In our effort to identify potent fluorinated small molecules as antidiabetic compounds, a novel fluorinated series of 2-chloro-6-(trifluoromethyl)benzyloxy arylidene derived Rhodanine and Rhodanine-acetic acid derivatives were synthesized and screened for α-glucosidase and α-amylase inhibitory activity. Newly synthesized compounds were characterized by 1 HNMR, 13 C NMR, and LCMS spectral data. Among the tested compounds, (Z)-5-(4-(2-chloro-6-(trifluoromethyl)benzyloxy) benzylidene)-2-thioxothiazolidin-4-one(5 a) and 2-((Z)-5-(4-(2chloro-6-(trifluoromethyl)benzyloxy)benzylidene)-4-oxo-2-thioxothiazoli-din-3-yl)acetic acid(6 a) emerged as most promising α-glucosidase inhibitors with IC 50 values 4.76 � 0.64 μM and 4.91 � 0.45 μM, respectively. Further, the kinetic inhibition experiments against yeast α-glucosidase for compounds 5 a and 6 a indicated that these are competitive inhibitors with inhibitory constant (Ki) 0.54 μg and 1.15 μg respectively.Molecular docking studies on α-glucosidase was performed by homology modelingfor the most potent compounds 5 a and 6 a to understand the putative binding mode. The study revealed substantial binding of the compounds to the active site of α-glucosidase, indicating that the position of the substituent plays a key role in its inhibitory potential.

As part of our effort to identify potent α-amylase inhibitors, in the present study, a novel series of fluorinated thiazolidinone-pyrazole hybrid molecules were prepared by the condensation of 3-(aryl/benzyloxyaryl)-pyrazole-4-carbaldehydes with fluorinated 2,3disubstituted thiazolidin-4-ones. The structures of the newly synthesized compounds were confirmed by infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and liquid chromatography-mass spectrometry data. All the compounds were screened for their αamylase inhibitory and free radical scavenging activities by DPPH (1,1-diphenyl-2picrylhydrazyl) and ABTS methods. Among the tested compounds, compound 8g emerged as a promising α-amylase inhibitor with IC 50 = 0.76 ± 1.23 µM, and it was found to be more potent than the standard drug acarbose (IC 50 = 0.86 ± 0.81 μM). Compounds 8b and 8g showed strong free radical scavenging activity compared to the standard butylated hydroxyl anisole. The kinetic study of compound 8g revealed the reversible, classical competitive inhibition mode on the α-amylase enzyme. Molecular docking and dynamic simulations studies were performed for the most potent compound 8g, which displayed remarkable hydrogen bonding with the α-amylase protein (PDB ID: 1DHK).

The halogen atoms on various positions of the N-arylamino ring played an advantageous role in elevating the potency of the molecules. Thus, these conjugates could be used as a lead for further optimization to achieve promising therapeutics.

Owing to its presence in several biological processes, Sirt1 acts as a potential therapeutic target for many diseases.

MRSA infection is one of the alarming diseases in the current scenario. Identifying newer molecules to treat MRSA infection is of urgent need. In the present study, we have designed fluorinated thiazolidinone derivatives with various aryl/heteroaryl units at 5 th position of the thiazolidinone core as promising anti-MRSA agents. All the compounds were screened for antibacterial activity against four bacterial strains. Among the tested compounds, the halogenated compounds with simple arylidene ring, (5Z 4f) and (5Z)-5-[(3,5-difluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3thiazol-4(5H)-one (4g) showed excellent activity with MIC 3.125 -6.25 μg/mL against S. aureus and P. aeruginosa organism. Furthermore, these potent compounds were screened against MRSA strains, ESKAPE panel organism, and H37Rv mycobacterium strain. Compounds 4c (MIC 0.39 μg/mL), and 4f (MIC 0.39 and 0.79 μg/mL) displayed promising activity against MRSA strains (ATCC and clinical isolates, respectively). The most potent compounds, 4c and 4f eradicated the growth of bacterial colonies in a time-kill assay indicated that these are bactericidal in nature. The preliminary toxicity study of the potent molecules revealed that these compounds are non-hemolytic in nature as they did not induce lysis in human RBCs. In addition, the molecular docking and dynamics studies of compounds 4b, 4c, 4f and 4g were carried out on MurB protein of S. aureus (PDB code: 1HSK). Docking results demonstrated remarkable hydrogen bonding interaction with key amino acids ARG310, ASN83, GLY79 and π-π interactions with TYR149 which confirm the mode of action of the molecules.

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