Novel Chalcone-Thiazole Hybrids as Potent Inhibitors of Drug Resistant Staphylococcus aureus

Abstract

A series of novel hybrids possessing chalcone and thiazole moieties were synthesized and evaluated for their antibacterial activities. In general this class of hybrids exhibited potency against Staphylococcus aureus, and in particular, compound 27 exhibited potent inhibitory activity with respect to other synthesized hybrids. Furthermore, the hemolytic and toxicity data demonstrated that the compound 27 was nonhemolytic and nontoxic to mammalian cells. The in vivo studies utilizing a S. aureus septicemia model demonstrated that compound 27 was as potent as vancomycin. The results of antibacterial activities underscore the potential of this scaffold that can be utilized for developing a new class of novel antibiotics.

Keywords: Chalcone−thiazole hybrids; MIC; Staphylococcus aureus; antibacterial activities.

Figure 1

Designing chalcone–thiazole hybrids by pharmacophore hybridization.

Figure 2

SAR of synthesized hybrids.

Scheme 1. Synthesis of Chalcone–Thiazole Hybrids

Reagents and conditions: (i) HMTA, TFA, 120 °C, 4 h; (ii) aq. H₂SO₄, 100 °C, 2 h; (iii) conc. HCl, p-R¹C₆H₄COCH₃, 1,4-dioxane, 80–90 °C, 2.5–3.5 h; (iv,v) ethanol, reflux, 3 h.

Figure 3

Effect of chalcone–thiazole hybrids on eukaryotic cells. (A) Influence of test compounds (22–36) on erythrocytes in the absence of human serum. Hemolytic effects of the test compounds were investigated, and the corresponding data for vancomysin and polymyxin B-sulfate are included for comparison. RBC was incubated at 100 μg/mL and 2% Trition X-100 was used as positive control. Hemoglobin released was measured at 540 nm and is expressed as a percentage of Trition X-100 induced hemolysis. (B) The MTT assay (right top panel) was used to measure the viability of Mammalian fibroblast cell line, L929 in the presence of compounds 22 and 27. In the assay, enzymes associated with metabolic activity will modify the MTT into a dye, blue formazan, which is measured at 550 nm. (C) Morphological changes on the L929 were investigated by using phase contrast microscopy. Cells were incubated for 24 h at 1× MIC for 24 h and stained with Giemsa stain before observation under the phase contrast microscope for the morphological changes.

Figure 4

Static and cidal curve with different concentrations of compound 27. (A) Compound 27 (1× and 10× MIC concentration) were incubated with S. aureus for 24 h, and at regular time points, aliquot was taken and CFU was calculated. In vivo antimicrobial activity of the compound 27. (B) BALB/C mice were initially made neutropenic by injecting cyclophosphamide (150 mg/kg of body weight), followed by S. aureus ATCC 29213 injection. After 3 h of post infection, compound 27 and vancomycin at 15 mg/kg of body weight was injected into mice twice at an interval of 3 h between injection. After 24 h, the mice were sacrificed and the organs (spleen, kidney, liver) were crushed before plating them on the TH plates for CFU determination. The data from three independent experiments were pooled, and the P-value was determined using the ANOVA on ranks by using Sigma stat software (***P < 0.001 and **P < 0.05).