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Journal articles on the topic 'DHFR inhibition'

Author: Grafiati

Published: 7 June 2025

Last updated: 2 August 2025

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1

Maskell, Jeffrey P., Armine M. Sefton, and Lucinda M. C. Hall. "Multiple Mutations Modulate the Function of Dihydrofolate Reductase in Trimethoprim-ResistantStreptococcus pneumoniae." Antimicrobial Agents and Chemotherapy 45, no. 4 (2001): 1104–8. http://dx.doi.org/10.1128/aac.45.4.1104-1108.2001.

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ABSTRACT Trimethoprim resistance in Streptococcus pneumoniaecan be conferred by a single amino acid substitution (I100-L) in dihydrofolate reductase (DHFR), but resistant clinical isolates usually carry multiple DHFR mutations. DHFR genes from five trimethoprim-resistant isolates from the United Kingdom were compared to susceptible isolates and used to transform a susceptible control strain (CP1015). All trimethoprim-resistant isolates and transformants contained the I100-L mutation. The properties of DHFRs from transformants with different combinations of mutations were compared. In a transfo

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2

Mayur, Bagane*1 Rutuparna Karkare2 Rajesh Jorgewad3 Saee Thakur4 Medha Petkar5 Amruta Patil6 Sneha Kagale7. "Revealing the Molecular Interactions: Investigating the Docking Studies of (N-(4-Carboxy-4-{4-[(2,4-diamino-pteridin-6-ylmethyl)-amino]-benzoylamino}-butyl)-phthalamic acid) with Dihydrofolate Reductase." International Journal in Pharmaceutical Sciences 2, no. 4 (2024): 321–30. https://doi.org/10.5281/zenodo.10932469.

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Dihydrofolate reductase (DHFR) is a vital enzyme in folate metabolism, and its inhibition is a well-established strategy for antibacterial and anticancer therapies. Here, we investigated the inhibitory mechanism of N-(4-Carboxy-4-{4-[(2,4-diamino-pteridin-6-ylmethyl)-amino]-benzoylamino}-butyl)-phthalamicacid(BDBM50011320), a small molecule identified through in silico docking to possess high affinity for human DHFR. In vitro enzymatic assays confirmed a sub-nanomolar Ki value for BDBM50011320, indicating potent inhibition of DHFR activity. To elucidate the binding mode and inhibitory mechanis

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3

Queener, S. F., V. Cody, J. Pace, P. Torkelson, and A. Gangjee. "Trimethoprim Resistance of Dihydrofolate Reductase Variants from Clinical Isolates of Pneumocystis jirovecii." Antimicrobial Agents and Chemotherapy 57, no. 10 (2013): 4990–98. http://dx.doi.org/10.1128/aac.01161-13.

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ABSTRACTPneumocystis jiroveciiis an opportunistic pathogen that causes serious pneumonia in immunosuppressed patients. Standard therapy and prophylaxis include trimethoprim (TMP)-sulfamethoxazole; trimethoprim in this combination targets dihydrofolate reductase (DHFR). Fourteen clinically observed variants ofP. jiroveciiDHFR were produced recombinantly to allow exploration of the causes of clinically observed failure of therapy and prophylaxis that includes trimethoprim. Six DHFR variants (S31F, F36C, L65P, A67V, V79I, and I158V) showed resistance to inhibition by trimethoprim, withKivalues fo

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4

Boese, Austin, Isabelle Young, Jihoon Kang, Courteney Malin, Jung Seok Hwang, and Sumin Kang. "Abstract 2334: Inhibition of DHFR modulates anti-tumor immunity." Cancer Research 82, no. 12_Supplement (2022): 2334. http://dx.doi.org/10.1158/1538-7445.am2022-2334.

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Abstract Lung cancer is the second most common type of cancer in both men and women and has the highest mortality rate. Non-small cell lung cancer (NSCLC) makes up most cases. Immune checkpoint inhibitors have significantly improved the clinical management of some NSCLC cases, yet many lung cancer patients still fail to respond to conventional immunotherapy. Therefore, more research is needed to characterize cellular pathways contribute to immune checkpoint inhibitor (ICI) resistance in NSCLC patients. Dysregulated cellular metabolism is a common feature of many cancer types, and metabolites a

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5

Bhoj, Priyanka S., Sandeep P. Bahekar, Shambhavi Chowdhary, et al. "Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite." Biomedicines 11, no. 3 (2023): 723. http://dx.doi.org/10.3390/biomedicines11030723.

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A series of Michael adducts of malononitrile and sulfonamide chalcones were synthesized, characterized, and evaluated for their antifilarial activity. Out of 14 compounds, N-(4-(4,4-dicyano-3-p-tolylbutanoyl)phenyl)benzenesulfonamide showed favorable drug-likeness properties with marked antifilarial effects at micro-molar dosages. Apoptosis in Brugia malayi microfilariae was confirmed by EB/AO staining, MTT assay, and cytoplasmic cytochrome c ELISA. Since chalcone and folate synthesis pathways share the same substrate, we hypothesize a structural analogy-based inhibition of folate metabolism b

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6

Mahnashi, Mater H., B. H. Prabhanjana, Sudarshan Seetammanavar, et al. "Synthesis and in silico studies of some new Schiff bases as antimicrobial and antitubercular agents." INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY 35, no. 01 (2025): 141. https://doi.org/10.59467/ijhc.2025.35.141.

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Ten pyridine carbohydrazide Schiff bases (3a-3e) and (5a-5e) were synthesized by refluxing pyridine carbohydrazides 1 and 4 with different ketones in the presence of ethanol and a few drops of glacial acetic acid. The synthesized compounds were biologically screened for antitubercular and antibacterial activity studies. The fit of these compounds within the active sites of the dihydrofolate reductase (DHFR) and enoyl ACP reductase was evaluated using molecular modeling techniques. The findings of the anticipated ADMET investigation showed that the compounds with the given names have drug-like

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7

Aragaw, Wassihun Wedajo, Brendon M. Lee, Xuan Yang, et al. "Potency boost of a Mycobacterium tuberculosis dihydrofolate reductase inhibitor by multienzyme F420H2-dependent reduction." Proceedings of the National Academy of Sciences 118, no. 25 (2021): e2025172118. http://dx.doi.org/10.1073/pnas.2025172118.

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Triaza-coumarin (TA-C) is a Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitor with an IC50 (half maximal inhibitory concentration) of ∼1 µM against the enzyme. Despite this moderate target inhibition, TA-C shows exquisite antimycobacterial activity (MIC50, concentration inhibiting growth by 50% = 10 to 20 nM). Here, we investigated the mechanism underlying this potency disconnect. To confirm that TA-C targets DHFR and investigate its unusual potency pattern, we focused on resistance mechanisms. In Mtb, resistance to DHFR inhibitors is frequently associated with mutation

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8

Aboge, Gabriel O., Honglin Jia, Mohamad A. Terkawi, et al. "Cloning, Expression, and Characterization of Babesia gibsoni Dihydrofolate Reductase-Thymidylate Synthase: Inhibitory Effect of Antifolates on Its Catalytic Activity and Parasite Proliferation." Antimicrobial Agents and Chemotherapy 52, no. 11 (2008): 4072–80. http://dx.doi.org/10.1128/aac.00384-08.

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ABSTRACT Dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a well-validated antifolate drug target in certain pathogenic apicomplexans, but not in the genus Babesia, including Babesia gibsoni. Therefore, we isolated, cloned, and expressed the wild-type B. gibsoni dhfr-ts gene in Escherichia coli and evaluated the inhibitory effect of antifolates on its enzyme activity, as well as on in vitro parasite growth. The full-length gene consists of a 1,548-bp open reading frame encoding a 58.8-kDa translated peptide containing DHFR and TS domains linked together in a single polypeptide chain.

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9

Avunoori, Sravanthi, Nayef Abdulaziz Aldabaan, Ibrahim Ahmed Shaikh, et al. "Synthesis and in silico studies of some new pyrrolylbenzamide derivatives as antitubercular and antimicrobial agents." INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY 34, no. 03 (2024): 353. http://dx.doi.org/10.59467/ijhc.2024.34.353.

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Eighteen new pyrrolylbenzamide derivatives (6a-6r) were synthesized by reacting N-(2,5-dimethyl- 1H-pyrrol-1-yl)-4-(2-hydrazineyl-2-oxoethoxy)benzamide (4) with substituted benzoic acids (5a-5r) in the presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, diisopropyl ethylamine and dimethyl formamide. The produced compounds were subjected to molecular docking studies against the dihydrofolate reductase (DHFR) and InhA mycobacterial enzymes. The compounds were biologically screened for antimycobacterial, and antibacterial activities along with InhA and DHFR enzym

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10

Batra, Apsara, and V. Girija Sastry. "Extraction of ursolic acid from Ocimum sanctum and synthesis of its novel derivatives: effects on extracellular homocysteine, dihydrofolate reductase activity and proliferation of HepG2 human hepatoma cells." Pteridines 24, no. 3 (2013): 191–99. http://dx.doi.org/10.1515/pterid-2013-0023.

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AbstractThe objective of the present study was to extract ursolic acid (UA) from Ocimum sanctum, to synthesize its bioactive derivatives, evaluate the anti-cancer effect of its derivatives and to establish the possible mechanism of action. In the present report, we extracted UA from whole plant of O. sanctum, synthesized its novel derivatives and investigated their effect on homocysteine metabolism and dihydrofolate reductase (DHFR) activity of HepG2 cells. UA and its derivatives UA-1, UA-2 and UA-3 down-regulated DHFR activity and increased extracellular homocysteine. UA-2 showed significant

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11

Dieckmann, A., and A. Jung. "The mechanism of pyrimethamine resistance in Plasmodium falciparum." Parasitology 93, no. 2 (1986): 275–78. http://dx.doi.org/10.1017/s0031182000051441.

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SUMMARYThe uptake of radioactive pyrimethamine by a sensitive and a resistant strain of Plasmodium falciparum, the metabolic fate of pyrimethamine inside these parasites and the kinetic properties of dihydrofolate reductase (DHFR) from both strains have been studied. Uptake of the drug was identical in both strains and no metabolite of pyrimethamine was found in either strain. DHFR from the resistant strain was 300 times less sensitive to inhibition by pyrimethamine than the enzyme from the sensitive strain, while the Michaelis constant for dihydrofolate remained unchanged and inhibition was c

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12

Liu, Jieying, David B. Bolstad, Erin S. D. Bolstad, Dennis L. Wright, and Amy C. Anderson. "Towards New Antifolates Targeting Eukaryotic Opportunistic Infections." Eukaryotic Cell 8, no. 4 (2009): 483–86. http://dx.doi.org/10.1128/ec.00298-08.

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ABSTRACT Trimethoprim, an antifolate commonly prescribed in combination with sulfamethoxazole, potently inhibits several prokaryotic species of dihydrofolate reductase (DHFR). However, several eukaryotic pathogenic organisms are resistant to trimethoprim, preventing its effective use as a therapeutic for those infections. We have been building a program to reengineer trimethoprim to more potently and selectively inhibit eukaryotic species of DHFR as a viable strategy for new drug discovery targeting several opportunistic pathogens. We have developed a series of compounds that exhibit potent an

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13

Uchiyama, Hitoji, Yoshihiro Sowa, Miki Wakada, et al. "Cyclin-Dependent Kinase Inhibitors Enhance Sensitivity to Methotrexate In Human T-Cell Leukemia Jurkat Cells." Blood 116, no. 21 (2010): 3976. http://dx.doi.org/10.1182/blood.v116.21.3976.3976.

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Abstract Abstract 3976 Methotrexate (MTX), a classical anti-folate drug, has been used in the treatment of various hematological malignancies. Since MTX prevents tumor cells from proliferating by inhibiting dihydrofolate reductase (DHFR), DHFR expression is a key determinant of resistance to MTX in malignant hematological tumor cells. In fact, it is well known that elevated expression of DHFR is a direct factor in clinical therapeutic resistance to MTX. Therefore, small compounds that repress DHFR expression may be useful as chemosensitizers in combination with MTX. First of all, we demonstrat

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14

Wang, Yangzhou, Jeremy A. Bruenn, Sherry F. Queener, and Vivian Cody. "Isolation of Rat Dihydrofolate Reductase Gene and Characterization of Recombinant Enzyme." Antimicrobial Agents and Chemotherapy 45, no. 9 (2001): 2517–23. http://dx.doi.org/10.1128/aac.45.9.2517-2523.2001.

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ABSTRACT While assays of many antifolate inhibitors for dihydrofolate reductase (DHFR) have been performed using rat DHFR as a target, neither the sequence nor the structure of rat DHFR is known. Here, we report the isolation of the rat DHFR gene through screening of a rat liver cDNA library. The rat liver DHFR gene has an open reading frame of 561 bp encoding a protein of 187 amino acids. Comparisons of the rat enzyme with those from other species indicate a high level of conservation at the primary sequence level and more so for the amino acid residues comprising the active site of the enzym

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15

Harer, Sunil, Manish Bhatia, and Vikram Kawade. "Synthesis, Antimicrobial Evaluation and Molecular Docking of Some Potential 2,6-disubstituted 1H-Benzimidazoles; Non-Classical Antifolates." Medicinal Chemistry 15, no. 7 (2019): 813–32. http://dx.doi.org/10.2174/1573406415666190206231555.

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Background: Dihydrofolate reductase is one of the important enzymes for thymidylate and purine synthesis in micro-organisms. A large number of drugs have been designed to inhibit microbial DHFR but over the period of time, some drugs have developed resistance and cross reactivity towards the enzyme. Over the past few decades, benzimidazoles, triazoles and their derivatives have been grabbing the attention of the synthetic chemists for their wide gamut of antibacterial and antifungal activities targeting microbial protein DHFR. Objective: Our goal behind present investigation is to explore benz

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16

NARE, B., J. LUBA, L. W. HARDY, and S. BEVERLEY. "New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity." Parasitology 114, no. 7 (1997): 101–10. http://dx.doi.org/10.1017/s0031182097001133.

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Leishmania and other trypanosomatid protozoa require reduced pteridines (pterins and folates) for growth, suggesting that inhibition of these pathways could be targeted for effective chemotherapy. This goal has not yet been realized, indicating that pteridine metabolism may be unusual in this lower eukaryote. We have investigated this possibility using both wild type and laboratory-selected antifolate-resistant strains, and with defined genetic knockouts of several pteridine metabolic genes. In Leishmania, resistance to the antifolate methotrexate is mediated through several mechanisms singly

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17

Santucci, Matteo, Rosaria Luciani, Eleonora Gianquinto, et al. "Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases." Pharmaceuticals 14, no. 12 (2021): 1246. http://dx.doi.org/10.3390/ph14121246.

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Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of a novel core structure inspiring new treatments of parasitic diseases targeting the trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate reductase (DHFR) enzymes. In total, 592 compounds were tested through medium-throughput screening assays. A subset of 14 compounds successfully inhibited the enzyme activity in the low micromolar range of at least one of the enzymes from both Trypa

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18

Baik, Jong Youn, Hye Jin Han, and Kelvin H. Lee. "DNA Double-Strand Breaks Affect Chromosomal Rearrangements during Methotrexate-Mediated Gene Amplification in Chinese Hamster Ovary Cells." Pharmaceutics 13, no. 3 (2021): 376. http://dx.doi.org/10.3390/pharmaceutics13030376.

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Methotrexate (MTX)-mediated gene amplification has been widely used in Chinese hamster ovary (CHO) cells for the biomanufacturing of therapeutic proteins. Although many studies have reported chromosomal instability and extensive chromosomal rearrangements in MTX-mediated gene-amplified cells, which may be associated with cell line instability issues, the mechanisms of chromosomal rearrangement formation remain poorly understood. We tested the impact of DNA double-strand breaks (DSBs) on chromosomal rearrangements using bleomycin, a DSB-inducing reagent. Bleomycin-treated CHO-DUK cells, which a

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19

SHARMA, R. D., S. BAG, N. R. TAWARI, M. S. DEGANI, K. GOSWAMI, and M. V. R. REDDY. "Exploration of 2, 4-diaminopyrimidine and 2, 4-diamino-s-triazine derivatives as potential antifilarial agents." Parasitology 140, no. 8 (2013): 959–65. http://dx.doi.org/10.1017/s0031182013000309.

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SUMMARYIn view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis, dihydrofolate reductase (DHFR) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the DHFR inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of DHFR can induce apopto

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20

Brophy, Victoria Hertle, John Vasquez, Richard G. Nelson, John R. Forney, Andre Rosowsky, and Carol Hopkins Sibley. "Identification of Cryptosporidium parvum Dihydrofolate Reductase Inhibitors by Complementation in Saccharomyces cerevisiae." Antimicrobial Agents and Chemotherapy 44, no. 4 (2000): 1019–28. http://dx.doi.org/10.1128/aac.44.4.1019-1028.2000.

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ABSTRACT There is a pressing need for drugs effective against the opportunistic protozoan pathogen Cryptosporidium parvum. Folate metabolic enzymes and enzymes of the thymidylate cycle, particularly dihydrofolate reductase (DHFR), have been widely exploited as chemotherapeutic targets. Although many DHFR inhibitors have been synthesized, only a few have been tested against C. parvum. To expedite and facilitate the discovery of effective anti-Cryptosporidium antifolates, we have developed a rapid and facile method to screen potential inhibitors of C. parvum DHFR using the model eukaryote, Sacch

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21

Galassi, Rossana, Camille Simon Oumarou, Alfredo Burini, et al. "A study on the inhibition of dihydrofolate reductase (DHFR) from Escherichia coli by gold(i) phosphane compounds. X-ray crystal structures of (4,5-dichloro-1H-imidazolate-1-yl)-triphenylphosphane-gold(i) and (4,5-dicyano-1H-imidazolate-1-yl)-triphenylphosphane-gold(i)." Dalton Transactions 44, no. 7 (2015): 3043–56. http://dx.doi.org/10.1039/c4dt01542h.

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22

Ma, Liang, and Joseph A. Kovacs. "Expression and Characterization of Recombinant Human-DerivedPneumocystis carinii Dihydrofolate Reductase." Antimicrobial Agents and Chemotherapy 44, no. 11 (2000): 3092–96. http://dx.doi.org/10.1128/aac.44.11.3092-3096.2000.

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ABSTRACT Dihydrofolate reductase (DHFR) is the target of trimethoprim (TMP), which has been widely used in combination with sulfa drugs for treatment and prophylaxis of Pneumocystis cariniipneumonia. While the rat-derived P. carinii DHFR has been well characterized, kinetic studies of human-derived P. carinii DHFR, which differs from rat-derived P. carinii DHFR by 38% in amino acid sequence, have not been reported to date. Here we report on the expression and kinetic characterization of the recombinant human-derived P. carinii DHFR. The 618-bp coding sequence of the human-derivedP. carinii DHF

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23

Barrow, Esther W., Jürg Dreier, Stefan Reinelt, Philip C. Bourne, and William W. Barrow. "In Vitro Efficacy of New Antifolates against Trimethoprim-Resistant Bacillus anthracis." Antimicrobial Agents and Chemotherapy 51, no. 12 (2007): 4447–52. http://dx.doi.org/10.1128/aac.00628-07.

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ABSTRACT Bacillus anthracis is innately resistant to trimethoprim (TMP), a synthetic antifolate that selectively inhibits several bacterial dihydrofolate reductases (DHFRs) but not human DHFR. Previously, we were able to confirm that TMP resistance in B. anthracis (MIC > 2,048 μg/ml) is due to the lack of selectivity of TMP for the B. anthracis DHFR (E. W. Barrow, P. C. Bourne, and W. W. Barrow, Antimicrob. Agents Chemother. 48:4643-4649, 2004). In this investigation, 24 2,4-diaminopyrimidine derivatives, representing a class of compounds with dihydrophthalazine side chains, were screened f

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Bare, Yohanes, Dewi Ratih Tirto Sari, Lydia Efliani Coriessa Meak, and Marsiana Coo Mogi. "In silico study of columbin from Tinospora crispa L as dihydrofolate reductase-thymidylate synthase (DHFR-TS) inhibitor." Bioscience 6, no. 1 (2022): 12. http://dx.doi.org/10.24036/0202261116090-0-00.

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The Brotowali plant is used to treat malaria. Tinospora crispa L contains active compounds that are good for health and has been widely used for medicine. Crude extract from Tinospora crispa L can be used as target dihydrofolate reductase-thymidylate synthase (DHFR-TS). This research study was to analyse the potential chemical content of Tinospora crispa L in the form of columbine compounds as a focus of malaria therapy through inhibition of dihydrofolate reductase-thymidylate synthase (DHFR-TS). In silico research method, columbine (CID: 188289) ligand was obtained from Pubchem while DHFR-TS

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25

Beck, Sungjun, Zhe Zhu, Michelli F. Oliveira, et al. "Mechanism of Action of Methotrexate Against Zika Virus." Viruses 11, no. 4 (2019): 338. http://dx.doi.org/10.3390/v11040338.

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Zika virus (ZIKV), which is associated with microcephaly in infants and Guillain-Barré syndrome, reemerged as a serious public health threat in Latin America in recent years. Previous high-throughput screening (HTS) campaigns have revealed several potential hit molecules against ZIKV, including methotrexate (MTX), which is clinically used as an anti-cancer chemotherapy and anti-rheumatoid agent. We studied the mechanism of action of MTX against ZIKV in relation to its inhibition of dihydrofolate reductase (DHFR) in vitro using Vero and human neural stem cells (hNSCs). As expected, an antiviral

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Omar, Abdelsattar M., Khadijah A. Mohammad, Ikhlas A. Sindi, Gamal A. Mohamed, and Sabrin R. M. Ibrahim. "Unveiling the Efficacy of Sesquiterpenes from Marine Sponge Dactylospongia elegans in Inhibiting Dihydrofolate Reductase Using Docking and Molecular Dynamic Studies." Molecules 28, no. 3 (2023): 1292. http://dx.doi.org/10.3390/molecules28031292.

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Dihydrofolate reductase (DHFR) is a crucial enzyme that maintains the levels of 5,6,7,8-tetrahydrofolate (THF) required for the biological synthesis of the building blocks of DNA, RNA, and proteins. Over-activation of DHFR results in the progression of multiple pathological conditions such as cancer, bacterial infection, and inflammation. Therefore, DHFR inhibition plays a major role in treating these illnesses. Sesquiterpenes of various types are prime metabolites derived from the marine sponge Dactylospongia elegans and have demonstrated antitumor, anti-inflammation, and antibacterial capaci

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Brown, Jennifer I., Peng Wang, Alan Y. L. Wong, et al. "Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity." Metabolites 13, no. 2 (2023): 151. http://dx.doi.org/10.3390/metabo13020151.

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Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved plasmodium DHFR inhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapies in the 1970s. Herein, current computational and chemical biology techniques were employed to re-investigate the anti-cancer activity of Cycloguanil and related compounds. In silico modeling was employed to identify promisi

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Bourne, C. R., E. W. Barrow, R. A. Bunce, P. C. Bourne, K. D. Berlin, and W. W. Barrow. "Inhibition of Antibiotic-Resistant Staphylococcus aureus by the Broad-Spectrum Dihydrofolate Reductase Inhibitor RAB1." Antimicrobial Agents and Chemotherapy 54, no. 9 (2010): 3825–33. http://dx.doi.org/10.1128/aac.00361-10.

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ABSTRACT The bacterial burden on human health is quickly outweighing available therapeutics. Our long-term goal is the development of antimicrobials with the potential for broad-spectrum activity. We previously reported phthalazine-based inhibitors of dihydrofolate reductase (DHFR) with potent activity against Bacillus anthracis, a major component of Project BioShield. The most active molecule, named RAB1, performs well in vitro and, in a cocrystal structure, was found deep within the active site of B. anthracis DHFR. We have now examined the activity of RAB1 against a panel of bacteria releva

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de Groot, R., D. O. Chaffin, M. Kuehn, and A. L. Smith. "Trimethoprim resistance in Haemophilus influenzae is due to altered dihydrofolate reductase(s)." Biochemical Journal 274, no. 3 (1991): 657–62. http://dx.doi.org/10.1042/bj2740657.

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We characterized a highly purified preparation of the chromosomally encoded dihydrofolate reductase (DHFR) from a trimethoprim-susceptible (Tmp8; strain MAP) and two trimethoprim-resistant (TmpR) strains (MAP/47 and MAP/42) of Haemophilus influenzae. The enzymes were purified between 650- and 3000-fold by gel-filtration and dye-ligand chromatography. The apparent molecular mass of the three proteins was 18400 Da by PAGE under denaturing and nondenaturing conditions. Total enzyme activity was greater in all fractions from the TmpR strains compared with the Tmp8 isolate. The three enzymes had a

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Joska, Tammy M., and Amy C. Anderson. "Structure-Activity Relationships of Bacillus cereus and Bacillus anthracis Dihydrofolate Reductase: toward the Identification of New Potent Drug Leads." Antimicrobial Agents and Chemotherapy 50, no. 10 (2006): 3435–43. http://dx.doi.org/10.1128/aac.00386-06.

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ABSTRACT New and improved therapeutics are needed for Bacillus anthracis, the etiological agent of anthrax. To date, antimicrobial agents have not been developed against the well-validated target dihydrofolate reductase (DHFR). In order to address whether DHFR inhibitors could have potential use as clinical agents against Bacillus, 27 compounds were screened against this enzyme from Bacillus cereus, which is identical to the enzyme from B. anthracis at the active site. Several 2,4-diamino-5-deazapteridine compounds exhibit submicromolar 50% inhibitory concentrations (IC50s). Four of the inhibi

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Ragab, Ahmed, Sawsan A. Fouad, Ola A. Abu Ali, et al. "Sulfaguanidine Hybrid with Some New Pyridine-2-One Derivatives: Design, Synthesis, and Antimicrobial Activity against Multidrug-Resistant Bacteria as Dual DNA Gyrase and DHFR Inhibitors." Antibiotics 10, no. 2 (2021): 162. http://dx.doi.org/10.3390/antibiotics10020162.

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Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition again

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Wróbel, Agnieszka, Dawid Maliszewski, Maciej Baradyn, and Danuta Drozdowska. "Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs." Molecules 25, no. 1 (2019): 116. http://dx.doi.org/10.3390/molecules25010116.

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A new series of trimethoprim (TMP) analogs containing amide bonds (1–6) have been synthesized. Molecular docking, as well as dihydrofolate reductase (DHFR) inhibition assay were used to confirm their affinity to bind dihydrofolate reductase enzyme. Data from the ethidium displacement test showed their DNA-binding capacity. Tests confirming the possibility of DNA binding in a minor groove as well as determination of the association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT)2 and poly (dG-dC)2. Additionally, the mechanism of action of the new compounds was stu

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Nerkar, A. G., A. K. Saxena, S. A. Ghone, and A. K. Thaker. "In SilicoScreening, Synthesis andIn VitroEvaluation of Some Quinazolinone and Pyridine Derivatives as Dihydrofolate Reductase Inhibitors for Anticancer Activity." E-Journal of Chemistry 6, s1 (2009): S97—S102. http://dx.doi.org/10.1155/2009/506576.

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Dihydrofolate reductase (DHFR) is the important target for anticancer drugs belonging to the class of antimetabolites as the enzyme plays important role in the de novo purine synthesis. We here report thein silicoscreening to obtain best fit molecules as DHFR inhibitors, synthesis of some ʻbest fitʼ quinazolinone from 2-phenyl-3-(substituted-benzilidine-amino) quinazolinones (Quinazolinone Shiff's bases) QSB1-5and pyridine-4-carbohydrazide Shiff's bases (ISB1-5) derivatives and theirin vitroanticancer assay. Synthesis of the molecules was performed using microwave assisted synthesis. The struc

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Shakil, Shazi, Adel M. Abuzenadah, Suzan M. Attar, Omar Fathaldin, Rajaa Al-Raddadi, and Mansour I. Sulaiman. "Molecular interaction of 4-amino-N’-(benzoyloxy)-N-(2,4- dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide with the methotrexate binding site of human DHFR, and its implication in rheumatoid arthritis." Tropical Journal of Pharmaceutical Research 19, no. 5 (2020): 1045–52. http://dx.doi.org/10.4314/tjpr.v19i5.20.

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Purpose: To identify an improved lead molecule for the human dihydrofolate reductase (DHFR) inhibition that ‘sits’ in the same binding cavity as methotrexate by high throughput computationalscreening.Methods: The 3-D structure of the DHFR binding site was examined using ‘CASTp3.0’. Structure based in silico screening of about 5 million drug candidates housed in the MCULE database was performed. The obtained molecule-hits were ranked in accordance with their VINA scores, made to pass through drug-likeness filters, ΔG cut-off criterion, toxicity-checker and finally ‘zero RO5 criterion’.Results:

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Avunoori, Sravanthi, Mater H. Mahnashi, Ibrahim Ahmed Shaikh, et al. "Synthesis and in silico studies of some new pyrrolyl benzamides as antitubercular agents." INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY 35, no. 02 (2025): 255. https://doi.org/10.59467/ijhc.2025.35.255.

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A new series of pyrrolyl benzamide derivatives (3a-3j) and Schiff base 4 were synthesized by reacting N-(2,5-dimethyl-1H-pyrrol-1-yl)-4-(2-hydrazenyl-2-oxoethoxy)benzamide (1) with substituted phenylacetic acids (2a-2j) and indole-3-carbaldehyde, respectively. Molecular docking was performed for these synthesized compounds against the InhA and dihydrofolate reductase (DHFR) mycobacterial enzymes. The compounds were biologically screened for antimycobacterial and antibacterial activities along with InhA and DHFR enzyme inhibition studies. The compounds were also analyzed for absorption, distrib

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El-Naggar, Mohamed, Hanan A. Sallam, Safaa S. Shaban, et al. "Design, Synthesis, and Molecular Docking Study of Novel Heterocycles Incorporating 1,3,4-Thiadiazole Moiety as Potential Antimicrobial and Anticancer Agents." Molecules 24, no. 6 (2019): 1066. http://dx.doi.org/10.3390/molecules24061066.

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A new series of 5-(3,5-dinitrophenyl)-1,3,4-thiadiazole derivatives were prepared and evaluated for their in vitro antimicrobial, antitumor, and DHFR inhibition activity. Compounds 9, 10, 13, and 16 showed strong and broad-spectrum antimicrobial activity comparable to Amoxicillin and Fluconazole as positive antibiotic and antifungal controls, respectively. Compounds 6, 14, and 15 exhibited antitumor activity against four human cancer cell lines, CCRF-CEM leukemia, HCT-15 colon, PC-3 prostate, and UACC-257 melanoma cell lines using Doxorubicin as a reference drug. Compounds 10, 13, 14, and 15 p

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Wang, Feng, Paras Jain, Gulcin Gulten, et al. "Mycobacterium tuberculosis Dihydrofolate Reductase Is Not a Target Relevant to the Antitubercular Activity of Isoniazid." Antimicrobial Agents and Chemotherapy 54, no. 9 (2010): 3776–82. http://dx.doi.org/10.1128/aac.00453-10.

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ABSTRACT Mycobacterium tuberculosis enoyl-acyl-ACP reductase (InhA) has been demonstrated to be the primary target of isoniazid (INH). Recently, it was postulated that M. tuberculosis dihydrofolate reductase (DHFR) is also a target of INH, based on the findings that a 4R-INH-NADP adduct synthesized from INH by a nonenzymatic approach showed strong inhibition of DHFR in vitro, and overexpression of M. tuberculosis dfrA in M. smegmatis conferred a 2-fold increase of resistance to INH. In the present study, a plasmid expressing M. tuberculosis dfrA was transformed into M. smegmatis and M. tubercu

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Widemann, Brigitte C., Frank M. Balis, and Peter C. Adamson. "Dihydrofolate Reductase Enzyme Inhibition Assay for Plasma Methotrexate Determination Using a 96-Well Microplate Reader." Clinical Chemistry 45, no. 2 (1999): 223–28. http://dx.doi.org/10.1093/clinchem/45.2.223.

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Abstract Microplate reader assays offer several advantages over conventional spectrophotometric assays. We adapted the dihydrofolate reductase (DHFR) enzyme inhibition assay for use in a 96-well microplate reader to measure plasma methotrexate (MTX) concentrations. The assay is linear from 0.01 to 0.1 μmol/L. The within-run CVs at 0.03 μmol/L and 0.08 μmol/L MTX were 4.0% and 2.7%, respectively, and the interday (total) CVs were 7.6% and 1.8%. Cross-reactivity with the inactive MTX metabolite 2,4-diamino-N10-methylpteroic acid (DAMPA) was 3.9%, significantly less than that described with comme

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MALIK, NASIR S., STEPHEN A. MATLIN, JOSEF FRIED, RUTH E. PAKYZ, and M. JAMES CONSENTINO. "The Contraceptive Effects of Etoprine on Male Mice and Rats." Journal of Andrology 16, no. 2 (1995): 169–74. http://dx.doi.org/10.1002/j.1939-4640.1995.tb01750.x.

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ABSTRACT: We had previously found that 2,4‐diaminopyrimidines affected spermatogenesis, possibly through the inhibition of testicular dihydrofolate reductase (DHFR). The current study examined the effects of etoprine, a highly lipophilic 2,4‐diaminopyrimidine that is also a potent DHFR inhibitor, on the fertility of male mice at various dosages (0.1–50 mg/kg/day) for 55 days and male rats at 5 mg/kg/day for 65 days. Two other substituted diaminopyrimidines were tested at dosages of 50 mg/kg/day for 55 days. Results of breeding trials along with assessment of various parameters indicative of ma

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Liang, Ruibin, and Amirhossein Bakhtiiari. "Multiscale simulation unravels the light-regulated reversible inhibition of dihydrofolate reductase by phototrexate." Journal of Chemical Physics 156, no. 24 (2022): 245102. http://dx.doi.org/10.1063/5.0096349.

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Molecular photoswitches are widely used in photopharmacology, where the biomolecular functions are photo-controlled reversibly with high spatiotemporal precision. Despite the success of this field, it remains elusive how the protein environment modulates the photochemical properties of photoswitches. Understanding this fundamental question is critical for designing more effective light-regulated drugs with mitigated side effects. In our recent work, we employed first-principles non-adiabatic dynamics simulations to probe the effects of protein on the trans to cis photoisomerization of phototre

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ITOH, Hideaki, and Yohtalou TASHIMA. "Novel 30 kDa protein possessing ATP-binding and chaperone activities." Biochemical Journal 326, no. 2 (1997): 567–72. http://dx.doi.org/10.1042/bj3260567.

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A 30 kDa protein was purified from pig liver cytosol by using ATP-Sepharose and Green A column chromatography. The partial amino acid sequences of the protein (95 amino acid residues) had no similarity with any proteins recorded in data banks. The protein was able to form a stable complex with unfolded dihydrofolate reductase (DHFR). The spontaneous refolding of chemically denatured DHFR was arrested by the 30 kDa protein. This inhibition presumably results from the formation of a stable complex between the 30 kDa protein and DHFR. Bound DHFR could be released from the protein with ATP. The pr

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Sasaki, Takayo, Sunita Ramanathan, Yukiko Okuno, Chiharu Kumagai, Seemab S. Shaikh, and David M. Gilbert. "The Chinese Hamster Dihydrofolate Reductase Replication Origin Decision Point Follows Activation of Transcription and Suppresses Initiation of Replication within Transcription Units." Molecular and Cellular Biology 26, no. 3 (2006): 1051–62. http://dx.doi.org/10.1128/mcb.26.3.1051-1062.2006.

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ABSTRACT Chinese hamster ovary (CHO) cells select specific replication origin sites within the dihydrofolate reductase (DHFR) locus at a discrete point during G1 phase, the origin decision point (ODP). Origin selection is sensitive to transcription but not protein synthesis inhibitors, implicating a pretranslational role for transcription in origin specification. We have constructed a DNA array covering 121 kb surrounding the DHFR locus, to comprehensively investigate replication initiation and transcription in this region. When nuclei isolated within the first 3 h of G1 phase were stimulated

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Kenny, Chang and VasudevaRao Avupati*. "SYNTHESIS, IN VITRO BIOLOGICAL AND COMPUTATIONAL EVALUATION OF SOME NOVEL PYRAZOLES AS POTENTIAL ANTICANCER AGENTS." IAJPS,CSK PUBLICATIONS 03, no. 10 (2016): 1223–36. https://doi.org/10.5281/zenodo.166357.

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<em>The major challenge in modern drug discovery has been the design and development of new anticancer drugs with improved efficacy and minimal side effects, especially due to a rapid rise in multidrug resistant tumors. In the recent past, United States Food & Drug Administration (US FDA) newly approved anticancer drug Crizotinib (Xalkori) possess a pyrazole nucleus as core moiety. Therefore in the present investigation, we have synthesised a series of pyrazoles <strong>KVP, KVP1-4</strong> and evaluated their potential as anticancer agents by using in vitro brine shrimp (Artemia salina) c

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Waqar, Afira, Affhan Shoaib, Aleema Ramzan Sethi, Khalid Hassan, Maryam Asghar, and Tanzeela Anees. "Isolation of Lactobacillus and Enzymatic Activity of Dihydrofolate Reductase (DHFR) in Musa spp." Journal of Sustainable Environment 2, no. 2 (2023): 16–20. http://dx.doi.org/10.58921/jse.02.02.033.

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Background: Bananas grown in the tropic and subtropic regions are among the important crops worldwide. Banana is a general term embracing a number of species or hybrids in the genus Musa, family Musceae. Objective: The present research discusses extensively the breakthrough in the utilization of Musa i.e. Banana from its unripe to ripening phase in order to conclude the presence of Lactobacilli and enzymatic activity of Dihydrofolate Reductase (DHFR). DHFR, a ubiquitous enzyme, is involved in the metabolism and stability of folate (vitamin B9), and causes the reduction of dihydrofolate into te

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Banerjee, D., E. Ercikan-Abali, M. Waltham, et al. "Molecular mechanisms of resistance to antifolates, a review." Acta Biochimica Polonica 42, no. 4 (1995): 457–64. http://dx.doi.org/10.18388/abp.1995_4899.

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Methotrexate (MTX) is a clinically important antifolate that has been used in combination with other chemotherapeutic agents in the treatment of malignancies including acute lymphocytic leukemia, osteosarcoma, carcinomas of the breast, head and neck, choriocarcinoma and non-Hodgkin's lymphoma. The primary target of MTX is the enzyme dihydrofolate reductase (DHFR) which catalyzes the reduction of folate and 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate. Understanding of MTX action has revealed how cells acquire resistance to this drug. The four known mechanisms of MTX resistance are a decrease

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46

Huang, Kai, Taro Narumi, Yixuan Zhang, et al. "Targeting MicroRNA-192-5p, a Downstream Effector of NOXs (NADPH Oxidases), Reverses Endothelial DHFR (Dihydrofolate Reductase) Deficiency to Attenuate Abdominal Aortic Aneurysm Formation." Hypertension 78, no. 2 (2021): 282–93. http://dx.doi.org/10.1161/hypertensionaha.120.15070.

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We have shown that endothelial-specific DHFR (dihydrofolate reductase) deficiency underlies eNOS (endothelial NO synthase) uncoupling and formation of abdominal aortic aneurysm (AAA). Here, we examined a novel role of microRNA-192-5p in mediating NOX (NADPH oxidase)-dependent DHFR deficiency and AAA formation. microRNA-192-5p is predicted to target DHFR. Intriguingly, homo sapiens–microRNA-192-5p expression was substantially upregulated in human patients with AAA. In human aortic endothelial cells exposed to hydrogen peroxide (H 2 O 2 ), homo sapiens–microRNA-192-5p expression was significantl

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47

Nowak, W., V. Cody, and A. Wojtczak. "Computer modeling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim." Acta Biochimica Polonica 48, no. 4 (2001): 903–16. http://dx.doi.org/10.18388/abp.2001_3856.

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Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infections. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed computer analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the total PTX-enzyme

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Jackson, H. C., K. Biggadike, E. McKilligin, et al. "6,7-disubstituted 2,4-diaminopteridines: novel inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase." Antimicrobial Agents and Chemotherapy 40, no. 6 (1996): 1371–75. http://dx.doi.org/10.1128/aac.40.6.1371.

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Four novel, disubstituted diaminopteridines have been identified which antagonize the uptake of a folate precursor (para-aminobenzoic acid) by rat-derived Pneumocystis carinii maintained in short-term axenic culture at concentrations ranging from 4.5 to 26 microM. The compounds were at least 10 to 100 times more active than trimethoprim in this assay. None of these entities exhibited toxicity to mammalian cell lines at < 100 microM. The same structures also caused significant inhibition of Toxoplasma gondii tachyzoite replication within Madin-Darby bovine kidney cells at concentrations rang

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Saleh, Asmaa, Omkulthom Al Kamaly, Ashwag S. Alanazi, and Omar Noman. "Phytochemical Analysis and Antimicrobial Activity of Rosmarinus officinalis L. Growing in Saudi Arabia: Experimental and Computational Approaches." Processes 10, no. 11 (2022): 2422. http://dx.doi.org/10.3390/pr10112422.

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Rosmarinus officinalis L. is widely distributed in Saudi Arabia. However, only a few studies have been reported regarding this species. In this study, we investigated the phytochemical analysis of R. officinalis essential oil using GC-MS analysis in order to identify its major components; the in vitro antimicrobial activity of the essential oil was also evaluated using disc diffusion assay against gram-positive (S. aureus) and gram-negative bacteria (E. coli), the antimicrobial activity was also assessed with molecular docking against several microbial proteins; TyRS, DNA gyrase and DHFR. The

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50

Urlaub, G., P. J. Mitchell, C. J. Ciudad, and L. A. Chasin. "Nonsense mutations in the dihydrofolate reductase gene affect RNA processing." Molecular and Cellular Biology 9, no. 7 (1989): 2868–80. http://dx.doi.org/10.1128/mcb.9.7.2868-2880.1989.

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Steady-state dihydrofolate reductase (dhfr) mRNA levels were decreased as a result of nonsense mutations in the dhfr gene. Thirteen DHFR-deficient mutants were isolated after treatment of Chinese hamster ovary cells with UV irradiation. The positions of most point mutations were localized by RNA heteroduplex mapping, the mutated regions were isolated by cloning or by enzymatic amplification, and base changes were determined by DNA sequencing. Two of the mutants suffered large deletions that spanned the entire dhfr gene. The remaining 11 mutations consisted of nine single-base substitutions, on

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