RESUMEN
The escalating severity of the menace posed by bacterial resistance has rendered the existing antibiotics less effective, thus necessitating the discovery of new antibacterial agents. The current study reports the exploration of substituted N-pyridinylaminonaphthols produced by a straightforward, one-pot multicomponent reaction process as antibacterial agents. The synthesized derivatives were assessed in vitro for their antibacterial properties against a panel of bacterial pathogens. The analogs 4b, 4g, 4h, 4i, 4j, 4l, 4r, and 4t exhibited potent inhibitory activity with minimum inhibitory concentration (MIC) values of 1-2 µg/mL. Notably, 4b, 4l, and 4t displayed an excellent selectivity index. Additionally, they were active against the multidrug-resistant bacterial strains, with 4l exhibiting the best activity against methicillin-resistant Staphylococcus aureus and vancomycin resistant staphylococcus aureus with a MIC of 1 µg/mL. 4l showed synergism with gentamycin and showed bactericidal property in a concentration-dependent manner. Furthermore, the molecule 4l inhibited the DNA gyrase supercoiling activity. Absorption, distribution, metabolism, excretion/toxicity parameters and pharmacokinetic properties were assessed via in silico techniques, which elucidate the potential mode of action. These findings demonstrate the potential of the N-pyridinylaminonaphthol derivatives as antibacterial agents against multidrug-resistant S. aureus.
RESUMEN
With the rise of multidrug-resistant tuberculosis, the imperative for an alternative and superior treatment regimen, incorporating novel mechanisms of action, has become crucial. In pursuit of this goal, we have developed and synthesized a new series of rhodanine-linked enamine-carbohydrazide derivatives, exploring their potential as inhibitors of mycobacterial carbonic anhydrase. The findings reveal their efficacy, displaying notable selectivity toward the mycobacterial carbonic anhydrase 2 (mtCA 2) enzyme. While exhibiting moderate activity against human carbonic anhydrase isoforms, this series demonstrates promising selectivity, positioning these compounds as potential antitubercular agents. Compound 6d was the best one from the series with a Ki value of 9.5 µM toward mtCA 2. Most of the compounds displayed moderate to good inhibition against the Mtb H37Rv strain; compound 11k showed a minimum inhibitory concentration of 1 µg/mL. Molecular docking studies revealed that compounds 6d and 11k show metal coordination with the zinc ion, like classical CA inhibitors.
Asunto(s)
Antituberculosos , Inhibidores de Anhidrasa Carbónica , Diseño de Fármacos , Hidrazinas , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis , Rodanina , Rodanina/farmacología , Rodanina/síntesis química , Rodanina/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Estructura-Actividad , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Antituberculosos/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Humanos , Hidrazinas/farmacología , Hidrazinas/síntesis química , Hidrazinas/química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismoRESUMEN
BACKGROUND: Descriptions of changes in invasive bacterial disease (IBD) epidemiology during the coronavirus disease 2019 (COVID-19) pandemic in the United States are limited. METHODS: We investigated changes in the incidence of IBD due to Streptococcus pneumoniae, Haemophilus influenzae, group A Streptococcus (GAS), and group B Streptococcus (GBS). We defined the COVID-19 pandemic period as 1 March to 31 December 2020. We compared observed IBD incidences during the pandemic to expected incidences, consistent with January 2014 to February 2020 trends. We conducted secondary analysis of a health care database to assess changes in testing by blood and cerebrospinal fluid (CSF) culture during the pandemic. RESULTS: Compared with expected incidences, the observed incidences of IBD due to S. pneumoniae, H. influenzae, GAS, and GBS were 58%, 60%, 28%, and 12% lower during the pandemic period of 2020, respectively. Declines from expected incidences corresponded closely with implementation of COVID-19-associated nonpharmaceutical interventions (NPIs). Significant declines were observed across all age and race groups, and surveillance sites for S. pneumoniae and H. influenzae. Blood and CSF culture testing rates during the pandemic were comparable to previous years. CONCLUSIONS: NPIs likely contributed to the decline in IBD incidence in the United States in 2020; observed declines were unlikely to be driven by reductions in testing.
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Infecciones Bacterianas , COVID-19 , Estados Unidos/epidemiología , Humanos , Lactante , Incidencia , Pandemias , COVID-19/epidemiología , Streptococcus pneumoniae , Haemophilus influenzae , Streptococcus agalactiaeRESUMEN
We analyzed 9630 invasive GAS surveillance isolates in the USA. From 2015-2017 to 2018-2019, significant increases in erythromycin-nonsusceptibility (18% vs 25%) and clindamycin-nonsusceptibility (17% vs 24%) occurred, driven by rapid expansions of genomic subclones. Prevention and control of clustered infections appear key to containing antimicrobial resistance.
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Clindamicina , Infecciones Estreptocócicas , Humanos , Estados Unidos/epidemiología , Clindamicina/farmacología , Eritromicina/farmacología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Streptococcus pyogenes/genética , Genómica , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/epidemiología , Farmacorresistencia Bacteriana/genéticaRESUMEN
Cancer is associated with uncontrolled cell proliferation invading adjoining tissues and organs. Despite the availability of several chemotherapeutic agents, the constant search for newer approaches and drugs is necessitated owing to the ever-growing challenge of resistance. Over the years, DNA has emerged as an important druggable therapeutic drug due to its role in critical cellular processes such as cell division and maintenance. Further, evading apoptosis stands out as a hallmark of cancer. Hence, designing new compounds that would target DNA and induce apoptosis plays an important role in cancer therapy. In the current work, we carried out the synthesis and anticancer evaluation of 1-aryl-4,6-dihydrobenzo[b]pyrazolo[3,4-d]azepin-5(1H)-ones/thiones (26 compounds) against selected human cancer cell lines. Among these, compounds 8ae, 8ad, 8cf, 10ad and Kenpaullone have shown good inhibitory properties against HeLa cells (IC50 < 2 µM) with good selectivity over the non-cancerous human embryonic kidney (Hek293T) cells. In cell cycle analysis, the compounds 8ad and 8cf have exhibited G2/M cell cycle arrest in HeLa cells. In addition, the compounds 8ad and 8cf induced apoptosis in a dose-dependent manner in the Annexin-V FITC staining assay. The DAPI staining clearly demonstrated the condensed and fragmented nuclei in 8ad, 8cf, 8ae and Kenpaullone-treated HeLa cells. In addition, these compounds strongly suppressed the healing after 48 h in in vitro cell migration assay. The DNA binding experiments indicated that compounds 8ae, 8cf, and 8ad as well as Kenpaullone interact with double-stranded DNA by binding in grooves which may interrupt the DNA replication and kill fast-growing cells. Molecular docking studies revealed the binding pose of 8ad and Kenpaullone at HT1 binding pocket of double-stranded DNA. Compounds 8ad and 8cf demonstrated moderate topo II inhibition which could be a possible reason for their anticancer properties. Compounds 8ad and 8cf may cause the topo II and DNA covalent complex, which leads to the inhibition of DNA replication and transcription. This eventually increases the DNA damage in cells and promotes cell apoptosis. With the above interesting biological profile, the new 1-aryl-2,6-dihydrobenzo[b]pyrazolo[3,4-d]azepin-5(4H)-one/thione derivatives have emerged as promising leads for the discovery of new anticancer agents.
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Antineoplásicos , Tionas , Humanos , Antineoplásicos/química , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Células HeLa , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Tionas/farmacología , Azepinas/química , Azepinas/farmacologíaRESUMEN
In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent.
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Antituberculosos , Mycobacterium tuberculosis , Animales , Chlorocebus aethiops , Antituberculosos/farmacología , Urea/farmacología , Células Vero , Relación Estructura-Actividad , Ácidos Carboxílicos/farmacología , Ésteres/farmacología , Tiourea/farmacología , Isoxazoles/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
The Carbonic anhydrase isoforms IX and XII play a significant role in regulating the intracellular and extracellular pH in hypoxic tumours abetting the metastasis of solid tumours. Selective and potent inhibitors targeting carbonic anhydrase IX and XII reduce the activity of these isoforms in hypoxic tumours, representing an antitumor and antimetastatic mechanism. Coumarin-based derivatives are selective inhibitors of CA isoforms IX and XII. In this study, we report the design and synthesis of new 3-substituted coumarin derivatives with different functional moieties and their inhibitory activity against various carbonic anhydrase isoforms. We found that the tertiary sulphonamide derivative 6c showed selective inhibition against CA IX with IC50 of 4.1 µM. Similarly, the carbothioamides 7c, 7b and oxime ether derivative 20a exhibited good inhibition against CA IX and CA XII. Additionally, the binding mode was predicted and validated using molecular docking and dynamic simulations.
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Anhidrasas Carbónicas , Humanos , Anhidrasa Carbónica IX , Simulación del Acoplamiento Molecular , Cumarinas , Éteres , HipoxiaRESUMEN
Rhodanine and its derivatives are an important class of heterocycles with diverse biological properties, including anticancer, antibacterial, and anti-mycobacterial activities. In the present work, four series of new Rhodanine derivatives were synthesized and evaluated for their inhibitory activity against carbonic anhydrase I, II, IX, and XII isoforms. Interestingly, the tested compounds exhibited good inhibitory activity against the cytosolic isoform human carbonic anhydrase (hCA) II and tumor-associated hCA IX. While the Rhodanine-benzylidene derivatives (3a-l) and Rhodanine-hydrazine derivatives (6a-e) are found to be selective against hCA II, the Rhodanine-N-carboxylate derivatives (8a-d) are found to be highly selective toward hCA IX. The Rhodanine-linked isoxazole and 1,2,4-oxadiazole derivatives (8ba, 8da, and 8db) exhibited inhibitory activity against hCA II and hCA IX. Among the tested compounds, 3b, 3j, 6d, and 8db were found to inhibit hCA II with Ki values of 9.8, 46.4, 7.7, and 4.7 µM, respectively. Furthermore, their mechanism of action is supported by molecular docking studies. Notably, the synthesized Rhodanine derivatives belong to a nonsulfonamide class of carbonic anhydrase inhibitors.
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Anhidrasas Carbónicas , Rodanina , Humanos , Anhidrasa Carbónica II , Anhidrasas Carbónicas/metabolismo , Rodanina/farmacología , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Inhibidores de Anhidrasa Carbónica/farmacología , Estructura MolecularRESUMEN
Carbonic anhydrase isoforms IX and XII are overexpressed in hypoxic tumor cells regulating various physiological processes such as cell proliferation, invasion, and metastasis, resulting in the onset and spread of cancer. Selective inhibition of these enzymes is a promising strategy for anticancer therapy. Coumarin derivatives were identified as selective and potent inhibitors of these isoforms. This study reports 6-aminocoumarin sulfonamide and oxime ether derivatives linked through a chloroacetyl moiety tethered to piperazine and piperidone, respectively, showing selective inhibition against human carbonic anhydrase (hCA) IX and XII with Ki ranging from 0.51 to 1.18 µM and 0.89-4.43 µM. While the sulfonamide derivative 8a exhibited submicromolar inhibition against hCA IX and XII with Ki 0.89 and 0.51 µM, the oxime ether derivatives showed lower activity than the sulfonamides, with the compound 5n inhibiting hCA IX and hCA XII with a Ki of 1.055 and 0.70 µM, respectively. The above results demonstrate the potential of these derivatives as selective, potent inhibitors of carbonic anhydrase IX and XII and provide a foundation for further optimization and development as effective anticancer agents. Further, the binding mode of the synthesized derivatives in the active site were examined using molecular docking and dynamic simulation studies.
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Anhidrasas Carbónicas , Simulación de Dinámica Molecular , Humanos , Anhidrasa Carbónica IX/química , Anhidrasa Carbónica IX/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Éter , Sulfonamidas/química , Anhidrasas Carbónicas/metabolismo , Cumarinas/farmacología , Cumarinas/química , Éteres de Etila , Éteres , Isoformas de Proteínas/metabolismo , Inhibidores de Anhidrasa Carbónica , Estructura MolecularRESUMEN
Herein, we report the design and synthesis of two series of pyrazole-tethered sulfamoyl phenyl acetamides and pyrazole-tethered sulfamoyl phenyl benzamides. The synthesized compounds were investigated for inhibiting two human carbonic anhydrases, human carbonic anhydrases (hCA) I and II, and those of the bacterial pathogen Mycobacterium tuberculosis, mtCA 1-3. The results indicate that, among the synthesized compounds, pyrazoles with 4-aminobenzene sulfonamide were more selective toward hCA I and II over mtCAs, and compounds with 3-aminobenzene sulfonamide were selective toward mtCA 1-3 over hCA I, II. Compound 6g showed significant and selective inhibition toward hCA I and II, with Ki values of 0.0366 and 0.0310 µM, respectively. Compound 5g exhibited the best inhibition toward mtCA 2, with a Ki value of 0.0617 µM. Among the benzamides, compound 9b exhibited significant activity toward mtCA 2, with a Ki value of 0.0696 µM. Selectivity of these compounds was further supported by docking studies. When tested for antitubercular activity, many compounds showed moderate to good inhibition against the Mtb H37Rv strain, with minimum inhibitory concentration (MIC) values in the range of 4-128 µg/mL.
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Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Humanos , Inhibidores de Anhidrasa Carbónica/farmacología , Relación Estructura-Actividad , Anhidrasa Carbónica II , Anhidrasas Carbónicas/metabolismo , Pirazoles/farmacología , Anhidrasa Carbónica I , Sulfonamidas/farmacología , Benzamidas , Estructura MolecularRESUMEN
BACKGROUND: Group A streptococci (GAS), although usually responsible for mild infections, can sometimes spread into normally sterile sites and cause invasive GAS disease (iGAS). Because both the risk of iGAS disease and occurrence of outbreaks are elevated within certain communities, such as those comprising people who inject drugs (PWID) and people experiencing homelessness (PEH), understanding the transmission dynamics of GAS is of major relevance to public health. METHODS: We used a cluster detection tool to scan genomes of 7552 Streptococcus pyogenes isolates acquired through the population-based Active Bacterial Core surveillance (ABCs) during 2015-2018 to identify genomically related clusters representing previously unidentified iGAS outbreaks. RESULTS: We found that 64.6% of invasive isolates were included within clusters of at least 4 temporally related isolates. Calculating a cluster odds ratio (COR) for each emm type revealed that types vary widely in their propensity to form transmission clusters. By incorporating additional epidemiological metadata for each isolate, we found that emm types with a higher proportion of cases occurring among PEH and PWID were associated with higher CORs. Higher CORs were also correlated with emm types that are less geographically dispersed. CONCLUSIONS: Early identification of clusters with implementation of outbreak control measures could result in significant reduction of iGAS.
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Infecciones Estreptocócicas , Abuso de Sustancias por Vía Intravenosa , Antígenos Bacterianos , Proteínas de la Membrana Bacteriana Externa , Brotes de Enfermedades , Humanos , Streptococcus pyogenes , Estados UnidosRESUMEN
BACKGROUND: The genomic features and transmission link of circulating Group A Streptococcus (GAS) strains causing different disease types, such as pharyngitis and invasive disease, are not well understood. METHODS: We used whole-genome sequencing to characterize GAS isolates recovered from persons with pharyngitis and invasive disease in the Denver metropolitan area from June 2016 to April 2017. RESULTS: The GAS isolates were cultured from 236 invasive and 417 pharyngitis infections. Whole-genome sequencing identified 34 emm types. Compared with pharyngitis isolates, invasive isolates were more likely to carry the erm family genes (23% vs 7.4%, P<.001), which confer resistance to erythromycin and clindamycin (including inducible resistance), and covS gene inactivation (7% vs 0.5%, P<.001). Whole-genome sequencing identified 97 genomic clusters (433 isolates; 2-65 isolates per cluster) that consisted of genomically closely related isolates (median single-nucleotide polymorphism=3 [interquartile range, 1-4] within cluster). Thirty genomic clusters (200 isolates; 31% of all isolates) contained both pharyngitis and invasive isolates and were found in 11 emm types. CONCLUSIONS: In the Denver metropolitan population, mixed disease types were commonly seen in clusters of closely related isolates, indicative of overlapping transmission networks. Antibiotic-resistance and covS inactivation was disproportionally associated with invasive disease.
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Faringitis , Infecciones Estreptocócicas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Colorado/epidemiología , Farmacorresistencia Bacteriana/genética , Genómica , Humanos , Faringitis/tratamiento farmacológico , Faringitis/epidemiología , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/epidemiología , Streptococcus pyogenesRESUMEN
Nursing home residents have experienced disproportionally high levels of COVID-19-associated morbidity and mortality and were prioritized for early COVID-19 vaccination (1). Following reported declines in vaccine-induced immunity after primary series vaccination, defined as receipt of 2 primary doses of an mRNA vaccine (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) or 1 primary dose of Ad26.COV2 (Johnson & Johnson [Janssen]) vaccine (2), CDC recommended that all persons aged ≥12 years receive a COVID-19 booster vaccine dose.* Moderately to severely immunocompromised persons, a group that includes many nursing home residents, are also recommended to receive an additional primary COVID-19 vaccine dose. Data on vaccine effectiveness (VE) of an additional primary or booster dose against infection with SARS-CoV-2 (the virus that causes COVID-19) among nursing home residents are limited, especially against the highly transmissible B.1.1.529 and BA.2 (Omicron) variants. Weekly COVID-19 surveillance and vaccination coverage data among nursing home residents, reported by skilled nursing facilities (SNFs) to CDC's National Healthcare Safety Network (NHSN)§ during February 14-March 27, 2022, when the Omicron variant accounted for >99% of sequenced isolates, were analyzed to estimate relative VE against infection for any COVID-19 additional primary or booster dose compared with primary series vaccination. After adjusting for calendar week and variability across SNFs, relative VE of a COVID-19 additional primary or booster dose was 46.9% (95% CI = 44.8%-48.9%). These findings indicate that among nursing home residents, COVID-19 additional primary or booster doses provide greater protection against Omicron variant infection than does primary series vaccination alone. All immunocompromised nursing home residents should receive an additional primary dose, and all nursing home residents should receive a booster dose, when eligible, to protect against COVID-19. Efforts to keep nursing home residents up to date with vaccination should be implemented in conjunction with other COVID-19 prevention strategies, including testing and vaccination of nursing home staff members and visitors.
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COVID-19 , SARS-CoV-2 , Vacuna BNT162 , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , Casas de Salud , Estados Unidos/epidemiología , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
Ever increasing drug resistance has become an impeding threat that continues to hamper effective tackling of otherwise treatable tuberculosis (TB). Such dismal situation necessitates identification and exploration of multitarget acting newer chemotypes with bactericidal efficacy as a priority, that could efficiently hinder uncontrolled spread of TB. In this context, herein we present design, synthesis and bio-evaluation of chalcone tethered bezoxazole-2-amines as promising anti-TB chemotypes. Preliminary screening of 24 compounds revealed initial hits 3,4,5-trimethoxyphenyl and 5-nitrofuran-2-yl derivative exhibiting selective inhibition of Mycobacterium tuberculosis (Mtb) H37Rv. Further, structural optimization of hit compounds generated 12 analogues, amongst which 5-nitrofuran-2-yl derivatives displayed potent inhibition of not only drug-susceptible (DS) Mtb but also clinical isolates of drug-resistant (DR) Mtb strains equipotently. Moreover, cell viability test against Vero cells found these compounds with favourable selectivity. Time kill analysis led to the identification of the lead compound (E)-1-(4-((5-chlorobenzo[d]oxazol-2-yl)amino)phenyl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one, that demonstrated bactericidal killing of Mtb bacilli. Together with acceptable microsomal stability, the lead compound of the series manifested all desirable traits of a promising antitubercular agent.
Asunto(s)
Mycobacterium tuberculosis , Nitrofuranos , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Aminas/farmacología , Animales , Antituberculosos/química , Benzoxazoles/farmacología , Chlorocebus aethiops , Pruebas de Sensibilidad Microbiana , Nitrofuranos/farmacología , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Células VeroRESUMEN
Acinetobacter baumannii, a Gram-negative, glucose non-fermentative coccobacilli are responsible for causing a wide range of opportunistic nosocomial infections, thus listed as a WHO "critical priority pathogen", for which identification and development of new antibacterial agents are an urgent unmet medical need. The current review attempts to present an overview of various mechanisms (enzymatic and non-enzymatic), virulence factors responsible for A. baumannii resistance. Furthermore, inhibitors of A. baumannii are categorized into different classes highlighting their MDR inhibition properties. In addition, novel adjuvants that potentiate existing antibiotics, as well as natural and synthetic compounds that limit biofilm formation in A. baumannii infections are discussed.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Infección Hospitalaria , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infección Hospitalaria/tratamiento farmacológico , Farmacorresistencia Bacteriana Múltiple , HumanosRESUMEN
In pursuit of potent anti-TB agents active against drug resistant tuberculosis (DR-TB), herein we report synthesis and bio-evaluation of a new series of isoxazole-carboxylic acid methyl ester based 2-substituted quinoline derivatives. Preliminary evaluation indicated selectivity towards Mtb H37Rv, with no inhibition of non-tubercular mycobacterial (NTM) & bacterial pathogen panel. Out of 36 synthesized compounds, majority exhibited substantial inhibition of Mtb H37Rv (MIC 0.5-8â µg/mL). Cell viability test against Vero cells revealed no significant cytotoxicity. Further, screening against drug resistant strains (DR-Mtb) found hit compound displaying promising potency (MIC 1-4â µg/mL). Structure optimization of the hit led to the identification of lead compound demonstrating potent inhibition of both drug-susceptible Mtb (MIC 0.12â µg/mL) and drug-resistant Mtb (MIC 0.25-0.5â µg/mL) along with a high selectivity index (SI) >80. Taken together, with appreciable selectivity and potent activity, these chemotypes show prospect to be turned into a potential anti-TB candidate.
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Fármacos Dermatológicos , Mycobacterium tuberculosis , Animales , Antituberculosos , Ácidos Carboxílicos , Chlorocebus aethiops , Fármacos Dermatológicos/farmacología , Ésteres , Isoxazoles , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Células VeroRESUMEN
Antimicrobial resistance is a serious challenge to modern medicine. Besides imposing high financial burden, multidrug resistant infections are directly responsible for high morbidity and mortality. Even though a number of antibiotics are currently available to treat infections caused by ESKAPE organisms, more and more bacterial strains are becoming resistant to these drugs. Prevailing circumstances pose an urgent unmet need for the development of newer antimicrobials to treat the infections caused by MDR organisms. Rhodanine and structurally related 5-membered heterocycles possess wide range of pharmacological activities. A number of these derivatives have shown good to potent inhibition against various microorganisms. They are reported to alter the function of DNA gyrase B, metallo-ß-lactamases, penicillin binding protein (PBP), Mur ligases, RNA polymerase, Enoyl ACP reductases, 1-deoxy-d-xylulose-5-phosphate reductoisomerase. etc which are vital in bacterial growth, survival and replication. In this study, we have generated a library of Rhodanine and related 5 membered heterocyclic derivatives and screened them against a panel of pathogens. Among all the compounds, 2a-i, 3a-b, 3g, 4, 6b-c, 6e, 6g, 12a-b and 14b-c have demonstrated good to moderate inhibition against S.â aureus (MIC 0.125-8â µg/mL). Further, compound 17b demonstrated moderate activity against A.â baumannii (MIC 8â µg/mL). In addition, compounds 2a, 2e, 4, 6c, 6g and 14b have shown good to mild inhibition against MDR S.â aureus including VRSA (MIC 0.5-16â µg/mL) with good selectivity index 20-1600. In addition, compound 2e inhibited the growth gradually after 6â h in time kill kinetic studies and not antagonized with the tested FDA approved drugs.
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Staphylococcus aureus Resistente a Meticilina , Rodanina , Antibacterianos/química , Cinética , Pruebas de Sensibilidad Microbiana , Rodanina/química , Rodanina/farmacología , Staphylococcus aureusRESUMEN
The quinoline moiety remains a privileged antitubercular (anti-TB) pharmacophore, whereas 8-nitrobenzothiazinones are emerging potent antimycobacterial agents with two investigational candidates in the clinical pipeline. Herein, we report the synthesis and bioevaluation of 30 piperazinyl-benzothiazinone-based quinoline hybrids as prospective anti-TB agents. Preliminary evaluation revealed 24/30 compounds exhibiting substantial activity (minimum inhibitory concentration [MIC] = 0.06-1 µg/ml) against Mycobacterium tuberculosis (Mtb) H37Rv. Cytotoxicity analysis against Vero cells found these to be devoid of any significant toxicity, with the majority displaying a selectivity index of >80. Furthermore, potent nontoxic compounds, when screened against clinical isolates of drug-resistant Mtb strains, demonstrated equipotent inhibition with MIC values of 0.03-0.25 µg/ml. A time-kill study identified a lead compound exhibiting concentration-dependent bactericidal activity, with 10× MIC completely eliminating Mtb bacilli within 7 days. Along with acceptable aqueous solubility and microsomal stability, the optimum active compounds of the series manifested all desirable traits of a promising antimycobacterial candidate.
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Mycobacterium tuberculosis , Quinolinas , Animales , Antituberculosos/farmacología , Chlorocebus aethiops , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Células Vero , Tiazinas/farmacologíaRESUMEN
Saccharin is a cyclic secondary sulfonamide, which is a selective inhibitor of the tumor-associated carbonic anhydrase (CA; EC 4.2.1.1) enzymes CA IX and CA XII compared to many primary sulfonamides. In this study, new saccharin-1,2,3-triazole and saccharin-1,2,4-oxadiazole hybrids were synthesized. All the newly synthesized molecules were screened for their CA-inhibitory activity against four important human CA (hCA) isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds 8a and 8f emerged as potent hCA II inhibitors (Ki = 3 µM). Compounds 6d, 6e and 7a, 7b were highly selective against hCA IX (6d, 6e) and hCA II (7a, 7b), with moderate inhibitory activity. The activity of these compounds was further confirmed by performing in silico docking studies against hCA II and hCA IX.
Asunto(s)
Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Humanos , Estructura Molecular , Sacarina/farmacología , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND: Treatment of severe group A Streptococcus (GAS) infections requires timely and appropriate antibiotic therapy. We describe the epidemiology of antimicrobial-resistant invasive GAS (iGAS) infections in the United States (US). METHODS: We analyzed population-based iGAS surveillance data at 10 US sites from 2006 through 2017. Cases were defined as infection with GAS isolated from normally sterile sites or wounds in patients with necrotizing fasciitis or streptococcal toxic shock syndrome. GAS isolates were emm typed. Antimicrobial susceptibility was determined using broth microdilution or whole genome sequencing. We compared characteristics among patients infected with erythromycin-nonsusceptible (EryNS) and clindamycin-nonsusceptible (CliNS) strains to those with susceptible infections. We analyzed proportions of EryNS and CliNS among isolates by site, year, risk factors, and emm type. RESULTS: Overall, 17 179 iGAS cases were reported; 14.5% were EryNS. Among isolates tested for both inducible and constitutive CliNS (2011-2017), 14.6% were CliNS. Most (99.8%) CliNS isolates were EryNS. Resistance was highest in 2017 (EryNS: 22.8%; CliNS: 22.0%). All isolates were susceptible to ß-lactams. EryNS and CliNS infections were most frequent among persons aged 18-34 years and in persons residing in long-term care facilities, experiencing homelessness, incarcerated, or who injected drugs. Patterns varied by site. Patients with nonsusceptible infections were significantly less likely to die. The emm types with >30% EryNS or CliNS included types 77, 58, 11, 83, and 92. CONCLUSIONS: Increasing prevalence of EryNS and CliNS iGAS infections in the US is predominantly due to expansion of several emm types. Clinicians should consider local resistance patterns when treating iGAS infections.