Fragment Discovery for the Design of Nitrogen Heterocycles as <i>Mycobacterium tuberculosis</i> Dihydrofolate Reductase Inhibitors

Shelke, Rupesh U.; Degani, Mariam S.; Raju, Archana; Ray, Mukti Kanta; Rajan, M. G. R.

doi:10.1002/ardp.201600066

Cited by 13 publications

(4 citation statements)

References 56 publications

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“…In the context of antifolate resistance, development of new generation antifolates based on novel chemotypes is warranted. Although the fragment-based screening approach has been successfully applied to DHFR enzymes in various bacteria and protozoa 41,42 , no similar study has yet been reported in the malaria parasite Plasmodium falciparum. Here, we describe the first fragment-based screening on PfDHFR.…”

Section: Discussionmentioning

confidence: 99%

Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening

Hoarau

Vanichtanankul

Srimongkolpithak

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidinebased antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits. Subsequent enzyme inhibition assay identified 11 fragments displaying IC 50 in the 28-695 lM range and selectivity for PfDHFR. In addition to the known pyrimidine, three new anti-PfDHFR chemotypes were identified. Fragments from each chemotype were successfully co-crystallized with PfDHFR, revealing a binding in the active site, in the vicinity of catalytic residues, which was confirmed by molecular docking on all fragment hits. Finally, comparison with similar non-hit fragments provides preliminary input on available growth vectors for future drug development.

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Section: Discussionmentioning

confidence: 99%

Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening

Hoarau

Vanichtanankul

Srimongkolpithak

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…These fragments showed high glide score from À 6.10 to À 7.85 kcal/mol. [45] Compound 134 exhibited remarkably anti-tubercular activity with MIC value of 6.25 μg/mL as compared to standard drug Rifampicin (0.313 μg/mL). The molecular docking study revealed that compound 134 showed good interaction with amino acid residues of glycerol (GOL) binding site of Mtb-DHFR enzyme such as Ile20, Arg23, Phe31, Leu50, Pro51 and Val54 among these residue Phe31 and Arg23 showed hydrogen bonding interaction.…”

Section: Antitubercular Activitymentioning

confidence: 95%

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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“…1), belonging to the xanthine compounds, can decrease smooth muscle tension, open air passages and promote the release of endogenous epinephrine and norepinephrine [1] . Theophylline can also inhibit the release of calcium ions (Ca 2+ ) from the endoplasmic reticulum of smooth muscle cells and reduce the intracellular Ca 2+ concentration, thereby generating an airway dilating effect, and it is a potent smooth muscle relaxant [2] . Theophylline is used to treat diseases including bronchial asthma, acute bronchitis, asthmatic bronchitis, and obstructive emphysema, in order to relieve the symptoms of wheezing [3,4] .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and activity study of novel theophylline derivatives as IDO1 inhibitors

Hou

Lou

et al. 2023

Preprint

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Indoleamine 2,3-dioxygenase 1 (IDO1), an immunomodulatory enzyme associated with tumor immune escape. Numerous studies have shown that it is an attractive therapeutic target for cancer diseases. To identify holo-IDO1 inhibitors with novel skeleton structures, a series of theophylline derivatives with 1,2,3-triazole groups were designed and synthesized by condensingtheophylline acetic acid and 4-aminophenylacetylene.In the IDO1 enzymatic activity assay, we found that compound 3c exhibited the best inhibitory effect(IC50 = 10.07µM). Molecular docking and affinity prediction analysis further elucidated the binding ability and mode of the dominant compounds. Our study suggested that the theophylline derivatives are potential holo-IDO1 inhibitors for future development.

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Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors

Cited by 13 publications

References 56 publications

Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening

Discovery of new non-pyrimidine scaffolds as Plasmodium falciparum DHFR inhibitors by fragment-based screening

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

Synthesis and activity study of novel theophylline derivatives as IDO1 inhibitors

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