Quinolone-3-amidoalkanol: A New Class of Potent and Broad-Spectrum Antimicrobial Agent

Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-positive and -negative bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.

[1]  Richard M. Beteck,et al.  Quinolone: a versatile therapeutic compound class , 2022, Molecular Diversity.

[2]  D. Warner,et al.  Arylnitro monocarbonyl curcumin analogues: Synthesis and in vitro antitubercular evaluation , 2022, Chemical biology & drug design.

[3]  D. Warner,et al.  Nitrothiazole‐Thiazolidinone Hybrids: Synthesis and in Vitro Antimicrobial Evaluation , 2022, Chemistry & biodiversity.

[4]  K. Read,et al.  Anti-trypanosomatid drug discovery: progress and challenges , 2022, Nature reviews. Microbiology.

[5]  D. Warner,et al.  Investigation of quinolone‐tethered aminoguanidine as novel antibacterial agents , 2022, Archiv der Pharmazie.

[6]  Vishal B. Siramshetty,et al.  Using in vitro ADME data for lead compound selection: An emphasis on PAMPA pH 5 permeability and oral bioavailability. , 2022, Bioorganic & medicinal chemistry.

[7]  Alan D. Lopez,et al.  Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis , 2022, The Lancet.

[8]  Richard M. Beteck,et al.  Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review , 2021, Pharmaceuticals.

[9]  D. Warner,et al.  Easy-To-Access Quinolone Derivatives Exhibiting Antibacterial and Anti-Parasitic Activities , 2021, Molecules.

[10]  T. Gabaldón,et al.  Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium , 2020, Antibiotics.

[11]  M. Torres,et al.  Diagnosis for Latent Tuberculosis Infection: New Alternatives , 2020, Frontiers in Immunology.

[12]  L. Cowen,et al.  Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond. , 2020, Chemical reviews.

[13]  C. Ayoub Moubareck,et al.  The Current Burden of Carbapenemases: Review of Significant Properties and Dissemination among Gram-Negative Bacteria , 2020, Antibiotics.

[14]  Elizabeth Cerceo,et al.  Trends, Epidemiology, and Management of Multi-Drug Resistant Gram-Negative Bacterial Infections in the Hospitalized Setting , 2020, Antibiotics.

[15]  Y. Doi,et al.  Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019) , 2020, Emerging microbes & infections.

[16]  Wen-Sen Lee,et al.  New Drugs for Multidrug-Resistant Gram-Negative Organisms: Time for Stewardship , 2019, Drugs.

[17]  Linda A. Kerns.  Drug-like properties : , 2018 .

[18]  D. Boulware,et al.  Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. , 2017, The Lancet. Infectious diseases.

[19]  R. Arenas,et al.  Leishmaniasis: a review , 2017, F1000Research.

[20]  WHO PUBLISHES LIST OF BACTERIA FOR WHICH NEW ANTIBIOTICS ARE URGENTLY NEEDED , 2017, Saudi Medical Journal.

[21]  S. Landfear,et al.  Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs , 2016, Antimicrobial Agents and Chemotherapy.

[22]  N. Indrawattana,et al.  Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens , 2016, BioMed research international.

[23]  C. Rosa,et al.  Thiazole compounds with activity against Cryptococcus gattii and Cryptococcus neoformans in vitro. , 2015, European journal of medicinal chemistry.

[24]  D. Boulware,et al.  Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda , 2015, Antimicrobial Agents and Chemotherapy.

[25]  G. Dalekos,et al.  Leishmaniasis revisited: Current aspects on epidemiology, diagnosis and treatment , 2015, Journal of translational internal medicine.

[26]  M. Antonelli,et al.  A multicenter multinational study of abdominal candidiasis: epidemiology, outcomes and predictors of mortality , 2015, Intensive Care Medicine.

[27]  M. Cooper,et al.  Helping Chemists Discover New Antibiotics. , 2015, ACS infectious diseases.

[28]  D. Boulware,et al.  Cryptococcal Meningitis: Diagnosis and Management Update , 2015, Current Tropical Medicine Reports.

[29]  Yuexin Li,et al.  Quinolone-3-Diarylethers: A New Class of Antimalarial Drug , 2013, Science Translational Medicine.

[30]  C. Leung,et al.  Treatment of tuberculosis: update 2010 , 2011, European Respiratory Journal.

[31]  Philimon N. Gona,et al.  Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[32]  N. Craft,et al.  Cutaneous and mucocutaneous leishmaniasis , 2009, Dermatologic therapy.

[33]  F. Frézard,et al.  Pentavalent Antimonials: New Perspectives for Old Drugs , 2009, Molecules.

[34]  L. Rice.  Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. , 2008, The Journal of infectious diseases.

[35]  Liping Zhou,et al.  Development of a high throughput equilibrium solubility assay using miniaturized shake-flask method in early drug discovery. , 2007, Journal of pharmaceutical sciences.

[36]  B. Ullman,et al.  Leishmania donovani singly deficient in HGPRT, APRT or XPRT are viable in vitro and within mammalian macrophages. , 2006, Molecular and biochemical parasitology.

[37]  D. Huryn,et al.  Experimental design on single-time-point high-throughput microsomal stability assay. , 2004, Journal of pharmaceutical sciences.

[38]  S. Beverley,et al.  An in vitro system for developmental and genetic studies of Leishmania donovani phosphoglycans. , 2003, Molecular and biochemical parasitology.

[39]  I. Smith,et al.  Mycobacterium tuberculosis Pathogenesis and Molecular Determinants of Virulence , 2003, Clinical Microbiology Reviews.

[40]  B. Faller,et al.  High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. , 2001, Journal of medicinal chemistry.

[41]  J. Barendregt,et al.  Global burden of disease , 1997, The Lancet.

[42]  D. Dwyer.  A monophasic medium for cultivating Leishmania donovani in large numbers. , 1972, The Journal of parasitology.

[43]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.