Novel 4-nitroimidazole analogues: synthesis, in vitro biological evaluation, in silico studies, and molecular dynamics simulation.

A new series of 4-nitroimidazole bearing aryl piperazines 7-16, tetrazole 17 and 1,3,4-thiadiazole 18 derivatives was synthesized. All derivatives were screened for their anticancer activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562, and Z138). Compound 17 proved the most potent compound of the series inhibiting proliferation of most of the selected human cancer cell lines with IC50 values in the low micromolar range. In addition, compound 11 exhibited IC50 values ranging 8.60-64.0 µM against a selection of cancer cell lines. These findings suggest that derivative 17 can potentially be a new lead compound for further development of novel antiproliferative agents. Additionally, 17-18 were assessed for their antibacterial and antituberculosis activity. Derivatives 17 and 18 were the most potent compounds of this series against both Staphylococcus aureus strain Wichita and a methicillin resistant strain of S. aureus (MRSA), as well as against Mycobacterium tuberculosis strain mc26230. The antiviral activity of 7-18 was also evaluated against diverse viruses, but no activity was detected. The docking study of compound 17 with putative protein targets in acute myeloid leukemia had been studied. Furthermore, the molecular dynamics simulation of 17 and 18 had been investigated.

Design, Synthesis, Docking Studies and Molecular Dynamics Simulation of New 1,3,5-Triazine Derivatives as Anticancer Agents Selectively Targeting Pancreatic Adenocarcinoma (Capan-1).

On the basis of remarkable anticancer profile of s-triazine nucleus, a new series of 2-methoxy-4-(3-morpholino-5-(arylamino)phenoxy)benzaldehyde derivatives 11 a-u was prepared and evaluated for in vitro antiproliferative activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562 and Z138). Compounds 11 o, 11 r and 11 s were the most potent anticancer agents on pancreatic adenocarcinoma (Capan-1) cell line with IC50 value of 1.4, 5.1 and 5.3 µM, respectively, while compounds 11 f, 11 g, 11 k, 11 l and 11 n displayed selective activity against the pancreatic adenocarcinoma (Capan-1) cell line with IC50 values of 7.3-11.5 µM. These results indicate that derivative 11 o may serve as a promising lead compound for the ongoing development of novel antiproliferative agents. The docking studies were conducted to predict the interactions of derivative 11 o with putative protein targets in pancreatic adenocarcinoma (Capan-1) cell line, specifically the prenyl-binding protein PDEδ. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that complex 11 o promoted a higher stability to the prenyl-binding protein PDEδ.

A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development.

Peptidoglycan is a carbohydrate with a cross-linked structure that protects the cytoplasmic membrane of bacterial cells from damage. The mechanism of peptidoglycan biosynthesis involves the main synthesizing enzyme glycosyltransferase MurG, which is known as a potential target for antibiotic therapy. Many MurG inhibitors have been recognized as MurG targets, but high toxicity and drug-resistant Escherichia coli strains remain the most important problems for further development. In addition, the discovery of selective MurG inhibitors has been limited to the synthesis of peptidoglycan-mimicking compounds. The present study employed drug discovery, such as virtual screening using molecular docking, drug likeness ADMET proprieties predictions, and molecular dynamics (MD) simulation, to identify potential natural products (NPs) for Escherichia coli. We conducted a screening of 30,926 NPs from the NPASS database. Subsequently, 20 of these compounds successfully passed the potency, pharmacokinetic, ADMET screening assays, and their validation was further confirmed through molecular docking. The best three hits and the standard were chosen for further MD simulations up to 400 ns and energy calculations to investigate the stability of the NPs-MurG complexes. The analyses of MD simulations and total binding energies suggested the higher stability of NPC272174. The potential compounds can be further explored in vivo and in vitro for promising novel antibacterial drug discovery.

Insights into the inhibitory potential of novel hydrazinyl thiazole-linked indenoquinoxaline against alpha-amylase: a comprehensive QSAR, pharmacokinetic, and molecular modeling study.

The rising prevalence of diabetes necessitates the development of novel drugs, especially given the side effects associated with current medications like Acarbose and Voglibose. A series of 36 Hydrazinyl thiazole-linked indenoquinoxaline derivatives with notable activity against alpha-amylase were studied. To create a molecular model predicting alpha-amylase activity, a QSAR study was performed on these compounds. Molecular descriptors were calculated using Chem3D and Gaussian software and then correlated with their IC50 biological activities to form a dataset. This model data was refined using PCA and modeled with MLR. The model's performance was statistically verified (R2 =0.800; Radj2 = 0.767; Rcv2 = 0.651) and its applicability domain was defined. It was predicted to possess high predictive power (Rtest2  = 0.872). Based on this, new compounds were proposed, and their activities were predicted using the developed model. Additionally, their binding ability to the biological target was studied through molecular docking and dynamics. Their pharmacokinetics were also evaluated using ADMET predictions. Two designed compounds named AE and AB emerged as particularly promising, displaying properties that suggest substantial therapeutic potential and they can form stable complexes into the binding pocket of alpha-amylase enzyme.Communicated by Ramaswamy H. Sarma.

Novel hybrid motifs of 4-nitroimidazole-piperazinyl tagged 1,2,3-triazoles: Synthesis, crystal structure, anticancer evaluations, and molecular docking study.

4-((4-(1-benzyl-2-methyl-4-nitro-1H-imidazole-5-yl)piperazine-1-yl)methyl)-1-substituted-1H-1,2,3-triazole motifs are designed and synthesized via click chemistry. The reaction of 1-(N1-benzyl- 2-methyl-4-nitro-1H-imidazole- 5-yl)-4-(prop-2-yn-1-yl) piperazine 5 as new scaffold with diverse primary azides to selectively produce 1,4-disubstituted-1,2,3-triazoles 9a-k, 10a-c and 11a-q. Physicochemical methods: when 1H NMR, 13C NMR, and HRMS are utilized to fully characterize all synthesized compounds. X-ray structural determination and analysis for compound 9a is also performed. The newly designed chromophores are assessed for their anti-proliferative potency against three selected human cancer cell lines (MCF-7, HepG2, and PC3), and one normal cell line (Dermal/Fibroblast). Compounds 9g and 9k have shown potent activities against the MCF-7 cell line with IC50 values of (2.00 ± 0.03 µM) and (5.00 ± 0.01 µM) respectively. ADMET studies and Molecular docking investigations are performed on the most active hybrid nitroimidazole derivatives 9g and 9k with 4-hydroxytamoxifen (4-OHT) at the human estrogen receptor alpha (hER) during binding active sites to study the ligand-protein interactions and free binding energies at atomic levels. The triazole ring in the 9g derivative forms a hydrogen bond with Asp58 with distance 3.2 Å. And it is found that polar contact with His231 amino acid residue. In silico assessment of the compounds showed very good pharmacokinetic properties based on their physicochemical values, also the ADMET criteria of the most active hybrid systems are within the acceptable range.

Discovery of novel potent drugs for influenza by inhibiting the vital function of neuraminidase via fragment-based drug design (FBDD) and molecular dynamics simulation strategies.

The current work describes a fragment linking methodology to generate new neuraminidase inhibitors. A total number of 28,977 fragments from Zinc 20 have been obtained and screened for neuraminidase receptor affinity. Using Schrödinger software, the highest-scoring 270 fragment hits (with scores greater than -7.6) were subjected to fragment combining to create 100 new molecules. These 100 novel compounds were studied using XP docking to evaluate the molecular interaction modes and their binding affinity to neuraminidase receptor. The top ten molecules were selected, for ADMET, drug-likeness features. Based on these characteristics, the best four developed molecules and Zanamivir were submitted to a molecular dynamics simulation investigation to estimate their dynamics within the neuraminidase receptor using Gromacs software. All MD simulation findings show that the generated complexes are very stable when compared to the clinical inhibitor (Zanamivir). In addition, the four designed neuraminidase inhibitors formed very stable complexes with neuraminidase receptor (with total binding energies ranging from -83.50 to -107.85 Kj/mol) according to the total binding energy calculated by MM-PBSA. For the objective of developing new influenza medications, these novel molecules have the potential to be further evaluated in vitro and in vivo for influenza drug discovery.Communicated by Ramaswamy H. Sarma.

Thiadiazine thione derivatives as anti-leishmanial agents: synthesis, biological evaluation, structure activity relationship, ADMET, molecular docking and molecular dynamics simulation studies.

During last decades, 3,5-disubstituted-tetrahydro-2H-thiadiazine-2-thione scaffold remains the center of interest due to their ease of preparation, diverse range substituents at N-3 and N-5 positions, and profound biological activities. In the current study, a series of 3,5-disubstituted-tetrahydro-2H-thiadiazine-2-thiones were synthesized in good to excellent yield, and the structure of the compounds were confirmed by various spectroscopic techniques such as FTIR, 1H-NMR, 13C-NMR and Mass spectrometry, and finally evaluated against Leishmania major. Whereas, all the evaluated compounds (1-33), demonstrate potential leishmanicidal activities with IC50 values in the range of (1.30- 149.98 uM). Among the evaluated compounds such as 3, 4, 6, and 10 exhibited excellent leishmanicidal activities with IC50 values of (2.17 µM), (2.39 µM), (2.00 µM), and (1.39 µM), respectively even better than the standard amphotericin B (IC50 = 0.50) and pentamidine (IC50 = 7.52). In order to investigate binding interaction of the most active compounds, molecular docking study was conducted with Leishmania major. Further molecular dynamic simulation study was also carried out to assess the stability and correct binding of the most active compound 10, within active site of the Leishamania major. Likewise, the physiochemical properties, drug likeness, and ADMET of the most active compounds were investigated, it was found that none of the compounds violate Lipiniski's rule of five, which show that this class of compounds had enough potential to be used as drug candidate in near future.Communicated by Ramaswamy H. Sarma.

Thiadiazine-thiones as inhibitors of leishmania pteridine reductase (PTR1) target: investigations and in silico approach.

Leishmaniasis is a widespread parasitic disease and is one of the major public health concerns in developing countries. Many drugs have been identified for leishmania as targets, but the potential toxicity and long-term treatment remain the most significant problems in terms of further development. The present study employed physicochemical investigations, structure-based virtual screening, ADMET analysis, molecular dynamics simulation, and MM-PBSA, to identify potential compounds for Leishmania. We evaluated 30,926 natural products from the NPASS database, and four potentials passed the pharmacokinetic ADMET studies and were verified using the molecular docking approach. Molecular docking results showed good binding interaction of the compounds with the active site of leishmania pteridine reductase enzyme PTR1, with compound TTC1 showing FRED and Autodock binding energies of -10.33 and -10.94, respectively, which were comparable with the antileishmania drugs of Allopurinol, Miltefosine and the original ligand, methotrexate. TTC1 compound was found to be favorable for hydrophobic interaction with PTR1. In addition, the physicochemical properties of the compounds were studied using the SwissADME web server. All compounds followed Lipinski's rule of five and can be considered as good oral candidates. The analysis of the 100 ns molecular dynamics simulation results based on the best-docked TTC1 with PTR1 receptor demonstrates stable interactions, and the complex undergoes low conformational fluctuations. The average of the calculated binding free energy of the TTC1-1e7w complex is (-68.67 kJ/mol), and the result demonstrated that the TTC1 promoted stability to the Leishmania-PTR1 complex. The potential compounds can be further explored for their antileishmanial activity.Communicated by Ramaswamy H. Sarma.

Nitroimidazoles Part 10. Synthesis, crystal structure, molecular docking, and anticancer evaluation of 4-nitroimidazole derivatives combined with piperazine moiety.

Piperazine-tagged imidazole derivatives 3a (symmetrical di-substituted piperazine) and 5-11 were synthesized through the combination of 4-nitroimidazole derivatives with piperazine moiety. The structural characterization was done by different physical and spectral techniques like NMR (1H and 13C) and mass spectrometry. The constituency of compound 3a was confirmed by X-ray structural analyses. All compounds were assessed for their antiproliferative inhibition potency against five human cancer cell lines namely MCF-7, PC3, MDA-231, A549 and Fibro dental. Compound 5 was found to be the most potent anticancer agents against MCF-7 cell line with IC50 values of (1.0 ± 0 µm) and against PC3 with IC50 value of (9.00 ± 0.028 µm). The molecular docking of compound 5 had been studied, and the results revealed that the newly designed 4-nitroimidazole combined with piperazine moiety derivatives bond to the hydrophobic pocket and polar contacts with high affinity.

Computational investigations of the binding mechanism of novel benzophenone imine inhibitors for the treatment of breast cancer.

4-Hydroxytamoxifen (4-OHT), the most common hormone used for the treatment of breast cancer, is a selective estrogen receptor modulator (SERM) inhibitor that acts as an antagonist in breast tissue and a partial agonist in the endometrium. However, the detailed molecular mechanism of 4-OHT structure modification has not been well investigated to date. Herein, molecular docking, molecular dynamics simulations and free energy calculations were performed to explore the mechanisms of the molecular interactions between newly designed benzophenone imines (BIs) and the three forms apo, antagonist and agonist of the human estrogen receptor hERα. The proposed inhibitors were designed by replacing the triarylethylene estrogenic scaffold found in 4-OHT with Schiff base triarylimine derivatives. The antiestrogen scaffold i.e. the O-alkyl side chain in 4-OHT was developed by incorporating an alanine amino acid side chain functionality into the triarylimine scaffold. Docking results reveal that the newly designed BIs bind to the hydrophobic open pocket of the apo and antagonist hERα conformations with higher affinity as compared to the natural and synthetic estrogen estradiol (E2) and 4-OHT. The analysis of the molecular dynamics simulation results based on six different systems of the best docked BI (5c) with hERα receptors demonstrates stable interactions, and the complex undergoes fewer conformational fluctuations in the open apo/antagonist hERα receptors as compared to the case of the closed agonist. In addition, the calculated binding free energies indicate that the main factor that contributes to the stabilization of the receptor-inhibitor complexes is hydrophobic interactions. This study suggests that the development of these Schiff base derivatives may be worth exploring for the preparation of new 4-OHT analogues.