Fighting Antibiotic Resistance: New Pyrimidine-Clubbed Benzimidazole Derivatives as Potential DHFR Inhibitors

Abstract

The present work describes the design and development of seventeen pyrimidine-clubbed benzimidazole derivatives as potential dihydrofolate reductase (DHFR) inhibitors. These compounds were filtered by using ADMET, drug-likeness characteristics calculations, and molecular docking experiments. Compounds 27, 29, 30, 33, 37, 38, and 41 were chosen for the synthesis based on the results of the in silico screening. Each of the synthesized compounds was tested for its in vitro antibacterial and antifungal activities using a variety of strains. All the compounds showed antibacterial properties against Gram-positive bacteria (Staphylococcus aureus and Staphylococcus pyogenes) as well as Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Most of the compounds either had a higher potency than chloramphenicol or an equivalent potency to ciprofloxacin. Compounds 29 and 33 were effective against all the bacterial and fungal strains. Finally, the 1,2,3,4-tetrahydropyrimidine-2-thiol derivatives with a 6-chloro-2-(chloromethyl)-1H-benzo[d]imidazole moiety are potent enough to be considered a promising lead for the discovery of an effective antibacterial agent.

Innovative Phospholipid Carriers: A Viable Strategy to Counteract Antimicrobial Resistance

“…Another molecule-based approach, often involving peptides, is to recognize and thus inhibit the principal factors that trigger antibiotic resistance: notable examples are the elimination of biofilms, blockage of multidrug resistance pumps (which could be over-expressed both for genetic reasons or due to heavy metal contamination), amelioration of bacterial membrane permeability, and disruption of vital bacterial processes like dihydrofolate reductase (DHFR) and translational elongation of protein inhibition [56][57][58]. While useful, this solution alone in the long term is insufficient since it faces the same obstacles as the principal resistance mechanism, namely target mutation and escaping, thanks to the innate adaptability of the bacteria.…”

In silico study of the admet properties of potential inhibitors of new Delhi methalo-ß-lactamase-1 (NDM-1)

“…Table 3 shows the in-silico values of the pharmacological properties obtained with ADMETlab 2.0, various parameters were calculated, such as the quantitative estimation of drug-likeness (QED), the NP score (similarity score with a natural product), the Lipinski rule, the Pfizer rule, the GSK rule, the Golden Triangle rule and the Chelator rule. The QED is a qualitative indicator of drug similarity that was introduced in 2012, it is based on a multicriteria optimization based on physicochemical and structural properties, where the quality of a compound is quantified by applying the concept of how "desired" it is (Serer, 2015;Haque et al, 2023). The range of values goes from zero (all unfavorable properties) to one (all favorable properties) (Serer, 2015).…”

“…Taking into account the values obtained for QED, it can be evidenced that they are in a range between 0.264 for M10.2 and 0.804 for M37, which indicates that all the molecules evaluated have favorable drug-likeness properties, compared to the reference antibiotics used (Meropenem QED = 0.559, Imipenem QED = 0.224). As for the NP values, these are in a range between -5 and 5, if the value obtained is positive, there is a probability that the molecule analyzed has a greater similarity with a natural product (Haque et al, 2023). The compounds under study presented values between -0.927 for M41 and 0.42 for M29, which allows us to infer that they are acceptable data for this parameter compared to the reference drugs (Meropenem NP = 0.782, Imipenem NP = 0.891).…”

Exploration and Biological Evaluation of 1,3-Diamino-7H-pyrrol[3,2-f]quinazoline Derivatives as Dihydrofolate Reductase Inhibitors

“…One area of progress is the development of more selective and efficacious antibacterial agents that overcome antibiotic resistance. 11,12 It is worth mentioning that iclaprim (RO48-2622) overcame some resistance issues and exhibited stronger antibacterial activity than TMP, which is now used for bacterial and skin structure infections. 13 In addition, the search for DHFR inhibitors has continued from various opportunistic organisms such as the protozoan parasites Plasmodium falciparum and Toxoplasma gondii and the fungus Candida albicans.…”

“…In the 1950s, methotrexate (MTX) and trimethoprim (TMP), as well-known DHFR inhibitors, were approved by United States Food and Drug Administration (FDA) and European Medicines Agency, respectively, for the treatment of cancer and bacterial infection. − Ongoing endeavors to create novel therapies centered around DHFR inhibition persist to this day. One area of progress is the development of more selective and efficacious antibacterial agents that overcome antibiotic resistance. , It is worth mentioning that iclaprim (RO48-2622) overcame some resistance issues and exhibited stronger antibacterial activity than TMP, which is now used for bacterial and skin structure infections . In addition, the search for DHFR inhibitors has continued from various opportunistic organisms such as the protozoan parasites Plasmodium falciparum and Toxoplasma gondii and the fungus Candida albicans.…”