Introduction to the study of structure-activity relationship of three ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate derivatives.

The discovery of antibiotics was an extraordinary medical breakthrough. However, resistance to these products has rapidly been developed by microbes and has evolved into a major global health problem. Herein we report the synthesis of a series of new 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (AE1) derivatives as well as a structure-antibacterial activities relationship of these compounds with an objective to find how to reinforce the activities of drugs. We used the second version of the Gewald reaction as described earlier by Mishra et al., 2012 to synthesize AE1. Then AE1 was converted into two new azocompounds AE2 and AE3 by a diazotization followed by coupling reaction with Aspirin and Paracetamol respectively and metal complex was prepared in a molar ratio 1:2 (metal: ligand) as reported on the equation below. The in vitro antimicrobial activity of the synthetized compounds have been evaluated against four bacterial strains using Levofloxacine hemihydrate as a standard drug. The MIC and MBC values of the compounds were determined by broth micro-dilution method. The synthetized compounds were identified by, by spectroscopic (UV, IR, 1H and 13C NMR) and mass spectrometry analyses. Antibacterial results showed that organic compounds AE2 and AE3 are less active than the complex AD18b. Indeed, AD18b showed greater activity against P. aeruginosa PA01 (64 μg/mL), E. coli ATCC 8739 (MIC = 128 μg/mL), S. aureus ATCC 25923 (MIC = 16 μg/mL) than compound AE2 and AE3 which showed almost similar activities on all trains. We found that the diazotization of AE1 had no meaningful effect on its activities whereas its complexation with bismuth salt reinforced (by the factor of 8) its antimicrobial activities. By this approach, we can both fight antibacterial resistance and remain within the SDGs just by modifying the structures of existing antibiotics.
Keywords: Structure-activity relationship, Antibacterial Activity, 2-aminothiophene, Complex