Antimicrobial screening and pharmacokinetic profiling of novel phenyl-[1,2,4]triazolo[4,3-a]quinoxaline analogues targeting DHFR and E. coli DNA gyrase B

Omar, Abdelsattar M.; Alswah, Mohamed; Ahmed, Hany E. A.; Bayoumi, Ashraf H.; El‐Gamal, Kamal M.; El-Morsy, Ahmed; Ghiaty, Adel; Afifi, Tarek H.; Sherbiny, Farag F.; Mohammed, Adel Saad; Mansour, Basem

doi:10.1016/j.bioorg.2020.103656

Cited by 24 publications

(12 citation statements)

References 43 publications

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“…The molecular modelling results indicated that the potent compound 117 showed hydrogen bonding interaction with Val115, Ile7, Asn64 and Arg70 amino acid residues. [42] Scheme 20. Synthesis of trimethoprim analogues.…”

Section: Antimicrobial Activitymentioning

confidence: 99%

An Insight into Synthetic Strategies and Recent Developments of Dihydrofolate Reductase Inhibitors

et al. 2021

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The dihydrofolate reductase (DHFR) is a significant target in cancer, microbial infection, fungal infection, malaria, leishmaniasis, and tuberculosis, among other diseases. The DHFR gene was discovered in prokaryotes and eukaryotes in the late 1950s and is found in all dividing cells. DHFR inhibitors are used for a variety of medicinal purposes. Increased resistance to therapeutic agents such as anticancer, antibiotic, anti‐tuberculosis, and antifungal sparked interest in the development of potent, broad‐spectrum medicines to address the issues. DHFR is a critical target in the development of innovative solutions to address the issues. Methotrexate, trimethoprim, sulfonamides, pyrimethamine, aminopterin, methotrexate, edatrexate, and pralatrexate are only a few of the medications that target DHFR. These medications are known as DHFR inhibitors. These inhibitors block the enzyme dihydrofolate reductase, resulting in a folic acid synthesis pathway that is compromised. The DHFR is involved in the conversion of dihydrofolate to tetrahydrofolate. Purine, pyrazole, pyrimidine, triazole, oxadiazole, and other heterocyclic motifs have shown to have a potential effect on the DHFR. In the medicinal chemistry community, a better understanding of the so‐called enzyme and biochemical underpinnings responsible for enzyme selectivity has led to the development of improved, unique, and new treatments. Several researchers are working on DHFR inhibitors intensely, using a variety of synthetic techniques, molecular modelling, mechanistic studies, in‐vitro and in‐vivo biological evaluations, and structure‐activity relationships (SAR). This review, compiles the findings of several research groups during the last five years. The molecular biology of DHFR, its biosynthetic pathway, and the powerful structure of DFHR inhibitors discovered during the search are all included in this review. The study also includes the latest developments in synthetic methods, molecular docking, and structure‐activity relationships.

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Section: Antimicrobial Activitymentioning

confidence: 99%

An Insight into Synthetic Strategies and Recent Developments of Dihydrofolate Reductase Inhibitors

et al. 2021

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“…Quinoline is a vital pharmacophore ring system present in a number of antifungal agents. [ 8,10 ] Quinoline derivatives possess diverse pharmacological activities, particularly antibacterial, [ 7,8 ] antifungal, [ 8,11–13 ] and antimalarial. [ 14,15 ]…”

Section: Introductionmentioning

confidence: 99%

“…Over the last two decades, there were several reports on novel quinoline derivatives as potential antimicrobial agents that target DNA gyrase. [7,8] Currently, fluoroquinolones are being utilized in the management of serious microbial infections such as bacterial pneumonia. However, bacterial resistance to such antimicrobials with no novel medications in the antimicrobials pipeline has driven intensive research in this area.…”

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confidence: 99%

“…[8,10] Quinoline derivatives possess diverse pharmacological activities, particularly antibacterial, [7,8] antifungal, [8,[11][12][13] and antimalarial. [14,15] 1.1 | Rationale and aim of the work On the basis of the aforementioned facts, inspired by the versatility of the quinoline moiety mentioned above, and as a continuation of our recent studies, [7,16,17] to identify new antimicrobial agents, the synthesis of three novel series of 6-methylquinoline-3-carbonitrile derivatives was carried out to obtain new molecules with higher potency. The design of new compounds depended on modifying structural aspects of the previously reported fluoroquinolones to evaluate their activities against pathogenic bacterial and fungal strains.…”

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confidence: 99%

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Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives

El-Shershaby

El‐Gamal

Bayoumi

et al. 2020

Archiv der Pharmazie

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Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram‐positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram‐negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66–5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad‐spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66–3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC50 value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.

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“…These include Pyridoxal 5'-diphospho-5'adenosine (PLP-AMP) [9], tyrosine-based diamides [20], 1H-pyrrole-2carboxamide moieties [21], N-phenylpyrrolamides [22], N-phenyl 4,5-dibromo-pyrrolmides [23], and (1,2,4) triazole (4,3-a)quinoxaline derivatives of diff erent heteroaromatization members [24], cinodine, clerocidin, albicidin, GSK299423, a series of tetrahydroindazoles, quinazoline-2,4-diones PD0305970 and PD0326448, QPT-1, quinolone based drug NXL-101 [25] etc. In addition to gyrB, even gyrA possesses a pocket which is capable of binding to coumarin or aminocoumarin, suggesting that any inhibitor like simocyclinone binding to gyrB may bind to gyrA.…”

Section: Introductionmentioning

confidence: 99%

Repurposing Potential of Diminazene Aceturate as an Inhibitor of the E. coli DNA Gyrase B

Dwivedi¹,

Ayyagarí²,

Chandran³

et al. 2020

J Biomed Res Environ Sci

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Drug-resistant Escherichia coli (E. coli) has overburdened the healthcare facilities in recent years and is getting hard to combat, mandating search for novel therapeutics with a broad antibacterial spectrum and high chemotherapeutic index. The 24 kDa domain of DNA gyrase B that is involved in the ATPase activity has been reported to be a promising target for inhibitors. A PDB structure (1KZN) of the 24kD domain of gyrase B with the co-crystallized ligand clorobiocin was used for the docking studies to explore a library of 2924 FDA approved drugs from www.zinc.docking.org. FlexX docking module from Biosolve IT was used for receptor preparation and in silico docking experiments. Docking studies on the pocket created around the reference ligand clorobiocin revealed the best score with diminazene aceturate and it also demonstrated interactions with the crucial amino acids present within the pocket. Diminazene aceturate has been conventionally been used as an antiparasitic molecule in animals and it has also been demonstrated to exhibit repurposing potential in the treatment of disorders triggered due to overproduction of inflammatory cytokines, pulmonary hypertension, ischemia-induced cardiac pathophysiology, etc. among others. Findings from this study indicate the possibility of repurposing the age-old molecule diminazene aceturate into a DNA gyrase B antagonist to combat not just the drug-resistant E. coli but also other gram-negative ESKAPE pathogens. It may also aid in alleviating the inflammatory response induced in the body of the patients suffering from septicemia caused by a variety of Gram-negative bacterial pathogens.

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Antimicrobial screening and pharmacokinetic profiling of novel phenyl-[1,2,4]triazolo[4,3-a]quinoxaline analogues targeting DHFR and E. coli DNA gyrase B

Cited by 24 publications

References 43 publications

An Insight into Synthetic Strategies and Recent Developments of Dihydrofolate Reductase Inhibitors

An Insight into Synthetic Strategies and Recent Developments of Dihydrofolate Reductase Inhibitors

Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives

Repurposing Potential of Diminazene Aceturate as an Inhibitor of the E. coli DNA Gyrase B

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