treatment. There is a need to identify biofilm inhibitors using diverse approaches and targeting different stages of biofilm formation. This review discusses discovery strategies that successfully identified a wide range of inhibitors and the processes used to characterize their inhibition mechanism and further improvement. Additionally, we examine the structure–activity relationship (SAR) for some of these inhibitors to optimize inhibitor activity.     

(1,3‐Diphenyl‐1H‐Pyrazol‐4‐yl)‐Methylamine Analogues as Inhibitors of Dipeptidyl Peptidases

A number of pyrazole compounds reported in literatures elicit anti‐hyperglycemic effects. By modifying the side chain of the heterocyclic skeleton, a new chemical class of DPP‐IV inhibitors structurally derived from the (pyrazol‐4‐yl)‐methylamine scaffold have been discovered and evaluated the biological activities of these inhibitors against DPP‐IV, DPP8, DPP‐II and FAP. The SAR studies showed the (1,3‐diphenyl‐1H‐pyrazol‐4‐yl)‐methylamines with 2,4‐dichloro substituents at the 3‐phenyl ring selectively preferred as DPP‐IV inhibitors, whereas with difluoro substituents at the 3‐phenyl ring selectively preferred as DPP8 inhibitors. The binding mode of representative compound 15h at the active site of DPP‐IV was predicted by computer model. In additional, 15h exhibited the ability to significantly decrease the glucose excursion in mice.     

Inhibition of Ras Signaling by Blocking Ras–Effector Interactions with Cyclic Peptides

Ras genes are frequently activated in human cancers, but the mutant Ras proteins remain largely “undruggable” through the conventional small‐molecule approach owing to the absence of any obvious binding pockets on their surfaces. By screening a combinatorial peptide library, followed by structure–activity relationship (SAR) analysis, we discovered a family of cyclic peptides possessing both Ras‐binding and cell‐penetrating properties. These cell‐permeable cyclic peptides inhibit Ras signaling by binding to Ras‐GTP and blocking its interaction with downstream proteins and they induce apoptosis of cancer cells. Our results demonstrate the feasibility of developing cyclic peptides for the inhibition of intracellular protein–protein interactions and of direct Ras inhibitors as a novel class of anticancer agents.     

A purified 124-kDa oat phytochrome does not possess a protein kinase activity

The presence of protein kinase activity in the purified phytochrome preparations [Wong, et al. (1986) J. Biol. Chem. 261, 12089-12097] has been re-examined. The phytochrome preparations having SAR (specific absorbance ratio, A668/A280 for the Pr form as a measure of phytochrome purity) values of greater than 0.95 were homogeneous on SDS gel, but could be further purified to a SAR value of 1.07 by repeated gel filtrations on a Bio-Gel A-0.5 m column. The protein kinase activity remained in the phytochrome preparations having SAR values less than 1.05, but it became undetectable in the phytochrome preparation with a SAR value of 1.07. Two dimensional gel electrophoresis of the phytochrome preparation (SAR, 0.89) showed that a phytochrome band with pl 5.8 had no kinase activity. Phosphorylating activity of the protein kinase was enhanced to some extent by polycations, polylysine and histone. Phytochrome served as a good substrate for this enzyme. The present data indicate that phytochrome has no intrinsic protein kinase activity, but a protein kinase is present in highly purified phytochrome preparations.