In-silico identification and exploration of small molecule coumarin-1,2,3-triazole hybrids as potential EGFR inhibitors for targeting lung cancer.

Globally, lung cancer is a significant public health concern due to its role as the leading cause of cancer-related mortalities. The promising target of EGFR for lung cancer treatment has been identified, providing a potential avenue for more effective therapies. The purpose of the study was to design a library of 1843 coumarin-1,2,3-triazole hybrids and screen them based on a designed pharmacophore to identify potential inhibitors targeting EGFR in lung cancer with minimum or no side effects. Pharmacophore-based screening was carried out and 60 hits were obtained. To gain a better understanding of the binding interactions between the compounds and the targeted receptor, molecular docking was conducted on the 60 screened compounds. In-silico ADME and toxicity studies were also conducted to assess the drug-likeness and safety of the identified compounds. The results indicated that coumarin-1,2,3-triazole hybrids COUM-0849, COUM-0935, COUM-0414, COUM-1335, COUM-0276, and COUM-0484 exhibit dock score of - 10.2, - 10.2, - 10.1, - 10.1, - 10, - 10 while reference molecule - 7.9 kcal/mol for EGFR (PDB ID: 4HJO) respectively. The molecular docking and molecular dynamics simulations revealed that the identified compounds formed stable interactions with the active site of EGFR, indicating their potential as inhibitors. The in-silico ADME and toxicity studies showed that the compounds had favorable drug-likeness properties and low toxicity, further supporting their potential as therapeutic agents. Finally, we performed DFT studies on the best-selected ligands to gain further insights into their electronic properties. The findings of this study provide important insights into the potential of coumarin-1,2,3-triazole hybrids as promising EGFR inhibitors for the management of lung cancer.

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.

Design, synthesis and anti-diabetic activity of triazolotriazine derivatives as dipeptidyl peptidase-4 (DPP-4) inhibitors.

Type 2 diabetes mellitus (T2DM) is one of the major global metabolic disorders characterized by insulin resistance and chronic hyperglycemia. Inhibition of the enzyme, dipeptidyl peptidase-4 (DPP-4) has been proved as successful and safe therapy for the treatment of T2DM since last decade. In order to design novel DPP-4 inhibitors, various in silico studies such as 3D-QSAR, pharmacophore modeling and virtual screening were performed and on the basis of the combined results of them, total 50 triazolo[5,1-c][1,2,4]triazine derivatives were designed and mapped on the best pharmacophore model. From this, best 25 derivatives were docked onto the active site of DPP-4 enzyme and in silico ADMET properties were also predicted. Finally, top 17 derivatives were synthesized and characterized using FT-IR, Mass, 1H NMR and 13C NMR spectroscopy. Purity of compounds was checked using HPLC. These derivatives were then evaluated for in vitro DPP-4 inhibition. The most promising compound 15q showed 28.05µM DPP-4 IC50 with 8-10-fold selectivity over DPP-8 and DPP-9 so selected for further in vivo anti-diabetic evaluation. During OGTT in normal C57BL/6J mice, compound 15q reduced blood glucose excursion in a dose-dependent manner. Chronic treatment for 28days with compound 15q improved the serum glucose levels in type 2 diabetic Sprague Dawley rats wherein diabetes was induced by high fat diet and low dose streptozotocin. This suggested that compound 15q is a moderately potent and selective hit molecule which can be further optimized structurally to increase the efficacy and overall pharmacological profile as DPP-4 inhibitor.

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.

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.

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.

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.

Medicinal chemistry strategies for the development of phosphodiesterase 10A (PDE10A) inhibitors - An update of recent progress.

Phosphodiesterase 10A is a member of Phosphodiesterase (PDE)-superfamily of the enzyme which is responsible for hydrolysis of cAMP and cGMP to their inactive forms 5'-AMP and 5'-GMP, respectively. PDE10A is highly expressed in the brain, particularly in the putamen and caudate nucleus. PDE10A plays an important role in the regulation of localization, duration, and amplitude of the cyclic nucleotide signalling within the subcellular domain of these regions, and thereby modulation of PDE10A enzyme can give rise to a new therapeutic approach in the treatment of schizophrenia and other neurodegenerative disorders. Limitation of the conventional therapy of schizophrenia forced the pharmaceutical industry to move their efforts to develop a novel treatment approach with reduced side effects. In the past decade, considerable developments have been made in pursuit of PDE10A centric antipsychotic agents by several pharmaceutical industries due to the distribution of PDE10A in the brain and the ability of PDE10A inhibitors to mimic the effect of D2 antagonists and D1 agonists. However, no selective PDE10A inhibitor is currently available in the market for the treatment of schizophrenia. The present compilation concisely describes the role of PDE10A inhibitors in the therapy of neurodegenerative disorders mainly in psychosis, the structure of PDE10A enzyme, key interaction of different PDE10A inhibitors with human PDE10A enzyme and recent medicinal chemistry developments in designing of safe and effective PDE10A inhibitors for the treatment of schizophrenia. The present compilation also provides useful information and future direction to bring further improvements in the discovery of PDE10A inhibitors.

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.

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.

Recent advances in the discovery of small molecule c-Met Kinase inhibitors.

c-Met is a prototype member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) and is the receptor for hepatocyte growth factor (HGF). Binding of HGF to its receptor c-Met, initiates a wide range of cellular signalling, including those involved in proliferation, motility, migration and invasion. Importantly, dysregulated HGF/c-Met signalling is a driving factor for numerous malignancies and promotes tumour growth, invasion, dissemination and/or angiogenesis. Dysregulated HGF/c-Met signalling has also been associated with poor clinical outcomes and resistance acquisition to some approved targeted therapies. Thus, c-Met kinase has emerged as a promising target for cancer drug development. Different therapeutic approaches targeting the HGF/c-Met signalling pathway are under development for targeted cancer therapy, among which small molecule inhibitors of c-Met kinase constitute the largest effort within the pharmaceutical industry. The review is an effort to summarize recent advancements in medicinal chemistry development of small molecule c-Met kinase inhibitors as potential anti-cancer agents which would certainly help future researchers to bring further developments in the discovery of small molecule c-Met kinase inhibitors.

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.

Synthesis and in vivo analgesic and anti-inflammatory activity of some bi heterocyclic coumarin derivatives.

Sets of coumarinyl ethers having chromone, benzofuranyl and 4-hydroxy coumarins (4, 5, 6) were prepared and tested for analgesic and antiinflammatory activity. The 4-(4'-acetyl-3'-hydroxy-phenoxymethyl)-coumarin 3 were synthesised by the reaction of 4-bromo methyl coumarin with 2, 4-dihydroxy acetophenones, were found to less active. Further compound 3 having the ortho hydroxy moiety was cyclised to chromones 4 and benzofurans 5 were found to enhance the analgesic and anti-inflammatory activity. The cyclisation to 4-hydroxy coumarin 6 was found to be reducing the anti-inflammatory and analgesic activity in this series. These newly synthesized compounds were found to produce less toxicity and less ulcerogenic effects.

Homology modeling, binding site identification and docking study of human angiotensin II type I (Ang II-AT1) receptor.

Ang II-AT1 receptors play an important role in mediating virtually all of the physiological actions of Ang II. Several drugs (SARTANs) are available, which can block the AT1 receptor effectively and lower the blood pressure in the patients with hypertension. Currently, there is no experimental Ang II-AT1 structure available; therefore, in this study we modeled Ang II-AT1 receptor structure using homology modeling followed by identification and characterization of binding sites and thereby assessing druggability of the receptor. Homology models were constructed using MODELLER and I-TASSER server, refined and validated using PROCHECK in which 96.9% of 318 residues were present in the favoured regions of the Ramachandran plots. Various Ang II-AT1 receptor antagonist drugs are available in the market as antihypertensive drug, so we have performed docking study with the binding site prediction algorithms to predict different binding pockets on the modeled proteins. The identification of 3D structures and binding sites for various known drugs will guide us for the structure-based drug design of novel compounds as Ang II-AT1 receptor antagonists for the treatment of hypertension.

Ligand and structure-based approaches for the identification of SIRT1 activators.

SIRT1 is a NAD(+)-dependent deacetylase that involved in various important metabolic pathways. Combined ligand and structure-based approach was utilized for identification of SIRT1 activators. Pharmacophore models were developed using DISCOtech and refined with GASP module of Sybyl X software. Pharmacophore models were composed of two hydrogen bond acceptor (HBA) atoms, two hydrogen bond donor (HBD) sites and one hydrophobic (HY) feature. The pharmacophore models were validated through receiver operating characteristic (ROC) and Güner-Henry (GH) scoring methods. Model-2 was selected as best model among the model 1-3, based on ROC and GH score value, and found reliable in identification of SIRT1 activators. Model-2 (3D search query) was searched against Zinc database. Several compounds with different chemical scaffold were retrieved as hits. Currently, there is no experimental SIRT1 3D structure available, therefore, we modeled SIRT1 protein structure using homology modeling. Compounds with Qfit value of more than 86 were selected for docking study into the SIRT1 homology model to explore the binding mode of retrieved hits in the active allosteric site. Finally, in silico ADMET prediction study was performed with two best docked compounds. Combination of ligand and structure-based modeling methods identified active hits, which may be good lead compounds to develop novel SIRT1 activators.

Synthesis of vanillin ethers from 4-(bromomethyl) coumarins as anti-inflammatory agents.

4-(Bromomethyl) coumarins 1 have been reacted with vanillins, 2 and 2A to obtain the corresponding ethers 3 and 5. Ethers 3 have been reacted with ethyl cyanoacetate to obtain the unsaturated esters 4. Ethers 5 have been converted to the corresponding 4-(2'-benzo[b] furanyl) coumarins 6 by an intramolecular aldol condensation. Eight compounds have been screened for their anti-inflammatory activity. Out of these the 5,6-benzo-4-2'-benzo[b]furanyl) coumarin (6c) and the aryloxymethyl coumarin (4) with p-formyl group were found to be most active.