Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors

Shao, Xuwei; AbdelKhalek, Ahmed; Abutaleb, Nader S.; Velagapudi, Uday Kiran; Yoganathan, Sabesan; Seleem, Mohamed N.; Talele, Tanaji T.

doi:10.1021/acs.jmedchem.9b01198

Cited by 21 publications

(18 citation statements)

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“…Screening a small panel of antiparasitic drugs against C. difficile. The MICs of all drugs were determined against two C. difficile clinical strains, as previously described (45)(46)(47). Briefly, 0.5 McFarland bacterial solution was prepared and diluted in brain heart infusion supplemented (BHIS) broth (inoculum size, ϳ5 ϫ 10 5 CFU/ml).…”

Section: Methodsmentioning

confidence: 99%

Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections

Abutaleb

Seleem

2020

Antimicrob Agents Chemother

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Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for the treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at concentrations of 0.5 μg/ml and 2 μg/ml, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3 log10 within 6 h. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficile in vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit the growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium, and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs.

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Section: Methodsmentioning

confidence: 99%

Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections

Abutaleb

Seleem

2020

Antimicrob Agents Chemother

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“…The broth microdilution assay 24,47,48 was used to determine the MICs of auranofin and control antibiotics in presence of SGF and SIF. Briefly, auranofin and control drugs were incubated with each of SGF and SIF for 2, 4 and 24 hours.…”

Section: Methodsmentioning

confidence: 99%

Auranofin, at clinically achievable dose, protects mice and prevents recurrence from Clostridioides difficile infection

Abutaleb

Seleem

2020

Sci Rep

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Clostridioides difficile is the leading cause of nosocomial infections and a worldwide urgent public health threat. Without doubt, there is an urgent need for new effective anticlostridial agents due to the increasing incidence and severity of C. difficile infection (CDI). The aim of the present study is to investigate the in vivo efficacy of auranofin (rheumatoid arthritis FDA-approved drug) in a CDI mouse model and establish an adequate dosage for treatment. The effects of increased C. difficile inoculum, and pre-exposure to simulated gastric intestinal fluid (SGF) and simulated intestinal fluid (SIF), on the antibacterial activity of auranofin were investigated. Auranofin's in vitro antibacterial activity was stable in the presence of high bacterial inoculum size compared to vancomycin and fidaxomicin. Moreover, it maintained its anti-C. difficile activity after being exposed to SGF and SIF. Upon testing in a CDI mouse model, auranofin at low clinically achievable doses (0.125 mg/kg and 0.25 mg/kg) significantly protected mice against CDI with 100% and 80% survival, respectively. Most importantly, auranofin (0.125 mg/kg and 0.25 mg/kg) significantly prevented CDI recurrence when compared with vancomycin. Collectively, these results indicate that auranofin could potentially provide an effective, safe and quick supplement to the current approaches for treating CDI. Clostridioides difficile is the worldwide leading cause of nosocomial infections and antibiotic-associated diarrhea 1. A recent report released by the Centers for Disease Control and Prevention (CDC) stated that about 223,900 patients were hospitalized with C. difficile infections (CDI) in the United States in 2017, which was associated with around 12,800 mortality cases and in excess of $1 billion healthcare cost 2. CDI symptoms range from mild to severe watery diarrhea to more severe life threatening complications such as pseudomembranous colitis, toxic megacolon, colon perforation, sepsis, systemic inflammatory response syndrome and shock 3. Disease manifestations are attributed to the toxin-mediated damage elicited by the two major toxins TcdA and TcdB. These toxins catalyze inactivation of host GTPases (Rac, Rho and CDC42) and perturbation of actin cytoskeleton, ultimately causing intense inflammation, loss of tight junctions of the intestinal mucosal layer, enormous fluid secretion, cell rounding and finally necrosis and apoptosis of the colonic mucosal cells 4,5. The incidence and severity of CDI has increased dramatically due to the overuse of antibiotics and the emergence of hypervirulent epidemic strains such as, but not limited to, pulsed-field gel type North American pulsotype 1 (NAP1) or PCR ribotype 027, which were responsible for several outbreaks globally 6,7. Moreover, the clinical management of CDI is hindered by the ability of C. difficile to produce spores which are highly resistant to environmental conditions, antibiotics and disinfection processes. Spores can persist on unsuitable environments for long periods and spread in the e...

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“…Finally, condensation of ammonia with N-acylaminothiophenes 44 allowed access to 3-unsubstituted thieno [2,3-d]pyrimidin-4-ones 45 [15,17]. The first synthetic route involved Pharmaceuticals 2022, 15, 35 9 of 58 25% ammonia heated at 105 • C in a sealed vial to obtain thieno [3,2-d]pyrimidin-4-one 46a after 3 h, with a 63% yield (Scheme 19).…”

Section: Cyclization With Nitrile Reactantsmentioning

confidence: 99%

“…Shao et al also reported the antibacterial activity of a series of thieno [3,2-d]pyrimidine-4-one [15], showing that such compounds may be effective against Clostridium difficile. This Gram-positive bacterium is naturally present in the intestinal flora of humans.…”

Section: Giri Et Al Identified New Thienomentioning

confidence: 99%

“…Finally, all derivatives exhibited low cytotoxicity against human colorectal adenocarcinoma (Caco-2), human ileocecal adenocarcinoma (HRT-18), and African green monkey kidney cells (Vero) and were inactive on Human Normal Microflora. Shao et al also reported the antibacterial activity of a series of thieno [3,2-d]pyrimidine-4-one [15], showing that such compounds may be effective against Clostridium difficile. This Gram-positive bacterium is naturally present in the intestinal flora of humans.…”

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Thienopyrimidine: A Promising Scaffold to Access Anti-Infective Agents

et al. 2021

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Thienopyrimidines are widely represented in the literature, mainly due to their structural relationship with purine base such as adenine and guanine. This current review presents three isomers—thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines and thieno[3,4-d]pyrimidines—and their anti-infective properties. Broad-spectrum thienopyrimidines with biological properties such as antibacterial, antifungal, antiparasitic and antiviral inspired us to analyze and compile their structure–activity relationship (SAR) and classify their synthetic pathways. This review explains the main access route to synthesize thienopyrimidines from thiophene derivatives or from pyrimidine analogs. In addition, SAR study and promising anti-infective activity of these scaffolds are summarized in figures and explanatory diagrams. Ligand–receptor interactions were modeled when the biological target was identified and the crystal structure was solved.

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Chemical Space Exploration around Thieno[3,2-d]pyrimidin-4(3H)-one Scaffold Led to a Novel Class of Highly Active Clostridium difficile Inhibitors

Cited by 21 publications

References 59 publications

Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections

Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections

Auranofin, at clinically achievable dose, protects mice and prevents recurrence from Clostridioides difficile infection

Thienopyrimidine: A Promising Scaffold to Access Anti-Infective Agents

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