Exploring The Antimicrobial Potential of Novel 1,2,4‒Triazole Conjugates with Pyrazole: Synthesis, Biological Activity and In Silico Docking.

In the present study, a new series of 1,2,4‒triazole linked pyrazole hybrids (5a‒5l) were synthesized from dimethyl amino pyrazole (1) in good yield by three-step reaction. The chemical structures of the resulted compounds were thoroughly elucidated using spectral analyses such as IR, 1H-NMR, 13C-NMR, mass spectra and elemental analysis. The target compounds were screened for their antimicrobial activities against the various standard pathogen strains, Gram‒(‒ve) (E. coli, P. aeruginosa, K. pneumoniae, A. baumannii), and Gram‒(+ve) (S. aureus,S. faecalis) microorganisms. According to the results obtained, in particular, compounds 5b, 5f, 5h and 5j was effective at inhibiting the antibacterial growth of all the bacteria's, having MIC values ranging 0.983‒14.862 mg/mL and compared to moxifloxacin (1.391‒22.01 mg mL-1). The most active compounds were chosen to interact with the DNA gyrase and topoisomerase-IV targets via molecular docking. These selected ligands interacted with PDB targets 2XCO, 1S16 and docked into the active site of amino acids Ala-269, Gly-413, Asn-405, Ser-1182, Thr-1185, His-1186, His-1186, Lys-1189, and Trp-1213. The pharmacokinetic properties, stability, and drug-likeness parameters of all target molecules were estimated using SwissADME and PkCSM protocols. The current study used in silico approaches combining e-pharmacophore modeling and structure-based molecular docking of targets to identify antimicrobial agents.

Design, synthesis and in silico molecular docking evaluation of novel 1,2,3-triazole derivatives as potent antimicrobial agents.

Chalcone and triazole scaffolds have demonstrated a crucial role in the advancement of science and technology. Due to their significance, research has proceeded on the design and development of novel benzooxepine connected to 1,2,3-triazolyl chalcone structures. The new chalcone derivatives produced by benzooxepine triazole methyl ketone 2 and different aromatic carbonyl compounds 3 are discussed in this paper. All prepared compounds have well-established structures to a variety of spectral approaches, including mass analysis, 1H NMR, 13C NMR, and IR. Among the tested compounds, hybrids 4c, 4d, 4i, and 4k exhibited exceptional antibacterial susceptibilities with MIC range of 3.59-10.30 µM against the tested S. aureus strain. Compounds 4c, 4d displayed superior antifungal activity against F. oxysporum with MIC 3.25, 4.89 µM, when compared to fluconazole (MIC = 3.83 µM) respectively. On the other hand, analogues 4d, 4f, and 4k demonstrated equivalent antitubercular action against H37Rv strain with MIC range of 2.16-4.90 µM. The capacity of ligand 4f to form a stable compound on the active site of CYP51 from M. tuberculosis (1EA1) was confirmed by docking studies using amino acids Leu321(A), Pro77(A), Phe83(A), Lys74(A), Tyr76(A), Ala73(A), Arg96(A), Thr80(A), Met79(A), His259(A), and Gln72(A). Additionally, the chalcone‒1,2,3‒triazole hybrids ADME (absorption, distribution, metabolism, and excretion), characteristics of molecules, estimations of toxicity, and bioactivity parameters were assessed.

New tetrazolopyrrolidine-1,2,3-triazole analogues as potent anticancer agents: design, synthesis and molecular docking studies.

1,2,3-Triazole and tetrazole derivatives bearing pyrrolidines are found to exhibit notable biological activity and have become useful scaffolds in medicinal chemistry for application in lead discovery and optimization. We report design, synthesis and molecular docking studies of tetrazolyl-1,2,3-triazole derivatives (7a-i) bearing pyrrolidine moiety and evaluating their anticancer activity against four cancer cell lines viz. Hela, MCF-7, HCT-116 and HepG2. The structures of the new compounds were ascertained by spectral means IR, NMR: 1H &13C and Mass spectrum. From the studies compounds7a and 7i exhibited significant anticancer activity against the Hela cell line with IC50 = 0.32 ± 1.00, 1.80 ± 0.22 µM when compared to reference drug Doxorubicin (IC50 = 2.34 ± 0.11 µM), whereas 7h, 7i, and 7b were found to be active against MCF-7, HCT-116 and HepG2 cell lines with IC50 = 3.20 ± 1.40, 1.38 ± 0.06 and 0.97 ± 0.12 µM respectively. Notably 7a exhibited highest conventional hydrogen bondings TyrA:40, SerA:17, LysA:117, AlaA:146, Tyr218 with 3HB4and SerA:17, LysA:117, AlaA:146, TyrA:40 with 6IBZ and docking energy - 10.85, - 8.21 kcal/mol respectively. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME. The results of the in vitro and in silico studies suggest that the tetrazole incorporated pyrrolidine-triazoles may possess the ideal structural requirements for further developing new anticancer agents.

Design, Synthesis, Molecular Docking, ADMET, and Biological Studies of Some Novel 1,2,3-Triazole Linked Tetrazoles as Anticancer Agents.

BACKGROUND: 1,2,3-Triazole-tetrazoles have received substantial attention because of their unique bioisosteric properties and an extraordinarily broad spectrum of biological activity, making them interesting for the drug design, and synthesis of a delightful class of widely investigated heterocyclic compounds. To address major health concerns, it is consequently important to devote ongoing effort to the identification and development of New Chemical Entities (NCEs) as possible anticancer medicines. METHODS: We began our initial investigation of the reaction between 5-(azidomethyl)-1H-pyrrolo[ 2,3-b]pyridine and 1-phenyl substituted-5-(prop-2-yn-1-ylthio)-1 H-tetrazole under click chemistry to give the corresponding triazole precursors and screened for their cytotoxicity reported by variations in therapeutic actions of the parent molecule. All of the prepared scaffolds were characterized by proton, carbon resonance spectroscopy, IR, and mass spectral techniques. RESULTS: When tested for in vitro antitumor activity the prepared compounds 7e, 7h had a significant anticancer activity against human adenocarcinoma Hs766T cell line with IC50 = 5.33, 4.92 µg/mL and Hs460 cell line with IC50 = 4.82, 6.15 µg/mL respectively. Final scaffolds 7f, 7h, and 7j acquire the highest potential drug binding scores ΔG = -10.42, -8.80, -9.37 Kcal/, with amino acids residues Ala A:11 (2.195 A˚), Asp A:119 (1.991 A˚), Thr A:58 (1.890 A˚), Lys A:16 (1.253 A˚), Asp A:38 (2.013 A˚), Lys A:117 (2.046 A˚) respectively and process Lipinski's rule of five as good agents for oral bioavailability. CONCLUSION: The molecular framework for the synthesis of novel Aza indole 1,2,3-triazole scaffolds coupled to tetrazole core was discovered in our study and evaluated for their anticancer activity.

Novel heterocyclic 1,3,4-oxadiazole derivatives of fluoroquinolones as a potent antibacterial agent: Synthesis and computational molecular modeling.

Design and synthesis of novel series of 1,3,4-oxadiazoles containing FQs derivatives and screened their antibacterial, antimycobacterial properties. The synthesized compounds were characterized by different spectral techniques like IR, 1H NMR, 13C NMR, mass and elemental analysis. The results of the antimicrobial activity and compounds 6d, 6b, 6e, 6f and 6a demonstrated potent antibacterial activities with zone of inhibition of 42, 36, 37, 34 and 30 mm against S. aureus, E. faecalis, S. pneumoniae, E. coli and K. pneumoniae, respectively. 1,3,4-Oxadiazole derivatives 6a, 6b, 6 g were showed excellent antimycobacterial activity against M. smegmatis H37Rv with MICs 22.35, 16.20, 20.28 µg/mL, respectively. FQs 6d and 6b exhibited highest hydrogen bonding interactions with Asp83 (3.11 A˚), Ser80 (2.15 A˚) Asp27 (σ-σ), Arg87 (Π-Π), Arg87 (Π-Π), Ser80 (σ-σ), Ala84 (σ-σ) and binding energies ΔG = - 6.41, - 6.97 kcal/mol with active site of topoisomerase-IV from S. pneumoniae [4KPE]. We performed a computational investigation of compounds 6a-j for their absorption, distribution, metabolism and excretion (ADME) properties by using the Molinspiration, Molsoft toolkits. The ligands 6f, 6d and 6b reveal the highest pharmacokinetic properties and possess maximum drug-likeness model score 1.59, 1.46 and 1.23, respectively.

Design, Synthesis and Biological Evaluation of Novel Heterocyclic Fluoroquinolone Citrate Conjugates as Potential Inhibitors of Topoisomerase IV: A Computational Molecular Modeling Study.

BACKGROUND & OBJECTIVE: A facile and efficient method for the synthesis of novel derivatives of FQ citrate conjugates with 1,2,4-triazoles and 1,3,4-oxadiazole scaffolds 8-11 using conventional, as well as microwave irradiation methods, was reported. Based on these original building blocks, the new derivatives of 3, 7-disubstituted fluoroquinolones bearing the oxadiazolyl-triazole groups were obtained. These invaluable derivatives are of great interest in medicinal and pharmaceutical studies because of their important biological properties. METHODS: All the reactions were examined under conventional as well as microwave mediated conditions. The structures of obtained compounds were confirmed by 1H NMR, 13C NMR, IR HRMS spectroscopy, and elemental analysis. The antibacterial and antifungal activities of these compounds were screened against Gram-positive, Gram-negative bacteria, and fungal stains by the agar well diffusion method. Cytotoxic assay of the title compounds was evaluated against cervical carcinoma cell line (HeLa) by using the MTT assay. The crystal structure of the Quinolone-DNA cleavage complex of type IV topoisomerase from S. pneumoniae (PDB ID: 3RAE) complex was obtained from the Protein Database (PDB, http:// www.rcsb.org). Molecular properties prediction-drug likeness was studied by Molinspiration and Molsoft software, while lipophilicity and solubility parameters were studied using the Osiris program. RESULTS: A novel approach for the synthesis of benzylthio-1,2,4-triazole and 1,3,4-oxadiazoles core with regioisomeric norfloxacin citrate conjugates was developed. Among the title compounds, 11b, 10a reveal pronounced activity against S. pneumoniae with minimum inhibitory concentrations of 0.89, 0.96 mg/mL and MBCs of 2.95, 2.80 mg/mL, respectively. Minimum Fungicidal Concentration (MFC) has been determined for each compound against two fungal strains. Compound 11b showed maximum anti-cancer activity against HeLa cell line with IC50 value 11.3 ± 0.41 comparable to standard drug DXN. For binding mode, active site residues and docking energies (ΔG =-7.9 Kcal/mol) for ligand 9b exhibited the highest hydrogen bonding (3.59274 A˚), Pi- Alkyl (5.14468 A˚) interactions with amino acid LEU479 of 3RAE protein. The compounds following the Lipinski 'Rule of five' were synthesized for antimicrobial and anti-cancer screening as oral bioavailable drugs/leads. Maximum drug likeness model score 1.52, 1.41 was found for compounds 10d, 11b. CONCLUSION: The present work, through simple synthetic approaches, led to the development of novel hybrids of fluoroquinolone containing citrate-triazole-oxadiazole pharmacophores that exhibited remarkable biological activities against different microorganisms and cell lines. The compounds showed suitable druglike properties and are expected to present good bioavailability profile. An efficient combination of molecular modeling and biological activity provided an insight into QSAR guidelines that could aid in further development and optimization of the norfloxacin derivatives.

Molecular Modeling Studies of Novel Fluoroquinolone Molecules.

BACKGROUND: Fluoroquinolones have been the centre of considerable scientific and clinical interest due to their broad spectrum pharmacological activities. Pefloxacin is an analogue of norfloxacin, which is a 3rd generation of fluoroquinolone antibiotic similar to ciprofloxacin. Pefloxacin is used to treat a variety of bacterial infections like respiratory tract, ear, nose and throat (ENT) infections, skin infections, and urinary tract infections. Hydrazone as a pharmacophore unit that attracts the medicinal chemists because of structure activity relationship (SAR) studies of fluoroquinolones especially the functionality at C-3 position. Consequently, recognition and development of potential ligands specifically for a protein target forms the primary goal in drug discovery process. Among the different theoretical approaches available, Gold and Glide are the molecular docking methods which find application protein ligand studies. In the current study, the DNA gyrase of Staphylococcus aureus has been used as the target protein to understand their possible interactions. METHODS: The crystal structure of DNA gyrase (topoisomerase II) was downloaded from the Protein Data Bank (PDB ID: 2XCS, 3FOE) and molecular docking studies were performed using the docking programs like Gold 3.2 (Genetic Algorithm for Ligand Docking), Glide 5.0 (Grid Based Ligand Docking with Energetic). Melting points were uncorrected and determined in open capillary tubes in a melting point apparatus. TLC was performed on silica gel-G and spotting was done using iodine/ KMnO4 staining or UV-light. The following experimental procedures are representive of the general procedures used to synthesize all compounds. RESULTS: The docking experiments of the title compounds with 2.1 Å crystal structure of DNA gyrase 2XCS, 3FOE using Gold 3.2 and Glide 5.0 is carried out to understand the binding interactions of the novel ligands with the protein, contributing for antibacterial activity. The compounds in general exhibited good binding interactions like H-bonding interaction and π-π interactions which stabilize the protein-ligand complexes and responsible for good fitness scores in both the protocols. CONCLUSION: In summary, a new series of novel pefloxacin hydrazones 5a-5n were studied for their interactions with Staphylococcus aureus DNA gyrase protein by Glide 5.0 and Gold 3.2 molecular docking protocols [PDB IDS: 2XCS, 3FOE]. Among the tested molecules, compound 5g exhibited a good Glide score value of - 7.73 and Glide energy -51.24 with emodel value of -66.16. The nice docking scores of 5g, 5a, 8h, 5m and 5b revealed that these compounds are well accommodated on the active site residues of DNA gyrase enzyme. From the docking study, we have explored the probable binding mode and the binding pattern of compounds 5f, 5l, 5h, 5d, and 5n showed that they strongly interact with in the active site of Staphylococcus aureus of DNA gyrase enzyme. From screening results it is found that compounds having aromatic ring substituted with electron releasing groups are showing potent docking scores and exhibited better fitness than reference compounds CPF and CA4. An efficient combination of molecular modeling and biological activity provided an insight into QSAR guide lines that could aid in further development and optimization of the pefloxacin derivatives.

Synthesis, molecular properties prediction and anticancer, antioxidant evaluation of new edaravone derivatives.

A series of new edaravone derivatives 3-7 have been synthesized, characterised using various spectroscopic techniques and screened for their in vitro anti-cancer, antioxidant activities. Structure of 5d was further substantiated through single crystal X-ray diffraction. Among the tested, 5l exhibited pronounced activity against PC3 cancer cells. Compounds 5i, 5l, 7c showed potent activity against A549 cancer cells. Products 5k, 6, 7c demonstrated good antioxidant activity with MIC values of 18.60, 16.27, 16.07µg/mL respectively. Further the reported analogues were also tested on normal HEK293T cells and displayed low to good safer profiles. Derivatives 5l and 7c have come out to be safer potent anticancer, antioxidant agents. Additionally, the target products were subjected to their molecular properties prediction and drug likeness by employing Molinspiration and Osiris property explorer toolkits. None of them violated Lipinski's boundaries classifying the title compounds as potential anticancer and antioxidant agents.