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Abstract

Quinolones represent an important class of broad-spectrum antibacterials, the main structural features of which are a 1,4 dihydro-4-oxo-quinolinyl moiety bearing an essential carboxyl group at position 3. Quinolones inhibit prokaryotic type II topoisomerases, namely DNA gyrase and, in a few cases, topoisomerase IV, through direct binding to the bacterial chromosome. Based on the hypothesis that these drugs could also bind to the viral nucleic acids or nucleoprotein-complexes, several quinolone derivatives were tested for their antiviral activity. Indeed, antibacterial fluoroquinolones were shown to be effective against vaccinia virus and papovaviruses; these preliminary results prompted the synthesis of modified quinolones to optimize antiviral action and improve selectivity index. The introduction of an aryl group at the piperazine moiety of the fluoroquinolone shifted the activity from antibacterial to antiviral, with a specific action against HIV. The antiviral activity seemed to be related to an inhibitory effect at the transcriptional level, and further evidence suggested a mechanism of action mediated by inhibition of Tat functions. Substitution of the fluorine at position 6 with an amine group to give aryl-piperazinyl-6-amino-quinolones improved the activity and selectivity against HIV-1: the most potent compound of this series was shown to inhibit virus replication through interference with Tat-TAR interaction. A comprehensive SAR investigation was performed based on additional chemical intervention to the quinolone template moiety, such as the introduction of nucleoside derivative functions. The information gained so far will be useful for future rational drug design aimed at developing new compounds with optimized antiviral activity.
... The switch between diphenol (hydroquinone) and diketone (quinone) occurs easily through oxido-reduction reactions. Quinones irreversibly bind with nucleophilic amino acids leading to the loss of protein functions, inhibit host-virus attachment and some viral enzymes 24 . The dianthroquinone hypericin inhibit retrovirus RTase, while chrysosplenol C inhibit picornavirus and rhinoviruses; but chrysophanol C and chrysophanic acid inhibits poliovirus replication 16,24 . ...
... Quinones irreversibly bind with nucleophilic amino acids leading to the loss of protein functions, inhibit host-virus attachment and some viral enzymes 24 . The dianthroquinone hypericin inhibit retrovirus RTase, while chrysosplenol C inhibit picornavirus and rhinoviruses; but chrysophanol C and chrysophanic acid inhibits poliovirus replication 16,24 . The introduction of an aryl group at the piperazine moiety of fluoroquinolone increases its activity; while substitution of fluorine with an amine group yielded aryl-piperazinyl-6-aminoquinolones that inhibit HIV-1 replication 24 . ...
... The dianthroquinone hypericin inhibit retrovirus RTase, while chrysosplenol C inhibit picornavirus and rhinoviruses; but chrysophanol C and chrysophanic acid inhibits poliovirus replication 16,24 . The introduction of an aryl group at the piperazine moiety of fluoroquinolone increases its activity; while substitution of fluorine with an amine group yielded aryl-piperazinyl-6-aminoquinolones that inhibit HIV-1 replication 24 . This relationship may be useful for rational drug design with optimized antiviral activity. ...
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Ethnomedicinal plants have been used as source of drugs for almost all diseases, but none are used against viruses probably because there are a very few specific viral targets for natural molecules to interact. Most of the available antiviral drugs often lead to side effects, viral resistance, recurrence and latency. A wide range of ethnomedicinal plants showed strong antiviral activities either by inhibiting replication, or genome synthesis of many viruses. Hence, development of new antivirals from natural source is an alternate approach. This review will discuss some of the promising antivirals of ethnomedicinal plants with proven in vitro and some documented in vivo activities. People of all continents have long used poultices and infusions of indigenous plants like cedar wood and cypress oil, juice of licorice, myrrh and poppy for the treatment of coughs and colds to parasitic infections and inflammation 1. The clinical virologists are looking into the antiviral plant extracts as (i) the effective life span of antiviral drug is limited; (ii) many viral diseases are intractable to most of the orthodox antivirals, (iii) development of viral resistance, latency and recurrence, and (iv) rapid spread of emerging and reemerging viral diseases like HIV/AIDS, SARS etc. All these spurred intensive investigation into the ethnomedicines, especially for people unable to afford expensive antivirals, and the impressive array of knowledge and wisdom of indigenous people about their generation old medicaments for the development of new or complementary antivirals.
... Fluoroquinolones are chemical derivatives of quinoline, the prodrome of chloroquine (6). Indeed, quinoline and quinolone based compounds are being investigated for their antiviral activity against various viruses such as Ebola and Dengue virus (7). ...
... Indeed, quinoline and quinolone based compounds are being investigated for their antiviral activity against various viruses such as Ebola and Dengue virus (7). Interestingly, fluoroquinolones have also been shown to exert antiviral actions against vaccinia virus, papovavirus, human cytomegalovirus, varicella-zoster virus, herpes simplex virus types 1 and 2, hepatitis C virus and HIV (6,8,9). A recent in silico study demonstrated that the fluoroquinolones, ciprofloxacin and moxifloxacin, exert strong capacity for binding to SARS-CoV-2 main protease (M pro ), indicating that fluoroquinolones may inhibit SARS-CoV-2 replication (10). ...
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Since the beginning of the COVID-19 pandemic, researchers have focused on repurposing of existing antibiotics, antivirals and anti-inflammatory drugs to find an effective therapy. Fluoroquinolones are broad spectrum synthetic antimicrobial agents, being chemical derivatives of quinoline, the prodrome of chloroquine. Interestingly, fluoroquinolones may exert antiviral actions against vaccinia virus, papovavirus, CMV, VZV, HSV-1, HSV-2, HCV and HIV. A recent in silico study has shown that the fluoroquinolones, ciprofloxacin and moxifloxacin, may inhibit viral replication by exhibiting stronger capacity for binding to SARS-CoV-2 main protease than chloroquine and nelfinavir, a protease inhibitor antiretroviral drug. Remarkably, fluoroquinolones have shown multiple immunomodulatory actions leading to an attenuation of the inflammatory response through the inhibition of pro-inflammatory cytokines. Noteworthy, respiratory fluoroquinolones, levofloxacin and moxifloxacin, constitute first line therapeutic agents for the management of severe community-acquired pneumonia. They are characterized by advantageous pharmacokinetic properties; higher concentrations in the lungs; and an excellent safety profile comparable to other antibiotics used to treat respiratory infections, such as macrolides and b-lactams. Based on their potential antiviral activity and immunomodulatory properties, the favorable pharmacokinetics and safety profile, we propose the use of respiratory fluoroquinolones as adjuncts in the treatment of SARS-CoV-2 associated pneumonia.
... Since boronic acids can form stable complexes with saccharides, compounds in which boronic acids were added to quinolones, were designed (87)(88)(89)(90)(91)(92) with the purpose of disrupting the binding of the virus to glycans in host cells [74]. The boronic acid moiety was introduced in quinolones because these derivatives are known to interact with DNA and also to have anti-viral activities [74,75]. This study suggests that the boronic acid is important to interfere with the importation of ribonucleoprotein (RNP) of IAV, complexes that are important for DNA replication of this virus, and delay the virus access into the nucleus of host cells. ...
Article
Boron containing compounds have not been widely studied in Medicinal Chemistry, mainly due to the idea that this group could confer some toxicity. Nowadays, this concept has been demystified and, especially after the discovery of the drug bortezomib, the interest for these compounds, mainly boronic acids, has been growing. In this review, several activities of boronic acids, such as anticancer, antibacterial, antiviral activity, and even their application as sensors and delivery systems are addressed. The synthetic processes used to obtain these active compounds are also referred. Noteworthy, the molecular modification by the introduction of boronic acid group to bioactive molecules has shown to modify selectivity, physicochemical, and pharmacokinetic characteristics, with the improvement of the already existing activities. Besides, the preparation of compounds with this chemical group is relatively simple and well known. Taking into consideration these findings, this review reinforces the relevance of extending the studies with boronic acids in Medicinal Chemistry, in order to obtain new promising drugs shortly.
... We envisaged an azatricyclic structural entity, the construction of 4-azatricyclo (5,2,1,0 2,6 ) alkanes, via the intramolecular [3 + 2]dipolar cycloaddition reaction of N-substituted maleimide with cyclopentadiene. In addition, Kossakowski group demonstrated that the rigid arylcyclo analogues having azatricyclo ring systems showed wide ranging pharmacological activities, such as anti-viral, anti-HIV, and antibacterial [8][9][10][11][12]. ...
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Background: A series of aryl-piperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-azatricyclo [5.2.1.02,6] dec-8-ene-3,5-dione were synthesized. The chemical structures of the desired compounds were identified by ¹H NMR, ESI-MS and elementary analytical. The anti-cancer and anti-angiogenesis activities of the newly synthesized compounds were evaluated by proliferation and migration assays, respectively. Results: The screening results demonstrated that compounds 2 and 5 showed potent anti-tumor activity (IC50 values ranging from 7.1 to 15.9μM) with low cytotoxic activities (IC50>79.3μM). Although compound 5 showed little effects on endothelia proliferation (IC50=65.3μM), it indeed significantly abrogated endothelia cell migration (IC50=6.7μM). Conclusions: This work may impart new direction for the investigations of aryl-piperazine derivatives and lead to the development of potent novel anti-tumor and anti-angiogenesis agents.
... Quinolones represent an important class of broad-spectrum antibacterial agents. Recently, quinolones have been reported to possess a variety of useful biological activities, including antitumor, antiparasitic, antifungal, and antiviral activities (Richter et al., 2004;Ahmed and Daneshtalab, 2012;Dalhoff, 2015). ...
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Murine gammaherpesvirus 68 (MHV-68) provides a valuable tool to screen novel therapeutic strategies against oncogenic gammaherpesviruses. The development and characterization of antiviral agents usually depend on appropriate screening assays. The aim of this study was to develop rapid and sensitive method for testing antiviral compounds against gammaherpesviruses. For this purpose, a recombinant MHV-68 expressing firefly luciferase (MHV-68/LUC) was constructed. The conditions for MHV-68/LUC infection in Vero cells suitable for novel antiviral screening assay in 96-well plate format were then optimized. The sensitivity of MHV-68/LUC to acyclovir (ACV) and ganciclovir (GCV) was measured by the optimized luciferase activity reduction assay. The 50% inhibition concentration (IC50) values for ACV and GCV were comparable to those determined by conventional plaque reduction assay. Therefore, the luciferase activity reduction assay can efficiently replace the plaque reduction assay. The great advantages of novel assay are represented by the significant reduction in assay time and rapid and objective measurement of the assay. In order to evaluate whether the luciferase activity reduction assay could be used as a screening system for novel antivirals, newly synthesized quinolone/quinoline derivatives were tested for their effects on the replication of MHV-68/LUC in vitro. The compound 2-(1-(b-D-Xylopyranosyl)-1,2,3-triazol-4-yl)-3,4-dibenzyloxy-quinoline showed significant antiviral activity and its IC50 against MHV-68/LUC was estimated to be 1,76 µg/ml. However, this compound was not suitable for in vivo testing due to its narrow selectivity index (SI = 11).
... These compounds are privileged scaffolds in medicinal chemistry and are ubiquitous substructures associated with relevant biologically active natural products. For instance, quinolin-2(1H)-ones were reported as antiulcer (e.g., rebamipide), antihistaminic (e.g., repirinast) [3] and anticancer (e.g., tipifarnib) [4] agents and have also demonstrated activity as antivirals [5], for instance as inhibitors of HIV-1 reverse transcriptase [6,7]. In addition, they are useful intermediates in organic synthesis. ...
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Palladium-catalysed reactions have had a large impact on synthetic organic chemistry and have found many applications in target-oriented synthesis. Their widespread use in organic synthesis is due to the mild conditions associated with the reactions together with their tolerance of a wide range of functional groups. Moreover, these types of reactions allow the rapid construction of complex molecules through multiple bond-forming reactions in a single step, the so-called tandem processes. Pd-catalysed reactions have been applied to the synthesis of a large number of natural products and bioactive compounds, some of them of complex molecular structures. This review article aims to present an overview of the most important Pd-catalysed reactions employed in the synthesis and transformations of quinolin-2(1H)-ones and quinolin-4(1H)-ones. These compounds are widely recognized by their diverse bioactivity, being privileged structures in medicinal chemistry and useful structural moieties for the development of new drug candidates. Furthermore, they hold significant interest due to their host–guest chemistry; applications in chemical, biochemical and environmental analyses and use in the development of new synthetic methods. In some cases, the quinolone formation step cannot be ascribed to a claimed Pd-catalysed reaction but this reaction is crucial to get the appropriate substrate for cyclization into the quinolone. Herein we present and discuss different economical, efficient and selective synthetic strategies to access quinolone-type compounds.
... They can inhibit nucleic acid unwinding activity of bacterial gyrases or topoisomerases. In addition to bacteria, several in vitro studies and clinical trials have also shown the efficacy of fluoroquinolones against different viruses [6][7][8][9][10][11][12], making them an ideal antiviral agent. ...
Article
Helicase enzyme is responsible for the unwinding of complementary nucleic acid strands, which is one of the preliminary steps in DNA replication. They are crucial for replication of an organism, including viruses. HCV and HIV are two clinically significant pathogens, responsible for millions of infections and deaths worldwide. Due to similar transmission routes, these viruses can establish co-infection in an individual. Individually, these infections are difficult to treat, however, in case of co-infection, the treatment becomes more difficult. Additionally, these viruses accumulate mutation in response to drug therapy that renders the treatment ineffective. HCV and HIV both encode enzyme containing helicase activity. The viral-encoded helicase plays a significant role in HIV and HCV life cycle. Here we propose viral helicases as an ideal single-hit target that can inhibit HIV and HCV co-infection. We also hypothesize that search for natural analogs sharing basic ring structure with a class of helicase inhibitors called fluoroquinolones can yield natural agents with superior antiviral (anti-helicase) activity with lower toxicity index. The fluoroquinolones and their analogs are currently not part of any antiviral regimens. Our proposal is to include fluoroquinolones-derived natural analogs as a conjugate therapy along with main regimens available against HCV and HIV co-infection.
... Since 1962, 4quinolone-3-carboxylic acid derivatives are clinically used as antibacterial agents worldwide 1 . Currently, fluoroquinolones are approved by the WHO as second-line drugs to treat tuberculosis (TB), and their use in multidrug-resistant (MDR)-TB is increasing due to the fact that they have a broad and potent spectrum of activity and can be administered orally.Recently, quinolones have been reported to display "nonclassical" biological activities, such as antitumor, anti-HIV-1 integrase, anti-HCV-NS3 helicase and -NS5B-polymerase activities [2][3][4][5] .Quinolone antibacterials corrupt the activities of prokaryotic DNA gyrase and topoisomerase IV, and induce cell death by generating high levels of double-stranded DNA breaks. Like bacterial cells, eukaryotic species require a type II topoisomerase, which modulate the topological state of the genetic material by passing an intact DNA helix through a transient double stranded break and represent the cellular targets for a wide variety of anticancer drugs.In view of the mechanistic similarities and sequence homologies exhibited by the two enzymes, tentative efforts to selectively shift from an antibacterial to an anti tumoral activity was made by synthesizing several novel functionalized quinolones, which exhibited potential antineoplastic activity against eukaryotic type II topoisomerases 6 .Thus, in addition to the antibacterial quinolones, specific members of this drug family display high activity against eukaryotic type II topoisomerases, as well as cultured mammalian cells and invivo tumor models. ...
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Background: A series of aryl-piperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-azatricyclo [5.2.1.0 2,6 ] dec-8-ene-3,5-dione were synthesized. The chemical structures of the desired compounds were identified by 1 H NMR, ESI-MS and elementary analytical. The anti-cancer and anti-angiogenesis activities of the newly synthesized compounds were evaluated by proliferation and migration assays, respectively. Results: The screening results demonstrated that compounds 2 and 5 showed potent anti-tumor activity (IC 50 values ranging from 7.1 to 15.9μM) with low cytotoxic activities (IC 50 > 79.3μM). Although compound 5 showed little effects on endothelia proliferation (IC 50 =65.3μM), it indeed significantly abrogated endothelia cell migration (IC 50 =6.7μM). Conclusions: This work may impart new direction for the investigations of aryl-piperazine derivatives and lead to the development of potent novel anti-tumor and anti-angiogenesis agents.
Article
A copper‐catalyzed three‐component synthetic method has been developed for the synthesis of substituted 4‐quinolone derivatives from substituted 3‐(2‐halophenyl)‐3‐oxopropane, aldehydes and aq. NH3 using water as an environmentally benign reaction media. Moreover, the synthetic utility of the obtained products has been successfully applied for the synthesis of available oxolinic acid and BQCA drugs. The key features of this approach include commercially available starting materials, broad scope, and moderate to good reaction yields. Reaction with formaldehyde, and other functionalities such as CN, ‐NO2, ‐SO2Ar, and ‐COAr were also successful. In addition, reaction with heterocyclic compounds such as 3‐(3‐bromothiophen‐2‐yl)‐3‐oxopropanenitrile proceeded smoothly to afford tetrahydrothieno[3,2‐b]pyridine‐6‐carbonitrile analogues. The practicality of the designed protocol was confirmed by gram scale synthesis of two derivatives.
Literature Review
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Cinoxacin (compound 64716) is a synthetic organic acid with antibacterial activity against most aerobic gram-negative bacilli. Minimal inhibitory concentrations of cinoxacin (agar-dilution method) were determined for 419 strains. Escherichia coli was the most susceptible group of organisms. The majority of Klebsiella sp., Enterobacter sp., Proteus sp., and Serratia marcescens were inhibited by 8 μg of cinoxacin per ml. Pseudomonas aeruginosa and all gram-positive isolates tested were resistant to 64 μg or less of cinoxacin per ml. Zones of inhibition using a 30-μg disk correlated well with agar-dilution minimal inhibitory concentrations (r = −0.9). Cinoxacin was bactericidal when tested with inocula of 5 × 106 organisms per ml. Resistance to cinoxacin was readily developed in all three strains tested by serial passage on drug-containing agar. The in vitro properties of this agent were similar to those of nalidixic acid.
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Pipemidic acid was absorbed well by the oral route. Its peak levels in plasma ranged from 4 to 12 μg/ml at an oral dose of about 50 mg/kg in mice, rats, dogs, monkeys, and men. The protein binding of pipemidic acid was about 20% in dog plasma and about 30% in human serum. Pipemidic acid was distributed to most of the organs and tissues tested at the concentrations comparable to or higher than the plasma level. Its concentrations in bile and urine were much higher than the plasma level. About 25 to 88% of orally administered pipemidic acid was excreted into urine in a bacteriologically active form, the percentage depending on the animals and doses employed. The remainder was excreted into feces in men. The main active principle in vivo was unchanged pipemidic acid itself. The mean lethal dose of pipemidic acid after a single oral dose was more than 16,000 mg/kg in mice. No abnormalities were observed in mice orally receiving pipemidic acid once a day for 4 weeks at doses of 1,000, 2,000, and 4,000 mg/kg per day, and in rats orally receiving the drug once a day for 2 weeks at doses of 400 and 1,600 mg/kg per day.
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A report is given of the antibacterial activity of a new compound, 8 ethyl 5 oxo 2 (1 piperazinyl) 5,8 dihydropyrido (2,3 d) pyrimidin 6 carboxylic acid. The compound was studied in vitro against both standard cultures and strains isolated from patients with urinary tract diseases.
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Infection of the human lymphocyte CEM cell line with the HIV-1 (human immunodeficiency virus-1, LAV-1 strain) results in cell death. A fluoroquinolone antibiotic, ofloxacin, protected the infected cells from HIV-1-mediated cytolysis. Other fluoroquinolones, e.g. ciprofloxacin, norfloxacin, and enoxacin, also protected the infected cells from HIV-1-mediated cytolysis. The d-isomer of ofloxacin (DR-3354) was about 50-fold less effective than the l-isomer (DR-3355). Almost none of the rescued cells had detectable HIV-antigens and they could be maintained for long periods in vitro without drugs.
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The uptake of the quinolone drug norfloxacin by Escherichia coli was investigated at initial rate kinetics at different pH and monovalent/divalent metal ion concentration. The results support a simple diffusion mechanism for quinolone incorporation into cells. The uptake process decreases under acidic conditions. The presence of Na+ or K+ ions does not affect the results to an appreciable extent, whereas divalent ions cause a dramatic decrease in drug incorporation. The antibacterial activity, evaluated under identical experimental conditions, shows a direct relationship with the uptake data. As a general explanation for the above results it is suggested that the ability of the drug to penetrate into cells is a function of its net charge. The molecule in the zwitterionic form exhibits maximum permeation properties, whereas the uptake is remarkably reduced when the drug bears a net charge as a result of ionization or complex formation with bivalent ions. These results allow further insight into the mechanism of quinolone access to the intracellular compartment.
Article
The in vitro inhibitory effects of quinolones on the bacterial DNA gyrase of Escherichia coli KL-16 and topoisomerase II of fetal calf thymus were compared. All the quinolones tested required higher concentrations to inhibit the topoisomerase II than to inhibit the DNA gyrase, and no correlation existed among their inhibitory activities against both enzymes. However, there was a large difference among the quinolones in their selectivities between the bacterial enzyme and its eucaryotic counterpart. The selectivity of ofloxacin was highest, and the selectivities of CI-934 and nalidixic acid were lowest.
Article
The antiviral activity of ofloxacin, a new quinolone derivative, against vaccinia virus (VV), herpes simplex virus (HSV) and influenza virus (InfV) was evaluated in both in vitro and in vivo experiments. As a result, ofloxacin showed inhibitory activity against VV in cultured mammalian cells, and prevented formation of pox tail lesions in VV-infected mice. However, it was less effective against HSV and InfV than VV. The antiviral activity of ofloxacin assessed by VV tail-lesion test was strongest when administered to mice through the oral route daily for five consecutive days post-infection. Nalidixic acid and novobiocin, well-known gyrase inhibitors, showed only weak antiviral activity in both in vitro and in vivo tests against VV. It was also demonstrated that ofloxacin inhibited virus-specific DNA and RNA syntheses. It was more inhibitory to VV topoisomerase than cellular topoisomerases. Thus, ofloxacin has selectivity for VV.
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The antimicrobial activity of cinoxacin, 1-ethyl-4(1H)-oxo-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid, previously reported as compound 64716, was determined and compared with other antimicrobial agents at a dosage of 12 mg/kg once daily in a descending pyelonephritis rat model with Escherichia coli and Proteus mirabilis as infecting organisms. Cinoxacin was considerably more effective than either nalidixic acid or oxolinic acid when all three were administered orally at 3 mg/kg four times daily. The presence of demonstrable serum activity with a high recovery in urine indicates cinoxacin possesses highly desirable properties of an effective oral chemotherapeutic agent for urinary tract infections.