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In this study, we mainly focused on some in vitro biological activities of a series of (5 or 6)-amino-2- (substituted phenyl and benzyl) benzoxazole derivatives. For this purpose, we tested cytotoxic and genotoxic activities of them on cancer cell lines and their topoisomerase inhibitory activities. We also tested their cytotoxic and genotoxic activities on non-cancerous cells (L929) and their mutagenic activities by Ames test to evaluate their effects on healthy cells. Only TD5 was found cytotoxic on all the tested cancer cell lines and did not exhibit either cytotoxic or genotoxic activities against healthy cells, whereas TD1, TD2, TD3 and TD7 were more cytotoxic against only HeLa cells. Only TD4 was found as mutagenic derivative. None of the compounds had any topoisomerase inhibitory activities nevertheless some of them caused inhibition of topoisomerase II activity. Additionally, we used an in silico model to predict the drug-like properties of them to evaluate their bioavailability to the QikProp Properties Predictions. All the calculated properties were found in a permissible range. According to the data obtained from biological activity studies, it can be concluded that the methylene bridge at the position 2 of benzoxazole ring decreases cytotoxic activity on cancer cells and inhibitory activity on DNA topoisomerases., (Copyright © 2022. Published by Elsevier Inc.)

DNA gyrase is an essential DNA topoisomerase that exists only in bacteria. Since novobiocin was withdrawn from the market, new scaffolds and new mechanistic GyrB inhibitors are urgently needed. In this study, we employed fragment screening and X-ray crystallography to identify new building blocks, as well as their binding mechanisms, to support the discovery of new GyrB inhibitors. In total, 84 of the 618 chemical fragments were shown to either thermally stabilize the ATPase domain of Escherichia coli GyrB or inhibit the ATPase activity of E. coli gyrase. Among them, the IC 50 values of fragments 10 and 23 were determined to be 605.3 μM and 446.2 μM, respectively. Cocrystal structures of the GyrB ATPase domain with twelve fragment hits were successfully determined at a high resolution. All twelve fragments were deeply inserted in the pocket and formed H-bonds with Asp73 and Thr165, and six fragments formed an additional H-bond with the backbone oxygen of Val71. Fragment screening further highlighted the capability of Asp73, Thr165 and Val71 to bind chemicals and provided diverse building blocks for the design of GyrB inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

S. aureus resistant to methicillin (MRSA) is one of the most-concerned multidrug resistant bacteria, due to its role in life-threatening infections. There is an urgent need to develop new antibiotics against MRSA. In this study, we firstly compiled a data set of 2,3-diaminoquinoxalines by chemical synthesis and antibacterial screening against S. aureus, and then performed cheminformatics modeling and virtual screening. The compound with the Specs ID of AG-205/33156020 was discovered as a new antibacterial agent, and was further identified as a Gyrase B (GyrB) inhibitor. In light of the common features, we hypothesized that the 6c as the representative of 2,3-diaminoquinoxalines also inhibited GyrB and eventually proved it. Via molecular docking and molecular dynamics simulations, we identified binding modes of AG-205/33156020 and 6c to the ATPase domain of GyrB. Importantly, these GyrB inhibitors inhibited the MRSA strains and showed selectivity to HepG2 and HUVEC. Taken together, this research work provides an effective ligand-based computational workflow for scaffold hopping in anti-MRSA drug discovery, and discovers two new GyrB inhibitors that are worthy of further development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Newly designed levofloxacin analogues were synthesized to act as topoisomerase II beta inhibitors (Topo2β). Their cytotoxic activity was screened against breast, liver, and leukemia cancer cell lines. The best activity against liver cancer cell line (Hep3B) was exhibited by the target compounds 3c, 3e, 4a, and 6d (IC 50  = 2.33, 1.38, 0.60 and 0.43, respectively). (L-SR) leukemia cancer cell line was pronouncedly affected by compounds 3b, 3g and 4a (IC 50  = 1.62, 1.41 and 1.61, sequentially). 3c possessed the best activity against breast cancer cell line (MCF-7) with IC 50  = 0.66. Compounds 3c, 3e, 3g, 4a and 4c exhibited Topo2β inhibition activities exceeding etoposide and levofloxacin as reference drugs and variant cell lines. In DNA-Flow cytometry cell cycle analysis, compound 3c arrested the cell cycle at G2/M phase like etoposide and levofloxacin, while compounds 3e and 4a exhibit its arrest at S phase. In addition, 3c, 3e and 4a showed a significant elevation in active caspase-3 levels (10.01, 8.98 and 10.71 folds, respectively). The effect of the new compounds on normal cells was also investigated including breast (MCF10a), liver (THLE2), and lymphocytic (PCS-800-011) normal cell lines., (Copyright © 2021. Published by Elsevier Inc.)

Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC 50 ranging from 5.44 to 8.90 µM, while compounds 27 and 32a were found to be the most potent DNA binders at IC 50 values of 36.02 and 48.30 µM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Etoposide (ETS), topoisomerase-II inhibitor, is a first-line anticancer therapeutics used in diverse cancer types. However, the therapeutic potential of this molecule has mainly impeded due to its detrimental toxicity profile, unfavorable rejection by the cancer cells due to P-glycoprotein (P-gp) efflux activity, and rapid hepatic clearance through extensive metabolism by Cytochrome-P450. To increase the therapeutic potency without significant adverse effects, the implication of novel ETS-nanoformulation strategies have recommended mainly. Nanomedicine based nanoformulation approaches based on nanoparticles (NPs), dendrimers, carbon-nanotubes (CNTs), liposomes, polymeric micelles, emulsions, dendrimers, solid-lipid NPs, etc offers immense potential opportunities to improve the therapeutic potential of pharmaceutically problematic drugs. This review provides an up-to-date argument on the work done in the field of nanomedicine to resolve pharmacokinetic and pharmacodynamic issues associated with ETS. The review also expounds the progress in regards to the regulatory, patenting and clinical trials related to the innovative formulation aspects of ETS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The antibacterial agents and therapies today are facing serious problems such as drug resistance. Introducing dual inhibiting effect is a valid approach to solve this trouble and bring advantages including wide adaptability, favorable safety and superiority of combination. We started from potential DNA Gyrase inhibitory backbone isatin to develop oxoindolin derivatives as atypical dual Gyrase (major) and FabH (assistant) inhibitors via a two-round screening. Aiming at blocking both duplication (Gyrase) and survival (FabH), most of synthesized compounds indicated potency against Gyrase and some of them inferred favorable inhibitory effect on FabH. The top hit I18 suggested comparable Gyrase inhibitory activity (IC 50  = 0.025 μM) and antibacterial effect with the positive control Novobiocin (IC 50  = 0.040 μM). FabH inhibitory activity (IC 50  = 5.20 μM) was also successfully introduced. Docking simulation hinted possible important interacted residues and binding patterns for both target proteins. Adequate Structure-Activity Relation discussions provide the future orientations of modification. With high potency, low initial toxicity and dual inhibiting strategy, advanced compounds with therapeutic methods will be developed for clinical application., (Copyright © 2019 Elsevier Inc. All rights reserved.)

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC 50  ≤ 1 μM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 μM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC 50  = 7.54 μM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of new 1,2,4-triazole and 1,3,4-oxadiazole derivatives was obtained via several steps sequential reactions of phenyl piperazine. Then, these compounds were converted to the corresponding fluoroquinolone hybrids via one pot three component Mannich reaction. All the reactions were examined under conventional and microwave mediated conditions, and optimum conditions were determined. The effect of different solvents and microwave power on microwave prompted reactions was investigated as well. All the newly synthesized compounds were characterized by FTIR, 1 H NMR, 13 C NMR and EI MS spectral techniques. The antimicrobial activity, DNA gyrase and Topoisomerase IV inhibition potentials were performed. The results obtained showed that fluoroquinolone hybrids possess good antimicrobial activity. Moreover, Fluoroquinolone-azole-piperazine hybrids synthesized in the present study displayed excellent DNA gyrase inhibition. To unveil the interaction mode of compounds to receptor, a molecular docking study was performed. With an average least binding energy of -9.5 kcal/mol, all compounds were found to have remarkable inhibitory potentials against DNA gyrase (E. coli)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Human DNA topoisomerases (topos) have been recognized as a good target molecule for the development of anticancer drugs because they play an important role in solving DNA topological problems caused by DNA strand separation during replication and transcription. In this study, we designed and synthesized 11 novel chromone backbone compounds possessing epoxy and halohydrin substituents with chirality. In the topos inhibition test, compounds 2, 9, 10, and 11 showed comparable topo I inhibitory activity at concentration of 100 μM compared to camptothecin, and all of the synthesized compounds showed moderate topo IIα inhibitory activity. Among them, compounds 9, 10 and 11 were more potent than the others in both topo I and IIα inhibitory activity. Compound 11 showed the most potent cell antiproliferative activity against all tested cancer cell lines with particularly strong inhibition (an IC 50 of 0.04 µM) of K562 myelogenous leukemia cancer cell proliferation. In the brief structure-activity relationship analysis, there was no clear correlation between stereochemistry and topos inhibitory and cytotoxic activity. 5(R),7(S)-bisepoxy-substituted compound 11 was the most potent DNA cross-linker and induced G2/M arrest in a cell cycle assay in a dose- and time-dependent manner. After the treatment time period induced apoptosis in K562 cells without increasing G2/M-phase cells. Overall, compound 11 showed good consistent inhibitory biological activity related to cancer cell proliferation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: Design and synthesis of novel nalidixic acid derivatives of potent anticancer and topoisomerase II inhibitory activities were our major aim., Materials & Methods: All the newly synthesized nalidixic acid derivatives were submitted to the National Cancer Institute (NCI), Bethesda, USA and were accepted for single dose screening. Further investigation via IC 50 determination of the most potent compound 6a against K-562 and SR leukemia cell lines. Finally, the topoisomerase II inhibitory activity, the cell cycle analysis and molecular docking of 6a were performed in order to identify the possible mechanism of the anticancer activity., Results: Compound 6a showed interesting selectivity against leukemia especially K-562 and SR subpanels with IC 50 35.29 µM and 13.85 µM respectively. Moreover, compound 6a revealed potent topoisomerase IIα and topoisomerase IIβ inhibitory activity compared with known topoisomerase inhibitors such as doxorubicin and topotecan with IC 50 1.30 µM and 0.017 µM respectively. Cell cycle analysis indicated that compound 6a induced cell cycle arrest at G2-M phase leading to inhibition of cell proliferation and apoptosis. Molecular modeling demonstrated that the potent topoisomerase inhibitory activity of 6a was due to the interaction with the topoisomerase II enzyme through coordinate bonding with the magnesium ion Mg 2+ , hydrogen bonding with Asp 545 and arene cation interaction with His 759., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Doxorubicin (DOX) is a chemotherapeutic agent of which the medical use is limited due to cardiotoxicity. While acute cardiotoxicity is reversible, chronic cardiotoxicity is persistent or progressive, dose-dependent and irreversible. While DOX mechanisms of action are not fully understood yet, 3 toxicity processes are known to occur in vivo: cardiomyocyte dysfunction, mitochondrial dysfunction and cell death. We present an in vitro experimental design aimed at detecting DOX-induced cardiotoxicity by obtaining a global view of the induced molecular mechanisms through RNA-sequencing. To better reflect the in vivo situation, human 3D cardiac microtissues were exposed to physiologically-based pharmacokinetic (PBPK) relevant doses of DOX for 2 weeks. We analysed a therapeutic and a toxic dosing profile. Transcriptomics analysis revealed significant gene expression changes in pathways related to "striated muscle contraction" and "respiratory electron transport", thus suggesting mitochondrial dysfunction as an underlying mechanism for cardiotoxicity. Furthermore, expression changes in mitochondrial processes differed significantly between the doses. Therapeutic dose reflects processes resembling the phenotype of delayed chronic cardiotoxicity, while toxic doses resembled acute cardiotoxicity. Overall, these results demonstrate the capability of our innovative in vitro approach to detect the three known mechanisms of DOX leading to toxicity, thus suggesting its potential relevance for reflecting the patient situation. Our study also demonstrated the importance of applying physiologically relevant doses during toxicological research, since mechanisms of acute and chronic toxicity differ., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The solid inclusion complex of gemifloxacin (GFX) and hydroxyl propyl β-cyclodextrin (HPβ-CD) was prepared and examined by UV-visible, FTIR, NMR, electrospray ionization mass spectrometry (ESI-MS) and fluorescence spectroscopy. The formation of inclusion complex has been confirmed on the basis of changes of spectroscopic properties. Further the interaction between GFX and HPβ-CD was studied using molecular modeling approaches. The results showed that HPβCD reacted with GFX to form a 1:1 host-guest inclusion complex. Based on the enhancement of the fluorescence intensity of GFX produced through complex formation, a simple, accurate, rapid and highly sensitive spectrofluorometric method for the determination of GFX in pharmaceutical formulation was developed. The linear relationships between the intensity and GFX concentration was obtained in the concentration range of 20-140 ng/mL with good correlation coefficients (0.9997). The limit of detection (LOD) was found to be 4 ng/mL. The proposed method was successfully applied to the analysis of GFX in pharmaceutical preparation., (Copyright © 2015 Elsevier B.V. All rights reserved.)