Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents

Wróbel, Agnieszka; Baradyn, Maciej; Ratkiewicz, Artur; Drozdowska, Danuta

doi:10.3390/ijms22073685

Cited by 28 publications

(21 citation statements)

References 61 publications

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“…Cotrimoxazole is the antibacterial combination product of trimethoprim and sulfamethoxazole. These components inhibit enzyme systems involved in the bacterial synthesis of tetrahydrofolic acid and block the initiation of protein synthesis among other cellular processes [ 50 , 51 , 52 , 53 ]. Together, these data suggest that in addition to inhibiting efflux in MexAB-OprM and MexXY-OprM overproducing strains, TXA09155 may have a secondary MOA synergistic with protein synthesis inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of a Conformationally Constrained Indole Carboxamide as a Potential Efflux Pump Inhibitor in Pseudomonas aeruginosa

Zhang¹,

Rosado-Lugo²,

Datta³

et al. 2022

Antibiotics

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Efflux pumps in Gram-negative bacteria such as Pseudomonas aeruginosa provide intrinsic antimicrobial resistance by facilitating the extrusion of a wide range of antimicrobials. Approaches for combating efflux-mediated multidrug resistance involve, in part, developing indirect antimicrobial agents capable of inhibiting efflux, thus rescuing the activity of antimicrobials previously rendered inactive by efflux. Herein, TXA09155 is presented as a novel efflux pump inhibitor (EPI) formed by conformationally constraining our previously reported EPI TXA01182. TXA09155 demonstrates strong potentiation in combination with multiple antibiotics with efflux liabilities against wild-type and multidrug-resistant (MDR) P. aeruginosa. At 6.25 µg/mL, TXA09155, showed ≥8-fold potentiation of levofloxacin, moxifloxacin, doxycycline, minocycline, cefpirome, chloramphenicol, and cotrimoxazole. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA09155. TXA09155 was determined to lower the frequency of resistance (FoR) to levofloxacin and enhance the killing kinetics of moxifloxacin. Most importantly, TXA09155 outperformed the levofloxacin-potentiation activity of EPIs TXA01182 and MC-04,124 against a CDC/FDA panel of MDR clinical isolates of P. aeruginosa. TXA09155 possesses favorable physiochemical and ADME properties that warrant its optimization and further development.

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Section: Resultsmentioning

confidence: 99%

Evaluation of a Conformationally Constrained Indole Carboxamide as a Potential Efflux Pump Inhibitor in Pseudomonas aeruginosa

Zhang¹,

Rosado-Lugo²,

Datta³

et al. 2022

Antibiotics

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“…Moreover, we also probed two other well-known inhibitors of DHFR, namely, methotrexate (MTX) and dihydrofolic acid (DHF) [ 28 ]. These inhibitors demonstrated the binding scores of −9.0 and −9.5 kcal/mol, so that we can conclude that ligands 3c and 4g are among the most promising antitubercular agents [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Novel Derivatives of 5,6,7,8-Tetrahydroquinazolines Using α-Aminoamidines and In Silico Screening of Their Biological Activity

Snizhko

Kyrychenko

Gladkov

2022

IJMS

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α-Aminoamidines are promising reagents for the synthesis of a diverse family of pyrimidine ring derivatives. Here, we demonstrate the use of α-aminoamidines for the synthesis of a new series of 5,6,7,8-tetrahydroquinazolines by their reaction with bis-benzylidene cyclohexanones. The reaction occurs in mild conditions and is characterized by excellent yields. It has easy workup, as compared to the existing methods of tetrahydroquinazoline preparation. Newly synthesized derivatives of 5,6,7,8-tetrahydroquinazoline bear protecting groups at the C2-tert-butyl moiety of a quinazoline ring, which can be easily cleaved, opening up further opportunities for their functionalization. Moreover, molecular docking studies indicate that the synthesized compounds reveal high binding affinity toward some essential enzymes of Mycobacterial tuberculosis, such as dihydrofolate reductase (DHFR), pantothenate kinase (MtPanK), and FAD-containing oxidoreductase DprE1 (MtDprE1), so that they may be promising candidates for the molecular design and the development of new antitubercular agents against multidrug-resistant strains of the Tubercle bacillus. Finally, the high inhibition activity of the synthesized compounds was also predicted against β-glucosidase, suggesting a novel tetrahydroquinazoline scaffold for the treatment of diabetes.

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“…Overall, BDBM18226 and BDBM50514994 showed better stability and specificity compared to MTX, making them promising candidates for inhibitory agents against mt-DHFR and h-DHFR for therapeutic intervention against TB and cancer. 40 …”

Section: Discussionmentioning

confidence: 99%

Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation

Haddoumi,

Mansouri,

Bendani

et al. 2023

Bioinform Biol Insights

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Dihydrofolate reductase (DHFR) is a crucial enzyme that catalyzes the conversion of folic acid. Its reserved properties and significance in both human (h-DHFR) and mycobacterium (mt-DHFR) make it a challenging target for developing drugs against cancer and bacterial infections. Although methotrexate (MTX) is commonly used for cancer therapy and bacterial infections, it has a toxic profile. In this study, we aimed to identify selective and non-toxic inhibitors against h-DHFR and mt-DHFR using an in silico approach. From a data set of 8 412 inhibitors, 11 compounds passed the toxicity and drug-likeness tests, and their interaction with h-DHFR and mt-DHFR was studied by performing molecular docking. To evaluate the inhibitory activity of the compounds against mt-DHFR, five known reference ligands and the natural ligand (dihydrofolate) were used to generate a pharmacophoric map. Two potential selective inhibitors for mt-DHFR and h-DHFR were selected for further investigation using molecular dynamics for 100 ns. As a result, BDBM18226 was identified as the best compound selective for mt-DHFR, non-toxic, with five features listed in the map, with a binding energy of –9.6 kcal/mol. BDBM50145798 was identified as a non-toxic selective compound with a better affinity than MTX for h-DHFR. Molecular dynamics of the two best ligands suggest that they provide more stable, compact, and hydrogen bond interactions with the protein. Our findings could significantly expand the chemical space for new mt-DHFR inhibitors and provide a non-toxic alternative toward h-DHFR for the respective treatment of tuberculosis and cancer therapy.

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Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents

Cited by 28 publications

References 61 publications

Evaluation of a Conformationally Constrained Indole Carboxamide as a Potential Efflux Pump Inhibitor in Pseudomonas aeruginosa

Evaluation of a Conformationally Constrained Indole Carboxamide as a Potential Efflux Pump Inhibitor in Pseudomonas aeruginosa

Synthesis of Novel Derivatives of 5,6,7,8-Tetrahydroquinazolines Using α-Aminoamidines and In Silico Screening of Their Biological Activity

Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation

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