Diketo acids and their amino acid/dipeptidic analogues as promising scaffolds for the development of bacterial methionine aminopeptidase inhibitors

Abstract

Using diketoesters as the template, various derivatives were designed and the selected compounds were synthesized as bacterial methionine aminopeptidase (MetAP) inhibitors. The results of in vitro antibacterial screening revealed fifteen compounds (1a-c, 1e-h, 1j, 1l, 2a-c, 3d, 5c and 5e) as potent against different bacterial strains. By using the MTT assay on human cell line (HepG2), the viability of cell proliferation was evaluated and nine compounds (1c, 1e, 1j, 1l, 2a,b, 3d, 5c and 5e) showed no cytotoxic effect at the concentration range of 50-450 mg ml À1 . In the biochemical evaluation against methionine aminopeptidase (MetAPs) from Streptococcus pneumonia (SpMetAP), Mycobacterium tuberculosis (MtMetAP), Enterococcus faecalis (EfMetAP) and human (HsMetAP), compounds displayed differential behaviour against these four enzymes. Moreover, compound 1g showed 84% inhibition of SpMetAP, while compound 3d selectively inhibited MtMetAP with 79% inhibition and little effect on HsMetAP at 100 mM concentration. At the same concentration, compound 5e exhibited 87% and 85% inhibition of EfMetAP and SpMetAP, respectively. Understanding the mode of binding through modeling at the active site provided the structural basis for the possible mode of inhibition. Together, these data will be useful for further development of diketo acid based inhibitors with improved potency and selectivity.

N‐Substituted 1,2,3‐Triazolyl‐Appended Indole‐Chalcone Hybrids as Potential DNA Intercalators Endowed with Antioxidant and Anticancer Properties

“…In extension of our work on the synthesis of bioactive small molecule inhibitors, we adopted a simple and efficient synthetic pathway to achieve the title compounds as shown in Scheme . The key intermediate, indole‐chalcone 1 was prepared by condensation of commercially available indole‐3‐aldehyde and 3‐nitroacetophenone in the presence of piperidine.…”

1,2,3-Triazole–quinazolin-4(3H)-one conjugates: evolution of ergosterol inhibitor as anticandidal agent

“…31.25 mg mL À1 for C. albicans. At predetermined time periods (0, 2,4,6,8,10,12,14,16,18,20,22, and 24 h) aer incubation with agitation at 37 C, 1 mL aliquot to each sample was removed from the conical ask and growth was measured turbidometrically at 600 nm using Thermo Multiskan spectrophotometer. Optical density (O.D.)…”

“…In our continuous efforts to design biologically active heterocycles, [12][13][14][15][16][17] we hypothesized albaconazole as a model for preparation of 1,2,3-triazole derivatives of quinazolin-4(3H)-one (5a-q and 6a-q) and studied their antifungal properties. Further, single crystal X-ray study of compounds 2 and 5c has been reported.…”

Monocyclicβ-lactam and unexpected oxazinone formation: synthesis, crystal structure, docking studies and antibacterial evaluation

“…Human erythrocytes from healthy individuals were collected in tubes containing EDTA as anti-coagulant. The erythrocytes were harvested by centrifugation for 10 min at 2000 rpm, 20 C and washed three times in PBS. To the pellet, PBS was added to yield a 10% (v/v) erythrocytes/PBS suspension.…”

“…Therefore, it has lent additional urgency to develop new molecular scaffolds having novel mode of action or to modify existing drug molecules. Considering the large pharmacological importance of b-lactams and in extension to our efforts to explore novel biologically active molecules 19,20 , we synthesized novel N-benzyl-3,4-diaryl substituted 2-azitidinone (b-lactam) derivatives (4a-g, 4i-s), while compounds 4h and 4t were isolated as highly substituted 1,3-oxazin-4-one derivatives. In silico pharmacokinetic and toxicity parameters were also assessed for all the synthesized compounds.…”