Molecular Diversity

Here, we describe design and synthesis of twelve novel compounds bearing primaquine motif and hydroxy- or halogenamine linked by an urea or bis-urea spacer. Preparation of ureas 3a–f started with the conversion of primaquine to benzotriazolide 2 and aminolysis of the later compound by 4-(2-aminoethyl)phenol or amino alcohols bearing fluorine atom, cycloalkyl or trifluoromethyl group under microwave irradiation. The four-step sequence leading to bis-ureas 6a–f included preparation of benzotriazolide 2 and two intermediates, semicarbazide 4 and benzotriazole bis-urea 5, which upon aminolysis with the same aminophenol or amino alcohols gave the title compounds. Antimycobacterial screening detected three active compounds against Mycobacterium marinum and M. tuberculosis, namely 3b, 3f and 6f, derived from cyclobutyl amino alcohol or amino phenol.

The leading cause of death worldwide is cancer. Although there are various therapies available to treat cancer, finding a successful one can be like searching for a needle in a haystack. Immunotherapy appears to be one of those needles in the haystack of cancer treatment. Immunotherapeutic agents enhance the immune response of the patient’s body to tumor cells. One of the immunotherapeutic targets, Cluster of Differentiation 47 (CD47), releases the "don't eat me" signal when it binds to its receptor, Signal Regulatory Protein (SIRPα). Tumor cells use this signal to circumvent the immune system, rendering it ineffective. To stop tumor cells from releasing the "don't eat me" signal, the CD47–SIRPα interaction is specifically targeted in this study. To do so, in silico peptides were designed based on the structural analysis of the interaction between two proteins using point mutations on the interacting residues with the other amino acids. The peptide library was designed and docked on SIRPα using computational tools. Later on, after analyzing the docked complex, the best of them was selected for MD simulation studies of 100 ns. Further analysis after MD studies was carried out to determine the possible potential anti-SIRPα peptides.

Members of the vascular endothelial growth factor (VEGF) family are crucial regulators of neovascularization and are classified as cystine knot growth factors that specifically bind cellular receptor tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3 with high but variable affinity and selectivity. The VEGF family has recently been expanded and currently comprises seven members: VEGF-A, VEGF-B, placenta growth factor (PlGF), VEGF-C, VEGF-D, viral VEGF (also known as VEGF-E), and snake venom VEGF (also known as VEGF-F). Although all members are structurally homologous, there is molecular diversity among the subtypes, and several isoforms, such as VEGF-A, VEGF-B, and PlGF, are generated by alternative exon splicing. These splicing isoforms exhibit differing properties, particularly in binding to co-receptor neuropilins and heparin. VEGF family proteins play multiple physiological roles, such as angiogenesis and lymphangiogenesis, while exogenous members (viral and snake venom VEGFs) display activities that are unique in physiology and function. This review will highlight the molecular and functional diversity of VEGF family proteins.

Aurora kinases are sub-divided into Aurora A, Aurora B, and Aurora C kinases that are considered as prospective targets for a new class of anticancer drugs. In this work, a 4-D-QSAR model using an LQTA-QSAR approach with previously reported 31 derivatives of benzo[e]pyrimido[5,4 -b][1,4]diazepin -6(11H)-one as potent Aurora kinase A inhibitors has been created. Instead of single conformation, the conformational ensemble profile generated for each ligand by using trajectories and topology information retrieved from molecular dynamics simulations from GROMACS package were aligned and used for the calculation of intermolecular interaction energies at each grid point. The descriptors generated on the basis of these Coulomb and Lennard-Jones potentials as independent variables were used to perform a PLS analysis using biological activity as dependent variable. A good predictive model was generated with nine field descriptors and five latent variables. The model showed $${Q}_{\mathrm{LOO}}^{2} = 0.718$$ ; $${R}^{2}= 0.915$$ and $${R}_{\mathrm{pred}}^{2}= 0.839$$ . This model was further validated systematically by using different validation parameters. This 4D-QSAR model gave valuable information to recognize features essential to adapt and develop novel potential Aurora kinase inhibitors.

Microbial biofilms play a critical role in environmental biotechnology and associated applications. Biofilm production can be enhanced by inhibiting the function of proteins that negatively regulate their formation. With this objective, an in silico approach was adopted to identify competitive inhibitors of eight biofilm-antagonistic proteins, namely AbrB and SinR (from Bacillus subtilis) and AmrZ, PDE (EAL), PslG, RetS, ShrA and TpbA (from Pseudomonas aeruginosa). Fifteen inhibitors that structurally resembled the natural ligand of each protein were shortlisted using ligand-based and structure-based virtual screening. The top four inhibitors obtained from molecular docking using Autodock Vina were further docked using SwissDock and DOCK 6.9 to obtain a consensus hit for each protein based on different scoring functions. Further analysis of the protein–ligand complexes revealed that these top inhibitors formed significant non-covalent interactions with their respective protein binding sites. The eight protein-ligand complexes were then subjected to molecular dynamics simulations for 30 ns using GROMACS. RMSD and radius of gyration values of 0.1–0.4 nm and 1.0–3.5 nm, respectively, along with hydrogen bond formation throughout the trajectory indicated that all the complexes remained stable, compact and intact during the simulation period. Binding energy values between –20 and –77 kJ/mol obtained from MM-PBSA calculations further confirmed the high affinities of the eight inhibitors for their respective receptors. The outcome of this study holds great promise to enhance biofilms that are central to biotechnological processes associated with microbial electrochemical technologies, wastewater treatment, bioremediation and the industrial production of value-added products.

A series of novel 3-(1H-benzo[d]imidazol-2-yl)-3,4-dihydro-2H-benzo[e][1,3] oxazine analogues synthesized through a two-step synthetic protocol. The structure of the compounds were established by interpretation 1H NMR, 13C NMR and Mass spectral data recorded after purification. All the title compounds 4a–k were screened for their in vitro anti-cancer activity against two breast cancer cell lines MCF 7 and MDA-MB-231 by using Doxorubicin as standard reference. Compound 4e displayed superior activity against both the cell lines MCF-7 and MDA-MB-231 with IC50 values of 8.60 ± 0.75 and 6.30 ± 0.54 µM respectively, compared to the Doxorubicin IC50 value of 9.11 ± 0.54 and 8.47 ± 0.47 µM. Compound 4i also indicated good activity with IC50 value of 9.85 ± 0.69 μM on par with Doxorubicin against MCF-7 cells. Compound 4g demonstrated best activity on par with standard reference to IC50 value of 8.52 ± 0.62 μM against MDA-MB-231 cell line. And all other compounds demonstrated good to moderate activity compared to Doxorubicin. Docking studies against EGFR showed that all the compounds have very good binding affinities towards the target. The predicted drug-likeness properties of all compounds enable them to be used as therapeutic agents.

In this paper, a series of bis(2,3-dihydroquinazolin-4(1H)-one) derivatives (4a–i, 10a–k) were synthesized by the one-pot pseudo-five-component reaction of isatoic anhydride with aromatic aldehydes and aromatic amines under reflux in glacial acetic acid. The synthesized compounds were screened for their antioxidant properties using the DPPH radical scavenging method. Compounds 4i and 10h showed potent radical scavenging activities at 20 $$\upmu \hbox {g}/\hbox {mL}$$ compared to BHA and ascorbic acid. The anticancer activity of compound 4f was evaluated against human breast cancer cell line (MCF 7), and the observed $$\hbox {GI}_{50}$$ was found to be 11.4 $$\upmu \hbox {m}$$ . The redox behaviour of some analogues was evaluated by cyclic voltammetric methods, and it is found that compound 7d possesses the maximum redox potential.

The human P-glycoprotein (P-gp) efflux pump is of great interest for medicinal chemists because of its important role in multidrug resistance (MDR). Because of the high polyspecificity as well as the unavailability of high-resolution X-ray crystal structures of this transmembrane protein, ligand-based, and structure-based approaches which were machine learning, homology modeling, and molecular docking were combined for this study. In ligand-based approach, individual two-dimensional quantitative structure–activity relationship models were developed using different machine learning algorithms and subsequently combined into the Ensemble model which showed good performance on both the diverse training set and the validation sets. The applicability domain and the prediction quality of the developed models were also judged using the state-of-the-art methods and tools. In our structure-based approach, the P-gp structure and its binding region were predicted for a docking study to determine possible interactions between the ligands and the receptor. Based on these in silico tools, hit compounds for reversing MDR were discovered from the in-house and DrugBank databases through virtual screening using prediction models and molecular docking in an attempt to restore cancer cell sensitivity to cytotoxic drugs.