(E)-N′-(Substituted-benzylidene)-2-(7-fluoro-2-methoxyquinolin-8-yl)acetohydrazide-hydrazone derivatives9a–nrepresent a new series of antibacterial agents and DNA gyrase inhibitors.

Rajasekhara Reddy Sabbasani

Department of Chemistry

School of Advanced Sciences

Vellore Campus

Sridhar P

Alagumuthu M

Arumugam S

Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

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VIT University

RSC Advances

Developing a new antibacterial drug by using (Z/E)-4-(4-substituted-benzylidene)-2-isoquinoline-1,3(2H,4H)-diones (5a–h) via DNA gyrase inhibition mechanism is the main aim of this study. DNA gyrase inhibition assay was executed to confirm the DNA gyrase inhibition potentials of 5a–h. DNA gyrase inhibitory potentials were further validated through molecular docking. Docking study was also intended to get more insight into the binding mode of 5a–h into the active site of DNA gyrase A. Agar well diffusion method antimicrobial activity on Gram −ve bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram +ve bacteria (Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent DNA gyrase inhibition was exhibited by the compound 5c, IC 50 0.55±0.12 μM; 5d, IC 50 0.65±0.075 μg/mL; 5e, IC 50 0.45±0.035 μM; 5f, IC 50 0.58±0.025 μM; 5h, IC 50 0.25±0.015 μM while Clorobiocin (standard) showed IC 50 0.5±0.05 μM. Apart from all the in vitro studies, a plausible mechanism of DNA gyrase inhibition was also proposed through the in silico validations that are including molecular docking, predicted SAR, functional group availability, pharmacokinetic, and ADMET properties. These predictions are well supported to confirm the druggability possibility of the most potent compounds among (Z/E)-4-(4-substituted-benzylidene)-2-isoquinoline-1,3(2H,4H) -diones (5a–h). © 2018 Wiley-VCH Verlag GmbH &amp; Co. KGaA, Weinheim

Molecular Informatics

Computational Approaches to Develop Isoquinoline Based Antibiotics through DNA Gyrase Inhibition Mechanisms Unveiled through Antibacterial Evaluation and Molecular Docking

Journal of Heterocyclic Chemistry

Synthesis and Molecular Drug Efficacy of Indoline-based Dihydroxy-thiocarbamides: Inflammation Regulatory Property Unveiled over COX-2 Inhibition, Molecular Docking, and Cytotoxicity Prospects

Bioorganic & Medicinal Chemistry

Drug efficacy of novel 3-O-methoxy-4-halo disubstituted 5,7-dimethoxy chromans; evaluated via DNA gyrase inhibition, bacterial cell wall lesion and antibacterial prospective

Relatively high molecular weight S-BINOLs with substituted functional groups were synthesized, and structures were elucidated by FTIR, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and HRMS. As a preliminary step, the compounds were docked into the active site of phosphoinositide3-kinase (PI3Kinase) (Protein Data Bank ID: 2IUG) that is a crucial regulator of apoptosis or programmed cell death. To ensure the PI3Kinase inhibition, because it was predicted as the most suitable bioactivity of these compounds, a competitive ELISA PI3Kinase inhibition study was carried out. Compounds 3, 4a, 4b, and 6 were assessed for cytotoxicity/antiproliferative effects on MCF-7 (breast cancer) and HCT116 (colon cancer) cell lines. In the docking studies, excellent binding affinities of 3, 4a, 4b, and 6 (−11.36, −14.52, −14.86, and −21.76 kcal/mol, respectively) and the inhibitory constants (ki) (4.75 nM, 81.64 pM, 78.23 pM, and 14.24 pM, respectively) encouraged us to carry out anticancer studies further. Excellent inhibitory values were obtained in the range of 82–90% relative activity and IC50 range of 5–12 nM. In the cytotoxicity, the relative inhibition activity was remarkably found high in MCF-7 cell lines as 89.14% (6), 82.18% (4b), 80.46% (3), and 74.78% (4a) with the IC50 range of 0.02–0.18 μM. No compounds were found inactive for the proposed activity in this study. The Structure Activity Relationship studies prove that compounds 3, 4a, 4b, and 6 are specific PI3Kinase inhibitors with the competence to cure breast cancers. © 2018 Wiley Periodicals, Inc.

Molecular Substantiation and Drug Efficacy of Relatively High Molecular Weight S-BINOLs; Appraised as Breast Cancer Medication and PI3Kinase Inhibitors

Novel QuinolineAcetohydrazide (QAh) derivatives (9a-n) were firstly evaluated in silico to determine their anti-inflammatory and anti-cancer efficacy via the mechanisms of COX1 and COX2 inhibition, and NF-ĸB, HDAC and Human Topoisomerase I pathways respectively. In the studied set, the trifluoro substituted QAh derivatives: (E)-N'-(4-(trifluoro methyl) benzylidene)-2-(7-fluoro-2-methoxy quinolin-8-yl) acetohydrazid and (E)-N'-(3-(trifluoro methyl) benzylidene)-2-(7-fluoro-2-methoxy quinolin-8-yl) acetohydrazide are determined to be potential leads, indicated from their best docked scores, relative ligand efficiency, and significant structural attributes evaluated by ab initio simulations. The only setback being their partition co-efficient that retrieved a red flag in the evaluation of their Lipinski parameters. The experimental in vitro studies confirmed the significant enhancement as COX-2 inhibitors and appreciable enhancement in MTT assay of breast and skin cancer cell lines. Significantly, trifluoro substituent in the quinoline scaffold can be reasoned to note the excellent binding affinity to all the evaluated drug targets. © 2017 Elsevier B.V.

Journal of Molecular Structure

Drug repurposing of novel quinoline acetohydrazide derivatives as potent COX-2 inhibitors and anti-cancer agents

Herein we report the synthesis of new hydrophobic <a href="https://www.sciencedirect.com/topics/chemistry/ionic-liquid">ionic liquid</a> by simple manipulations starting from d-galactose. The synthesized ionic liquid 1-methyl-3-(((3aS,5S,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:4′,5′-d]pyran-5-yl)methyl)-1H-imidazol-3-ium hexafluorophosphate(V) (IL 5) was completely characterized by sophisticated analytical techniques. IL 5 was investigated as adsorbent for the sequestration of Pb2&nbsp;+ ions from <a href="https://www.sciencedirect.com/topics/physics-and-astronomy/aqueous-solutions">aqueous solution</a> and this is proved as its potential application. Batch mode studies were done, by varying the batch parameters such as pH, IL dose, contact time, initial <a href="https://www.sciencedirect.com/topics/chemistry/metal-ion">metal ion</a> concentration and temperature. Various mathematical models such as kinetic models and isotherms were employed to understand the mechanism of sequestration. Thermodynamic investigations suggest that the sequestration of Pb2&nbsp;+ ions is spontaneous and exothermic in nature. The maximum loading capacity of IL 5 was found to be 374.9&nbsp;mg&nbsp;g−&nbsp;1. Desorption and regeneration analysis revealed the repeated use of IL 5 in industrial processes. These results suggest that IL 5 is a potential <a href="https://www.sciencedirect.com/topics/chemistry/sorbent">sorbent</a> for the elimination of Pb2&nbsp;+ ions from aqueous solution.

Journal of Molecular Liquids

Hydrophobic d-galactose based ionic liquid for the sequestration of Pb2+ ions from aqueous solution

White spot syndrome virus (WSSV), an aquatic virus infecting shrimps and other crustaceans, is widely distributed in Asian subcontinents including India. The infection has led to a serious economic loss in shrimp farming. The WSSV genome is approximately 300 kb and codes for several proteins mediating the infection. The envelope proteins VP26 and VP28 play a major role in infection process and also in the interaction with the host cells. A comprehensive study on the viral proteins leading to the development of safe and potent antiviral therapeutic is of adverse need. The novel synthesized compound 3-(1-chloropiperidin-4-yl)-6-fluoro benzisoxazole 2 is proved to have potent antiviral activity against WSSV. The compound antiviral activity is validated in freshwater crabs (Paratelphusa hydrodomous). An in silico molecular docking and simulation analysis of the envelope proteins VP26 and VP28 with the ligand 3-(1-chloropiperidin-4-yl)-6-fluoro benzisoxazole 2 are carried out. The docking analysis reveals that the polar amino acids in the pore region of the envelope proteins were involved in the ligand binding. The influence of the ligand binding on the proteins is validated by the molecular dynamics and simulation study. These in silico approaches together demonstrate the ligand's efficiency in preventing the trimers from exhibiting their physiological function. © 2016 John Wiley & Sons Ltd.

Journal of Fish Diseases

Molecular docking and simulation studies of 3-(1-chloropiperidin-4-yl)-6-fluoro benzisoxazole 2 against VP26 and VP28 proteins of white spot syndrome virus

Synthesis of quinoline acetohydrazide-hydrazone derivatives evaluated as DNA gyrase inhibitors and potent antimicrobial agents

A new class of d-xylose derived imidazolium-based chiral ionic liquids were designed and synthesized via simple tuning approaches.

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