Discovery of novel phthalimide analogs

In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives (4a–i, 5a–f, and 6a-c) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds 4c, 4f, 4g, 4h, 4i, 5c, 5d, 5e, and 6c (MIC range from 0.49 to 31.5 μg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target enzymes

Exploring the Dual Inhibitory Activity of Novel Anthranilic Acid Derivatives towards α-Glucosidase and Glycogen Phosphorylase Antidiabetic Targets: Design, In Vitro Enzyme Assay, and Docking Studies

A few new anthranilate diamide derivatives, 3a–e, 5a–c and 7a–d, were designed, synthesized, and evaluated for their inhibitory activity against two interesting antidiabetic targets, α-glucosidase and glycogen phosphorylase enzymes. Different instrumental analytical tools were applied in identification and conformation of their structures like; 13C NMR, 1H NMR and elemental analysis. The screening of the novel compounds showed potent inhibitory activity with nanomolar concentration values. The most active compounds (5c) and (7b) showed the highest inhibitory activity against α-glucosidase and glycogen phosphorylase enzymes IC50 = 0.01247 ± 0.01 µM and IC50 = 0.01372 ± 0.03 µM, respectively. In addition, in vivo testing of the highly potent α-glucosidase inhibitor (7b) on rats with DTZ-induced diabetes was done and showed significant reduction of blood glucose levels compared to the reference drug. Furthermore, a molecular docking study was performed to help understand the binding interactions of the most active analogs with these two enzymes. The data obtained from the molecular modeling were correlated with those obtained from the biological screening. These data showed considerable antidiabetic activity for these newly synthesized compounds

Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits

The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool ‘Emergent Self-Organizing Maps’ for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity

Exploring the Dual Inhibitory Activity of Novel Anthranilic Acid Derivatives towards α-Glucosidase and Glycogen Phosphorylase Antidiabetic Targets: Design, In Vitro Enzyme Assay, and Docking Studies

A few new anthranilate diamide derivatives, 3a–e, 5a–c and 7a–d, were designed, synthesized, and evaluated for their inhibitory activity against two interesting antidiabetic targets, α-glucosidase and glycogen phosphorylase enzymes. Different instrumental analytical tools were applied in identification and conformation of their structures like; 13C NMR, 1H NMR and elemental analysis. The screening of the novel compounds showed potent inhibitory activity with nanomolar concentration values. The most active compounds (5c) and (7b) showed the highest inhibitory activity against α-glucosidase and glycogen phosphorylase enzymes IC50 = 0.01247 ± 0.01 µM and IC50 = 0.01372 ± 0.03 µM, respectively. In addition, in vivo testing of the highly potent α-glucosidase inhibitor (7b) on rats with DTZ-induced diabetes was done and showed significant reduction of blood glucose levels compared to the reference drug. Furthermore, a molecular docking study was performed to help understand the binding interactions of the most active analogs with these two enzymes. The data obtained from the molecular modeling were correlated with those obtained from the biological screening. These data showed considerable antidiabetic activity for these newly synthesized compounds

The Design and Development of Potent Small Molecules as Anticancer Agents Targeting EGFR TK and Tubulin Polymerization

Some novel anthranilate diamides derivatives 4a–e, 6a–c and 9a–d were designed and synthesized to be evaluated for their in vitro anticancer activity. Structures of all newly synthesized compounds were confirmed by infra-red (IR), high-resolution mass (HR-MS) spectra, 1H nuclear magnetic resonance (NMR) and 13C nuclear magnetic resonance (NMR) analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using erlotinib as a reference drug against two different types of breast cancer cells. The molecular docking study was performed for representative compounds against two targets, epidermal growth factor receptor (EGFR) and tubulin in colchicine binding site to assess their binding affinities in order to rationalize their anticancer activity in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the anthranilate diamide showed excellent activity with nanomolar or sub nanomolar half maximal inhibitory concentration (IC50) values against tumor cells. EGFR tyrosine kinase (TK) inhibition assay, tubulin inhibition assay and apoptosis analysis were performed for selected compounds to get more details about their mechanism of action. Extensive structure activity relationship (SAR) analyses were also carried out

Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits

The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool ‘Emergent Self-Organizing Maps’ for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity

Design, Synthesis and Cytotoxic Evaluation of Novel Chalcone Derivatives Bearing Triazolo[4,3-a]-quinoxaline Moieties as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects

A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a–k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b–c, and 7e–g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC50 values in the 1.65 to 34.28 µM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a–c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 µM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets

Design and Synthesis of Novel Imidazole Derivatives Possessing Triazole Pharmacophore with Potent Anticancer Activity, and In Silico ADMET with GSK-3β Molecular Docking Investigations

A library of novel imidazole-1,2,3-triazole hybrids were designed and synthesized based on the hybrid pharmacophore approach. Therefore, copper(I)catalyzed click reaction of thiopropargylated-imidazole 2 with several organoazides yielded two sets of imidazole-1,2,3-triazole hybrids carrying different un/functionalized alkyl/aryl side chains 4a–k and 6a–e. After full spectroscopic characterization using different spectral techniques (IR, 1H, 13C NMR) and elemental analyses, the resulted adducts were screened for their anticancer activity against four cancer cell lines (Caco-2, HCT-116, HeLa, and MCF-7) by the MTT assay and showed significant activity. In-silico molecular docking study was also investigated on one of the prominent cancer target receptors, i.e., glycogen synthase kinase-3β (GSK-3β), revealing a good binding interaction with our potent compound, 4k and was in agreement with the in vitro cytotoxic results. In addition, the ADMET profile was assessed for these novel derivatives to get an insight on their pharmacokinetic/dynamic attributes. Finally, this research design and synthesis offered click chemistry products with interesting biological motifs mainly 1,2,3 triazoles linked to phenyl imidazole as promising candidates for further investigation as anticancer drugs