Secretory N-acyl homoserine lactones (AHLs) mediate quorum sensing (QS) in bacteria. AHLs are shown to be inhibitory for an unrelated group of bacteria and might mimic host signalling elements, thereby subverting the regulatory events in host cells. This study investigated the AHL produced by Acinetobacter baumannii and analysed its effect on other bacterial species and mammalian cells. Chemically characterized AHL had an m/z value of 325 with a molecular formula C18H31NO4 and showed its inhibitory potential against Staphylococcus aureus. Molecular docking studies identified D-alanine-D-alanine synthetase A, a cell wall synthesizing enzyme of S. aureus having a strong binding affinity towards AHL. Electron microscopy showed the disruption and sloughing off of the S. aureus cell wall when treated with AHL. In vitro experiments revealed that this bacteriostatic AHL showed time-dependent activity and induced apoptosis in cancer cell lines. This compound could be a potential structural backbone for constructing new AHL analogues against S. aureus. The findings emphasize the need to re-evaluate all previously characterized AHLs for any additional new biological functions other than QS.
We have achieved a facile synthesis of a combinatorial library of densely substituted pyrazolo[3,4-b]-4,7-dihydropyridines- the mimics of antigenital wart drug podophyllotoxin-from 5-aminopyrazoles and 4-(methylthio) 4H-chromenes. The C(4) pyrazolyl 4H-chromenes, which also possess structural features of podophyllotoxin, were isolable intermediates in the two-step, one-pot condensation. The condensation took place in a one-pot, multicomponent manner when 3-oxo-3-phenylpropanenitriles, hydrazine (precursors for 5-aminopyrazoles) and 4-(methylthio)-4H-chromenes were heated in refluxing ethanol. The condensation, however, stops at 4H-chromene stage when methyl hydrazine or phenylhydrazine were employed. Our findings offer an opportunity for synthesis of a combinatorial library of podophyllotoxin mimics, thus paving the way for discovery of lead candidates for cancer treatment.
The C(4) N‐heteroaryl 2‐amino‐3‐nitro‐4H‐chromenes are podophyllotoxin (POD) mimics as they possess the pharmacophore features of the anticancer natural product. We have achieved a facile synthesis of several such 4H‐chromenes by substitution of C(4) SMe in N‐alkyl 4‐(methylthio)‐3‐nitro‐4H‐chromen‐2‐amines with heteroaromatic amines like 2‐aminopyridines and 2‐aminopyrimidines. Resulting 4H‐chromenes were evaluated for anticancer activity against prostate and lung cancer cell lines. Two of the 4H‐chromenes showed significant anti‐cancer activity, even better than POD. Both of them were non‐toxic towards normal cell‐lines. In silico ADMET studies revealed drug‐likeliness of all the 4H‐chromenes. Molecular docking studies with αβ tubulin concurred with in vivo results and revealed that the 4H‐chromenes bind to the active site of POD. Molecular dynamics simulation studies on the complexes of αβ tubulin with the two best 4H‐chromenes revealed high stability. Overall, our studies revealed that the two 4H‐chromenes could act as lead compounds for further development of potent anticancer drugs.
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