A comprehensive review of synthetic strategies and SAR studies for the discovery of PfDHODH inhibitors as antimalarial agents. Part 1: triazolopyrimidine, isoxazolopyrimidine and pyrrole-based (DSM) compounds.

One of the deadliest infectious diseases, malaria, still has a significant impact on global morbidity and mortality. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the fourth step in de novo pyrimidine nucleotide biosynthesis and has been clinically validated as an innovative and promising target for the development of novel targeted antimalarial drugs. PfDHODH inhibitors have the potential to significantly slow down parasite growth at the blood and liver stages. Several PfDHODH inhibitors based on various scaffolds have been explored over the past two decades. Among them, triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based derivatives known as DSM compounds showed tremendous potential as novel antimalarial agents, and one of the triazolopyrimidine-based compounds (DSM265) was able to reach phase IIa clinical trials. DSM compounds were synthesized as PfDHODH inhibitors with various substitutions based on structure-guided medicinal chemistry approaches and further optimised as well. For the first time, this review provides an overview of all the synthetic approaches used for the synthesis, alternative synthetic routes, and novel strategies involving various catalysts and chemical reagents that have been used to synthesize DSM compounds. We have also summarized SAR study of all these PfDHODH inhibitors. In an attempt to assist readers, scientists, and researchers involved in the development of new PfDHODH inhibitors as antimalarials, this review provides accessibility of all synthetic techniques and SAR studies of the most promising triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based PfDHODH inhibitors.

Discovery of novel tetrahydrobenzo[b]thiophene-3-carbonitriles as histone deacetylase inhibitors.

The discovery and development of isoform-selective histone deacetylase (HDAC) inhibitor is a challenging task because of the sequence homology among HDAC enzymes. In the present work, novel tetrahydro benzo[b]thiophene-3-carbonitrile based benzamides were designed, synthesized, and evaluated as HDAC inhibitors. Pharmacophore modeling was our main design strategy, and two novel series of tetrahydro benzo[b]thiophene-3-carbonitrile derivatives with piperidine linker (series 1) and piperazine linker (series 2) were identified as HDAC inhibitors. Among all the synthesised compounds, 9h with 4-(aminomethyl) piperidine linker and 14n with piperazine linker demonstrated good activity against human HDAC1 and HDAC6, respectively. Both the compounds also exhibited good antiproliferative activity against several human cancer cell lines. Both these compounds (9h and 14n) also induced cell cycle arrest and apoptosis in U937 and MDA-MB-231 cancer cells. Overall, for the first time, this research discovered potent isoform-selective HDAC inhibitors using cyclic linker instead of the aliphatic chain and aromatic ring system, which were reported in known HDAC inhibitors.

Synthesis of 2-,4,-6-, and/or 7-substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents: 3D QSAR-assisted design.

Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC50 value of 1.56 µM and 1.22 µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.

Liquid phase combinatorial synthesis of 1,2,5-trisubstituted benzimidazole derivatives as human DHODH inhibitors.

The synthesis of 1,2,5-trisubstituted benzimidazole derivatives was carried out using liquid phase combinatorial approach using soluble polymer assisted support (PEG5000). Synthesised compounds were characterised by FTIR, ESI-MS, 1H NMR and 13C NMR. The purity of compounds was confirmed with HPLC analysis. Compounds were also docked into the binding site of human dihydroorotate dehydrogenase (hDHODH). The synthesised compounds were screened for hDHODH enzyme inhibition assay using brequinar as standard compound. The synthesised compounds demonstrated comparative biological activity. Synthesised compounds 8d and 8e demonstrated IC50 value of 81±2nM and 97±2nM, respectively.

Synthesis, anti-inflammatory, analgesic, 5-lipoxygenase (5-LOX) inhibition activities, and molecular docking study of 7-substituted coumarin derivatives.

In the present study, 7-subsituted coumarin derivatives were synthesized using various aromatic and heterocyclic amines, and evaluated in vivo for anti-inflammatory and analgesic activity, and for ulcerogenic risk. The most active compounds were evaluated in vitro for 5-lipoxygenase (5-LOX) inhibition. Docking study was performed to predict the binding affinity, and orientation at the active site of the enzyme. In vivo anti-inflammatory and analgesic activity, and in vitro 5-LOX enzyme inhibition study revealed that compound 33 and 35 are the most potent compounds in all the screening methods. In vitro kinetic study of 35 showed mixed or non-competitive type of inhibition with 5-LOX enzyme. Presence of OCH3 group in 35 and Cl in 33 at C6-position of benzothiazole ring were found very important substitutions for potent activity.

A Patent Review of Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors as Anticancer Agents and their Other Therapeutic Applications (1999-2022).

Highly proliferating cells, such as cancer cells, are in high demand of pyrimidine nucleotides for their proliferation, accomplished by de novo pyrimidine biosynthesis. The human dihydroorotate dehydrogenase (hDHODH) enzyme plays a vital role in the rate-limiting step of de novo pyrimidine biosynthesis. As a recognised therapeutic target, hDHODH plays a significant role in cancer and other illness. In the past two decades, small molecules as inhibitors hDHODH enzyme have drawn much attention as anticancer agents, and their role in rheumatoid arthritis (RA), and multiple sclerosis (MS). In this patent review, we have compiled patented hDHODH inhibitors published between 1999 and 2022 and discussed the development of hDHODH inhibitors as anticancer agents. Therapeutic potential of small molecules as hDHODH inhibitors for the treatment of various diseases, such as cancer, is very well recognised. Human DHODH inhibitors can rapidly cause intracellular uridine monophosphate (UMP) depletion to produce starvation of pyrimidine bases. Normal cells can better endure a brief period of starvation without the side effects of conventional cytotoxic medication and resume synthesis of nucleic acid and other cellular functions after inhibition of de novo pathway using an alternative salvage pathway. Highly proliferative cells such as cancer cells do not endure starvation because they are in high demand of nucleotides for cell differentiation, which is fulfilled by de novo pyrimidine biosynthesis. In addition, hDHODH inhibitors produce their desired activity at lower doses rather than a cytotoxic dose of other anticancer agents. Thus, inhibition of de novo pyrimidine biosynthesis will create new prospects for the development of novel targeted anticancer agents, which ongoing preclinical and clinical experiments define. Our work brings together a comprehensive patent review of the role of hDHODH in cancer, as well as various patents related to the hDHODH inhibitors and their anticancer and other therapeutic potential. This compiled work on patented DHODH inhibitors will guide researchers in pursuing the most promising drug discovery strategies against the hDHODH enzyme as anticancer agents.

Recent advances on patents of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors as antimalarial agents.

INTRODUCTION: Pyrimidine nucleotides are essential for the parasite's growth and replication. Parasites have only a de novo pathway for the biosynthesis of pyrimidine nucleotides. Dihydroorotate dehydrogenase (DHODH) enzyme is involved in the rate-limiting step of the pyrimidine biosynthesis pathway. DHODH is a biochemical target for the discovery of new antimalarial agents. AREA COVERED: This review discussed the development of patented PfDHODH inhibitors published between 2007 and 2023 along with their chemical structures and activities. EXPERT OPINION: PfDHODH enzyme is involved in the rate-limiting fourth step of the pyrimidine biosynthesis pathway. Thus, inhibition of PfDHODH using species-selective inhibitors has drawn much attention for treating malaria because they inhibit parasite growth without affecting normal human functions. Looking at the current scenario of antimalarial drug resistance with most of the available antimalarial drugs, there is a huge need for targeted newer agents. Newer agents with unique mechanisms of action may be devoid of drug toxicity, adverse effects, and the ability of parasites to quickly gain resistance, and PfDHODH inhibitors can be those newer agents. Many PfDHODH inhibitors were patented in the past, and the dependency of Plasmodium on de novo pyrimidine provided a new approach for the development of novel antimalarial agents.

Medicinal chemistry approaches for the discovery of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors as antimalarial agents.

Malaria is a severe human disease and a global health problem because of drug-resistant strains. Drugs reported to prevent the growth of Plasmodium parasites target various phases of the parasites' life cycle. Antimalarial drugs can inhibit key enzymes that are responsible for the cellular growth and development of parasites. Plasmodium falciparum dihydroorotate dehydrogenase is one such enzyme that is necessary for de novo pyrimidine biosynthesis. This review focuses on various medicinal chemistry approaches used for the discovery and identification of selective P. falciparum dihydroorotate dehydrogenase inhibitors as antimalarial agents. This comprehensive review discusses recent advances in the selective therapeutic activity of distinct chemical classes of compounds as P. falciparum dihydroorotate dehydrogenase inhibitors and antimalarial drugs.

Structure-guided discovery of adenosine triphosphate-competitive casein kinase 2 inhibitors.

Casein kinase 2 (CK2) is a ubiquitous, highly pleiotropic serine-threonine kinase. CK2 has been identified as a potential drug target for the treatment of cancer and related disorders. Several adenosine triphosphate-competitive CK2 inhibitors have been identified and have progressed at different levels of clinical trials. This review presents details of CK2 protein, structural insights into adenosine triphosphate binding pocket, current clinical trial candidates and their analogues. Further, it includes the emerging structure-based drug design approaches, chemistry, structure-activity relationship and biological screening of potent and selective CK2 inhibitors. The authors tabulated the details of CK2 co-crystal structures because these co-crystal structures facilitated the structure-guided discovery of CK2 inhibitors. The narrow hinge pocket compared with related kinases provides useful insights into the discovery of CK2 inhibitors.

Hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) Simulation: A Tool for Structure-Based Drug Design and Discovery.

Quantum Mechanics (QM) is the physics-based theory that explains the physical properties of nature at the level of atoms and sub-atoms. Molecular mechanics (MM) construct molecular systems through the use of classical mechanics. So, when combined, hybrid quantum mechanics and molecular mechanics (QM/MM) can act as computer-based methods that can be used to calculate the structure and property data of molecular structures. Hybrid QM/MM combines the strengths of QM with accuracy and MM with speed. QM/MM simulation can also be applied for the study of chemical processes in solutions, as well as in the proteins, and has a great scope in structure-based drug design (SBDD) and discovery. Hybrid QM/MM can also be applied to HTS to derive QSAR models. Due to the availability of many protein crystal structures, it has a great role in computational chemistry, especially in structure- and fragment-based drug design. Fused QM/MM simulations have been developed as a widespread method to explore chemical reactions in condensed phases. In QM/MM simulations, the quantum chemistry theory is used to treat the space in which the chemical reactions occur; however, the rest is defined through the molecular mechanics force field (MMFF). In this review, we have extensively reviewed recent literature pertaining to the use and applications of hybrid QM/MM simulations for ligand and structure-based computational methods for the design and discovery of therapeutic agents.

Structure- and ligand-based drug design methods for the modeling of antimalarial agents: a review of updates from 2012 onwards.

Malaria still persists as one of the deadliest infectious disease having a huge morbidity and mortality affecting the higher population of the world. Structure and ligand-based drug design methods like molecular docking and MD simulations, pharmacophore modeling, QSAR and virtual screening are widely used to perceive the accordant correlation between the antimalarial activity and property of the compounds to design novel dominant and discriminant molecules. These modeling methods will speed-up antimalarial drug discovery, selection of better drug candidates for synthesis and to achieve potent and safer drugs. In this work, we have extensively reviewed the literature pertaining to the use and applications of various ligand and structure-based computational methods for the design of antimalarial agents. Different classes of molecules are discussed along with their target interactions pattern, which is responsible for antimalarial activity. Communicated by Ramaswamy H. Sarma.

Capillary electrophoresis methods for impurity profiling of drugs: A review of the past decade.

Capillary electrophoresis (CE) is widely used for the impurity profiling of drugs that contain stereochemical centers in their structures, analysis of biomolecules, and characterization of biopharmaceuticals. Currently, CE is the method of choice for the analysis of foodstuffs and the determination of adulterants. This article discusses the general theory and instrumentation of CE as well as the classification of various CE techniques. It also presents an overview of research on the applications of different CE techniques in the impurity profiling of drugs in the past decade. The review briefly presents a comparison between CE and liquid chromatography methods and highlights the strengths of CE using drug compounds as examples. This review will help scientists, fellow researchers, and students to understand the applications of CE techniques in the impurity profiling of drugs.

Integrated structure-guided computational design of novel substituted quinolizin-4-ones as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors.

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a known drug target for the development of antimalarial agents. Herein, we presented integrated structure-guided computational strategies for the design of novel quinolizin-4-ones as PfDHODH inhibitors. PROCHECK and ERRAT analysis were performed for the validation of co-crystal structures of PfDHODH enzyme bound to the inhibitors available on PDB. Based on the results, PDB ID: 6i55 was selected for further structure-guided in silico studies. Five featured-based pharmacophore model (AADRR) was generated, and validated using GH scoring (0.74) and ROC analysis (0.94). Validated structure-based model was further used as a 3D search query to screen the ZINC database. Retrieved database compounds ZINC00386658, ZINC08439293, and ZINC09089086 were found in agreement with query features based on their highest fitness scores. HTVS, SP and XP docking studies with these retrieved hits demonstrated important interactions (His185. Arg265) with PfDHODH. Mapping of features of the pharmacophore model on these retrieved hits along with the role played by scaffolds and functional groups in docking study helped in the selection of quinolizin-4-one as a main scaffold and different functional groups for the design of novel compounds as PfDHODH inhibitors. In silico ADMET prediction study suggested that designed quinolizin-4-ones are "drug-like" candidates and can be synthesised without too many difficulties. In docking study of newly designed compounds, 8d exhibited the highest docking score of - 12.78 kcal/mol and formed important polar interactions (His185. Arg265) with the PfDHODH. PfDHODH-8d complex showed stable RMSD between 2.5 Å and 3 Å during 100 ns MD simulation study. The RMSD, RMSF and RoG analysis of the PfDHODH-8d complex indicated the absolute stability of the complex. Overall, combined in silico study identified quinolizin-4-ones as selective PfDHODH inhibitors.

Histone deacetylase 2: A potential therapeutic target for cancer and neurodegenerative disorders.

Histone deacetylases (HDACs) have been implicated in a number of diseases including cancer, cardiovascular disorders, diabetes mellitus, neurodegenerative disorders and inflammation. For the treatment of epigenetically altered diseases such as cancer, HDAC inhibitors have made a significant progress in terms of development of isoform selective inhibitiors. Isoform specific HDAC inhibitors have less adverse events and better safety profile. A HDAC isoform i.e., HDAC2 demonstrated significant role in the development of variety of diseases, mainly involved in the cancer and neurodegenerative disorders. Discovery and development of selective HDAC2 inhibitors have a great potential for the treatment of target diseases. In the present compilation, we have reviewed the role of HDAC2 in progression of cancer and neurodegenerative disorders, and information on the drug development opportunities for selective HDAC2 inhibition.

Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based on 3D QSAR, HQSAR, and Docking Study with In Silico Prediction of Activity and Toxicity.

Deazaflavin-dependent nitroreductase (Ddn) is an emerging target in the field of anti-tuberculosis agents. In the present study, 2-nitroimidazooxazine derivatives as Ddn activators were aligned for CoMFA, CoMSIA and HQSAR analysis. The best CoMFA and CoMSIA model were generated with leave-one-out correlation coefficients (q2) of 0.585 and 0.571, respectively. Both the CoMFA and CoMSIA models were also validated by a test set of 11 compounds with satisfactory [Formula: see text] value of 0.701 and 0.667, respectively. Results of 3D QSAR and HQSAR study were used for the designing of novel and potent nitroimidazooxazine derivatives as Ddn activators. 21 novel compounds were designed, and docked into the Ddn enzyme. In docking study compound ng11 showed interaction with key amino acid residues such as Tyr65 and Tyr133, and also showed better ADMET compatibility. The ADMET prediction, docking study and the predicted activity of novel designed compounds revealed that compound ng11 showed good potential as Ddn activators for the treatment of tuberculosis.

Medicinal Chemistry of Potassium Channel Modulators: An Update of Recent Progress (2011-2017).

BACKGROUND: Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability. OBJECTIVE: Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecules as potassium channel modulators have received great scientific attention. METHODS: In this review, we have compiled the literature, patents and patent applications (2011 to 2017) related to different chemical classes of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical classes of selective small molecule have emerged as potassium channel modulators over the past years. CONCLUSION: This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field.

CoMFA, CoMSIA, Topomer CoMFA, HQSAR, molecular docking and molecular dynamics simulations study of triazine morpholino derivatives as mTOR inhibitors for the treatment of breast cancer.

mTOR has become a promising target for many types of cancer like breast, lung and renal cell carcinoma. CoMFA, CoMSIA, Topomer CoMFA and HQSAR were performed on the series of 39 triazine morpholino derivatives. CoMFA analysis showed q2 value of 0.735, r2cv value of 0.722 and r2pred value of 0.769. CoMSIA analysis (SEHD) showed q2 value of 0.761, r2cv value of 0.775 and r2pred value of 0.651. Topomer CoMFA analysis showed q2 value of 0.693, r2 (conventional correlation coefficient) value of 0.940 and r2pred value of 0.720. HQSAR analysis showed q2,r2and r2pred values of 0.694, 0.920 and 0.750, respectively. HQSAR analysis with the combination of atomic number (A), bond type (B) and atomic connections showed q2 and r2 values of 0.655 and 0.891, respectively. Contour maps from all studies provided significant insights. Molecular docking studies with molecular dynamics simulations were carried out on the highly potent compound 36. Furthermore, four acridine derivatives were designed and docking results of these designed compounds showed the same interactions as that of the standard PI-103 which proved the efficiency of 3D-QSAR and MD/MS study. In future, this study might be useful prior to synthesis for the designing of novel mTOR inhibitors.

3D QSAR-based design and liquid phase combinatorial synthesis of 1,2-disubstituted benzimidazole-5-carboxylic acid and 3-substituted-5H-benzimidazo[1,2-d][1,4]benzodiazepin-6(7H)-one derivatives as anti-mycobacterial agents.

Tuberculosis (TB) is one of the world's deadliest infectious diseases, caused by Mycobacterium tuberculosis (Mtb). In the present study, a 3D QSAR study was performed for the design of novel substituted benzimidazole derivatives as anti-mycobacterial agents. The anti-tubercular activity of the designed compounds was predicted using the generated 3D QSAR models. The designed compounds which showed better activity were synthesized as 1,2-disubstituted benzimidazole-5-carboxylic acid derivatives (series 1) and 3-substituted-5H-benzimidazo[1,2-d][1,4]benzodiazepin-6(7H)-one derivatives (series 2) using the liquid phase combinatorial approach using a soluble polymer assisted support (PEG5000). The compounds were characterized by 1H-NMR, 13C-NMR, FTIR and mass spectrometry. HPLC analysis was carried out to evaluate the purity of the compounds. We observed that the synthesised compounds inhibited the growth of intracellular M. tuberculosis H37Rv in a bactericidal manner. The most active compound 16 displayed an MIC value of 0.0975 µM against the Mtb H37Rv strain in liquid cultures. The lead compound was also able to inhibit the growth of intracellular mycobacteria in THP-1 macrophages.

Combined in silico approaches for the identification of novel inhibitors of human islet amyloid polypeptide (hIAPP) fibrillation.

Human islet amyloid polypeptide (hIAPP) is a natively unfolded polypeptide hormone of glucose metabolism, which is co-secreted with insulin by the ß-cells of the pancreas. In patients with type 2 diabetes, IAPP forms amyloid fibrils because of diabetes-associated ß-cells dysfunction and increasing fibrillation, in turn, lead to failure of secretory function of ß-cells. This provides a target for the discovery of small organic molecules against protein aggregation diseases. However, the binding mechanism of these molecules with monomers, oligomers and fibrils to inhibit fibrillation is still an open question. In this work, ligand and structure-based in silico approaches were used to identify novel fibrillation inhibitors and/or fibril binding compounds. The best pharmacophore model was used as a 3D search query for virtual screening of a compound database to identify novel molecules having the potential to be therapeutic agents against protein aggregation diseases. Docking and molecular dynamics simulation studies were used to explore the interaction pattern and mechanism of the identified novel small molecules with predicted hIAPP structure, its aggregation prone conformation and fibril forming segments. We show that catechins with galloyl group and molecules having two to three planar apolar rings bind to hIAPP structures and fibril forming segments with greater affinity. The differences in binding affinities of different compounds against several fibril forming segments of the peptide suggest that a mixture of active compounds may be required for treatment of aggregation diseases.

Molecular modeling study for the design of novel acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulations.

Acetyl-CoA carboxylase (ACC) enzyme plays an important role in the regulation of biosynthesis and oxidation of fatty acids. ACC is a recognized drug target for the treatment of obesity and diabetes. Combination of ligand and structure-based in silico methods along with activity and toxicity prediction provides best lead compounds in the drug discovery process. In this study, a data-set of 100 ACC inhibitors were used for the development of comparative molecular field analysis (CoMFA) and comparative molecular similarity index matrix analysis (CoMSIA) models. The generated contour maps were used for the design of novel ACC inhibitors. CoMFA and CoMSIA models were used for the predication of activity of designed compounds. In silico toxicity risk prediction study was carried out for the designed compounds. Molecular docking and dynamic simulations studies were performed to know the binding mode of designed compounds with the ACC enzyme. The designed compounds showed interactions with key amino acid residues important for catalysis, and good correlation was observed between binding free energy and inhibition of ACC.