Imidazole and carbazole derivatives as potential anticancer agents: molecular docking studies and cytotoxic activity evaluation

Carbazoles and imidazole represent two important classes of heterocycles which exhibit diverse biological activities such as antitumor properties. In this study, imidazole (C1-C3) and carbazole (C4 and C5) derivatives were evaluated for their cytotoxic activity against three human cancer cell lines namely, MCF7 (human breast cancer), HT29 (human colon cancer), and HeLa (human cervical cancer). Carbazole derivatives (C4 and C5) with IC50 < 10 µM showed greater cytotoxic effect than imidazole derivatives (C1-C3). Furthermore, all compounds exhibited better anticancer activity against MCF-7 than other two cell lines (HT-29, HeLa) and compound C4 was the most potent compound with the IC50 values of 2.5, 5.4 and 4.0 µM, against MCF-7, Hela and HT-29 cell lines, respectively. Physicochemical properties of compounds were calculated and their correlation with the IC50 values on MCF-7 cell line investigated. Surface area and polarizability of compounds showed good correlation by R2 = 0.8396 and R2 = 0.834, respectively. Docking studies of these compounds were also performed on the DNA as proposed target to comprehend their binding interactions and binding energies. The docking energy of compounds ranged from - 11.32 to -13.48 kcal/mol. Compound C3 with energy of -13.48 kcal/mol had the highest docking energy. Docking results indicated that these compounds (C1-C5) had strong affinity in binding to the DNA.                     KEY WORDS: Imidazole, Carbazole, Molecular docking, Cancer, MTT assay   Bull. Chem. Soc. Ethiop. 2020, 34(2), 377-384 DOI: https://dx.doi.org/10.4314/bcse.v34i2.1

Scope of Selective Heterocycles from Organic and Pharmaceutical Perspective

Scope of Selective Heterocycles from Organic and Pharmaceutical Perspective is a compilation of bioactive-chosen heterocyclic scaffolds intended for postgraduates, research scholars, pharmaceutical scientists, and others interested in an appreciation of the title subject. It is an edited book and is not comprehensive as well in the mentioned field. Few synthetic strategies along with bioactivity are presented, and some limitations were raised in order to arouse curiosity of the reader

Synthetic strategies for 5- and 6-membered ring azaheterocycles facilitated by iminyl radicals

The author thanks EaStCHEM for financial support.The totality of chemical space is so immense that only a small fraction can ever be explored. Computational searching has indicated that bioactivity is associated with a comparatively small number of ring-containing structures. Pyrrole, indole, pyridine, quinoline, quinazoline and related 6-membered ring-containing aza-arenes figure prominently. This review focuses on the search for fast, efficient and environmentally friendly preparative methods for these rings with specific emphasis on iminyl radical mediated procedures. Oxime derivatives, particularly oxime esters and oxime ethers, are attractive precursors for these radicals. Their use is described in conventional thermolytic, microwave-assisted and UV-vis based preparative procedures. Photoredox catalyzed protocols involving designer oxime ethers are also covered. Choice can be made amongst these synthetic strategies for a wide variety of 5- and 6-membered ring heterocycles including phenanthridine and related aza-arenes. Applications to selected natural products and bioactive molecules including trispheridine, vasconine, luotonin A and rutaecarpine are included.Publisher PDFPeer reviewe

Coumarin and Its Derivatives

Coumarins are widely distributed in nature and can be found in a large number of naturally occurring and synthetic bioactive molecules. The unique and versatile oxygen-containing heterocyclic structure makes them a privileged scaffold in Medicinal Chemistry. Many coumarin derivatives have been extracted from natural sources, designed, synthetized, and evaluated on different pharmacological targets. In addition, coumarin-based ion receptors, fluorescent probes, and biological stains are growing quickly and have extensive applications to monitor timely enzyme activity, complex biological events, as well as accurate pharmacological and pharmacokinetic properties in living cells. The extraction, synthesis, and biological evaluation of coumarins have become extremely attractive and rapidly developing topics. A large number of research and review papers have compiled information on this important family of compounds in 2020. Research articles, reviews, communications, and concept papers focused on the multidisciplinary profile of coumarins, highlighting natural sources, most recent synthetic pathways, along with the main biological applications and theoretical studies, were the main focus of this book. The huge and growing range of applications of coumarins described in this book is a demonstration of the potential of this family of compounds in Organic Chemistry, Medicinal Chemistry, and different sciences related to the study of natural products. This book includes 23 articles: 17 original papers and six review papers

Heterocyclic Compounds from Marine Organisms

Marine drugs have drawn considerable attention due to their significant biological and pharmacological properties, such as antimicrobial or antibacterial activities and antitumor effects, among others. The frequent occurrence of heterocyclic motifs in the structure of many of these targets has revealed the key role of these units as promising pharmacophores. In this Special Issue we have gathered several original papers which highlight the isolation, structural elucidation and biological essays of newly isolated heterocyclic marine drugs, as well as reviews which give an overview of the isolation, synthesis and pharmacological activities of different classes of marine heterocycles

Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E^{V600E} Inhibitory Pathways

A series of novel 3-cyanopyridone/pyrazoline hybrids (21–30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects

Drug Design, Docking Studies, Synthesis and In-Vitro Evaluation of Certain Novel Isoxazole Incorporated Coumarin Derivatives as Potent α - Amylase Inhibitors

The present work was focused on the designing and synthesis of novel isoxazole derivatives incorporated with coumarin moiety having α-amylase enzyme inhibitory activity. For this, following approach has been adopted. PHASE I: LITERATURE REVIEW Literature survey showed that coumarin is a drug like scaffold and is a core skeleton for the active sites involved in enzyme inhibiton in Type 2 diabetes. It also revealed that isoxazole possess enzyme inhibition for Type 2 diabetes. PHASE II: DRUG DESIGN APPROACH It involves the following stages: Stage 1: Identification of target α-amylase was selected as the target enzyme as its inhibition will prevent carbohydrate hydrolysis. The target enzyme (1UA7) was downloaded from RCBs Protein Databank. Stage 2: Lead optimization Lead optimisation was done by computation of drug likness score. Isoxazole derivatives of coumarin were the desired compounds with good molecular properties and bioactivity score, ie., the compounds A1, A3, A4 and K1, K3, K5 showed good scores. PHASE III: SYNTHESIS AND PHYSICAL CHARACTERIZATION A) Synthesis of the designed compounds In this work, ten new compounds are designed in which Six different isoxazole derivatives were synthesized by using three aromatic aldehydes and three aromatic ketones with coumarin moiety. The first step involved the synthesis of 6- acetyl 7- hydroxy 4- methyl coumarin by acetylation. Chalcones were prepared from 6- acetyl 7- hydroxy 4-methyl coumarin by using different aromatic aldehydes and aromatic ketones. Finally, the chalcones were reacted with hydroxylamine hydrochloride to form isoxazoles. B) Physical characterization Melting point of all the newly synthesised compounds was determined by capillary tube method. Rf values were determined by fixing various suitable solvent system on precoated silicagel- G plates. PHASE IV: SPECTRAL STUDIES The structure of the synthesised compounds was established by using IR, 1H NMR, and Mass spectral data. PHASE V: EVALUATION OF BIOLOGICAL ACTIVITIES Evaluation of α-amylase inhibitory activity All the newly sysnthesised compounds were screened for in vitro α-amylase inhibitory activity. All compounds showed significant activity in inhibition of the α-amylase enzyme. Comparatively A1 and K1 showed good % of inhibition activity, while A3, A4, K3, K5 showed moderate activity. CONCLUSION • The present study establishes that computational tools help in minimizing the tedious process of drug discovery and delivers new drug candidate more quickly. • α-amylase enzyme was selected as target and virtual screening made selection of lead compounds easier and coumarin was selected as lead molecule. • From among the ten docked molecules, six molecules with good Binding affinity were chosen for further laboratory synthesis. Drug likeness was predicted insilico before proceeding for synthesis. • Compounds A1, A3, A4 and K1, K3, K5 were found to have significant binding score against target enzyme α-amylase. compared to standard drug Acarbose. The selected derivatives were planned for synthesis. • The proposed Six compounds of isoxazole derivatives with coumarin ring system were synthesised in good yield using the developed schemes. • All the reactions were monitored by TLC one spot technique and the structures of the synthesised compounds were confirmed by IR, 1H NMR, Mass spectra. • Compounds A1, K1 and K3 exhibited maximum α-amylase inhibitory activity. Among the synthesized compounds, A1 and K1 can be taken for further studies as the lead molecule and acute toxicity studies are to be done on these promising compounds

Synthesis, biological evaluation and molecular docking studies of novel indole- and benzofuran-chalcone and benzofuran-quinazoline hybrids as anticancer agents

Text in EnglishSpecially prepared 2-amino-5-bromo-3-iodoacetophenone and 5-bromo-2-hydroxy-3 iodoacetophenone were subjected to Claisen-Schmidt aldol condensation with benzaldehyde derivatives followed by sequential and/or one-pot palladium catalyzed Sonogashira cross coupling and heteroannulation of the 3-alkynylated intermediates to afford indole-chalcones and benzofuran-chalcones, respectively. The indole-chalcones derivatives were, in turn, subjected to trifluoroacetic anhydride in tetrahydrofuran under reflux to afford the corresponding 3-trifluoroacetyl substituted indole-chalcone derivatives. The coupling constant values (Jtrans) of about 16.0 Hz for the chalcone derivatives corresponding to the vinylic protons confirmed the trans geometry of the α,β-unsaturated carbonyl framework in all the cases. Their trans geometry of the chalcone derivatives was further confirmed by single crystal X-ray diffraction (XRD) analyses. Further structural elaboration of the ambident electrophilic α,β unsaturated carbonyl (chalcone) moiety of the indole-chalcones and the analogous benzofuran chalcones with 2-aminothiophenol afforded novel benzothiezapine-appended indole and benzofuran hybrids, respectively. Sonogashira cross-coupling of 5-bromo-2-hydroxy-3 iodoacetophenone with terminal acetylenes followed by heteroannulation of the intermediate 3-alkynylated 5-bromo-2-hydroxyacetophenones afforded the corresponding 7-acetyl-2-aryl-5-bromobenzofurans in a single-pot operation. The oximes derived from the 7-acetyl–substituted 2-aryl-5-bromobenzofurans were subjected to Beckmann rearrangement with triflic acid in acetonitrile under reflux. We isolated the corresponding 7-amino-2-aryl-5 bromobenzofuran derivatives formed from hydrolysis in situ of the intermediate 7-acetamide 2-aryl-5-bromobenzofurans. Amino-dechlorination of the 4-chloroquinazoline derivatives with the 7-aminobenzofurans afforded novel benzofuran 4-aminoquinazoline hybrids. The prepared compounds were characterized using a combination of nuclear magnetic resonance (1H-NMR & 13C-NMR including 19F-NMR), infrared (IR) and mass spectroscopic techniques complemented with single crystal X-ray diffraction (XRD) analyses and/or density functional (DFT) method. The benzofuran-chalcone 203a–y derivatives were evaluated for anti-growth effect against the breast cancer (MCF-7) cell line by the MTT cell viability assay. Their mode of cancer cell death (apoptosis versus necrosis) was detected by Annexin V-Cy3 SYTOX staining and caspase-3 activation. The most cytotoxic compounds 203i and 203o were also evaluated for potential to inhibit tubulin polymerization and/or epidermal growth factor receptor-tyrosine kinase (EGFR-TK) phosphorylation. The experimental results were complemented with theoretical data from molecular docking into ATP binding site of the EGFR and colchicine binding site of tubulin, respectively. The benzofuran–4-aminoquinazoline hybrids 215a–j, on the other hand, were evaluated for antiproliferative propeties in vitro against the human lung cancer (A549), epithelial colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (C3A) cell lines. The benzofuran-aminoquinazoline hybrids were also evaluated for potential to induce apoptosis and for their capability to inhibit EGFR-TK phosphorylation complemented with molecular docking (in silico) into the ATP binding site of EGFR. Mechanistic studies demonstrated that the benzofuran-appended aminoquinazoline hybrids 215d and 215j induced apoptosis via activation of caspase-3 pathway. Moreover, compounds 215d and 215j exhibited significant and moderate inhibitory effects against EGFR (IC50 = 29.3 nM and 61.5 nM, respectively) when compared to Gefitinib (IC50 = 33.1 nM). Molecular docking of compounds 215 into EGFR-TK active site suggested that they bind to the region of EGFR like Gefitinib does.ChemistryD. Phil. (Chemistry

Multiple Targeting Approaches on Histamine H-3 Receptor Antagonists

With the very recent market approval of pitolisant (Wakix (R)), the interest in clinical applications of novel multifunctional histamine H-3 receptor antagonists has clearly increased. Since histamine H-3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H-3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures

In-Silico Docking, Design and Synthesis of Certain Benzotriazole Derivatives and Study of their Antialzheimer’s Activity

The present Study was focused on predicting the protein-ligand interactions, design, synthesis and evaluation of substituted Benzotriazole derivatives as possible anticholinesterase inhibitors. IN SILICO STUDIES: • Selection of target: Cholinesterase inhibitors was selected as the target for Anti-Alzheimer’s activity. The corresponding target was downloaded from RCSB protein databank (PDB: 4EY7, & 4BDS). • Selection of lead: The lead Benzotriazole was selected based on several literature reviews. Derivatives of Benzotriazole, Benzotriazole hybrids were reported to have anticholinesterase activity. • Lead optimization: Lead optimization was done by observing in-silico ADMET studies and computation of molecular and ADME properties. All the selected ligands had good ADMET properties and hence were eligible for the further study. • Docking: Molecular docking studies were performed using glide software. The ligands were docked with the target (4EY7 & 4BDS). The ligands BA-1A to 1D and BE-2A to 2D was showing best docked pose. SYNTHESIS: In this present work two schemes were developed for the compounds to be synthesized. Eight new compounds were synthesized. Benzotriazole was the starting compounds for both the schemes. In the first scheme, O-phenylenediamine was reacted with sodium nitrite and acetic acid to form Benzotriazole. By treating substituted benzoic acid with thionyl chloride to form a substituted acid chloride and further Benzotriazole and substituted acid chloride reacts to obtain desired products. In second scheme, synthesized Benzotriazole was treated with Ethyl chloroacetate to form intermediate ethyl-1H-Benzotriazoyl-acetate and further treated with various primary amines to obtain desired products. PHYSICAL CHARACTERIZATION: Melting point of newly synthesized compounds were determined. Rf values were determined by fixing various suitable solvent system on precoated silica gel G plates. The structure was finally characterized by UV, IR, Mass, and 1HNMR Spectra. IN-VITRO ENZYME INHIBITORY ACTIVITY: Neurodegenerative disease is characterized by decrease in the level of neurotransmitters, oxidative stress and neuro inflammation in brain, mostly the treatments are based on enhancing the Cholinergic function in brain there by improve the level of neuro transmitter from break down. Cholinesterase inhibitors were developed based on cholinergic hypothesis of Alzheimer’s disease, where Cholinesterase inhibitors reduce the degradation of the synaptic acetylcholine; improve level of acetylcholine in a dose-dependent manner. AChE and BuChE are two different enzymes located in brain that responsible for hydrolysis. Rivastigmine; dual AChE and BuChE inhibitors where it was used as standard. All the newly synthesized compounds were screened for anticholinesterase activity using Ellman’s method and all the compounds showed moderate activity. It was observed that the nature and size of the substituents play a role in influencing the activity of the compounds. The compounds BA-D and BE-2A showed good percentage inhibition for AChE activity when compared to the standard Rivastigmine. Similarly, the compounds BA-2C and BE-2A shows good percentage inhibition for BuChE activity when compared with the standard Rivastigmine. This clearly demonstrate that our compounds have potential to increase the level of acetyl choline and it could also be used in prevention and control of Alzheimer’s disease. CONCLUSION: After analyzing the results of the present work, following conclusions were made, The present work basically aims to identify the correct conformations of ligands in the active site protein and to predict the affinity of the ligand towards the protein. Structural based drug design approach proved to be a tool in minimizing the tedious drug discovery process. The In silico molecular and ADME properties was established the compounds to be pharmacokinetically active. QIKPROP was used for filtering the compounds and selecting the lead compounds. Docking results confirmed the possibility of Benzotriazole moiety to possess anticholinesterase activity. The binding energy obtained from docking study further confirmed the possibility of the affinity of the selected leads towards the enzyme Cholinesterase. The compounds were synthesized based on the developed scheme and good yields obtained. Synthesized compounds structures were confirmed by Melting point, Rf value, UV, IR, Mass and NMR spectra. All compounds were screened for anti-Alzheimer’s activity all the showed the better activity. Derivatives of Benzotriazole were proven as a potent anti-Alzheimer’s agents via anticholinesterase inhibition. Novel structure based drug design process helped to screen several compounds for specific activity. Present work could be considered as preliminary study of the titled moiety towards AChE & BuChE activity and further confirmation can be done by several site specific inhibitory actions