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A scaffold hopping strategy to generate new aryl-2-amino pyrimidine MRSA biofilm inhibitors.

ABSTRACT: Infections that stem from bacterial biofilms are difficult to eradicate. Within a biofilm state, bacteria are upwards of 1000-fold more resistant to conventional antibiotics, necessitating the development of alternative approaches to treat biofilm-based infections. One such approach is the development of small molecule adjuvants that can inhibit/disrupt bacterial biofilms. When such molecules are paired with conventional antibiotics, these dual treatments present a combination approach to eradicate biofilm-based infections. Previously, we have demonstrated that small molecules containing either a 2-amino pyrimidine (2-AP) or a 2-aminoimidazole (2-AI) heterocycle are potent anti-biofilm agents. Herein, we now report a scaffold hopping strategy to generate new aryl 2-AP analogs that inhibit biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA). These molecules also suppress colistin resistance in colistin resistant Klebsiella pneumoniae, lowering the minimum inhibitory concentration (MIC) by 32-fold.

SUBMITTER: Weig AW

PROVIDER: S-EPMC8127629 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The use of herbicide safeners can significantly alleviate herbicide injury to protect crop plants and expand the application scope of the existing herbicides in the field. Sanshools, which are well known as spices, are N-alkyl substituted compounds extracted from the Zanthoxylum species and have several essential physiological and pharmacological functions. Sanshools display excellent safener activity for the herbicide metolachlor in rice seedlings. However, the high cost of sanshools extraction and difficulties in the synthesis of their complicated chemical structures limit their utilization in agricultural fields. Thus, the present study designed and synthesized various N-alkyl amide derivatives via the scaffold-hopping strategy to solve the challenge of complicated structures and find novel potential safeners for the herbicide metolachlor. In total, 33 N-alkyl amide derivatives (2a-k, 3a-k, and 4a-k) were synthesized using amines and saturated and unsaturated fatty acids as starting materials through acylation and condensation. The identity of all the target compounds was well confirmed by 1H-NMR, 13C-NMR, and high-resolution mass spectrometry (HRMS). The primary evaluation of safener activities for the compounds by the agar method indicated that most of the target compounds could protect rice seedlings from injury caused by metolachlor. Notably, compounds 2k and 4k displayed excellent herbicide safener activities on plant height and demonstrated relatively similar activities to the commercialized compound dichlormid. Moreover, we showed that compounds 2k and 4k had higher glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO) activities in rice seedlings, compared to the metolachlor treatment. In particular, 2k and 4k are safer for aquatic organisms than dichlormid. Results from the current work exhibit that compounds 2k and 4k have excellent crop safener activities toward rice and can, thus, be promising candidates for further structural optimization in rice protection.

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A scaffold hopping strategy to generate new aryl-2-amino pyrimidine MRSA biofilm inhibitors.

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