Synthesis, DFT investigations, antibacterial activity, and SAR-study of novel thiophene-coumarin hybrids

Abstract

• Eight thiophene-coumarin hybrids were synthesized and their structures are characterized by IR, NMR , and Mass analyses. • The azo-based hybrids ( 3 and 5) and carboxamide-based hybrids ( 7 and 9 ) exhibited non-planar structure. • Both hybrids presented comparable FMO's energies but the carboxamide analogues were smaller than azo-based hybrids. • Hybrids 7a and 5b showed strong activity with IC 50 values < 37 µg/mL and < 68 µg/mL against S. aureus and S. epidermidis , respectively. • The docking analysis reveals the precise dynamics of the interaction between our targeting hybrids and 4URO protein A series of thiophene-coumarin hybrids ( 3, 5, 7 , and 9 ) has been produced from the reaction of various thiocarbamoyl compounds with 3-bromoacetylcoumarin. The DFT/B3LYP approach revealed that the synthesized hybrids have a non-planar configuration. The explored hybrids exhibited close HOMO-LUMO energies, whereas the carboxamide analogues 7 and 9 presented lower energies than azo derivatives 3 and 5 . The increase in antibiotic resistance presents a significant danger to public health, necessitating the development of novel antimicrobial medications. The antibacterial properties of the synthesized thiophene-coumarin hybrids were evaluated against representative microorganisms, including Gram-positive and Gram-negative bacteria, along with fungi, and they exhibited diverse antibacterial activity. The hybrids 7a and 5b showed strong activity (IC 50 < 37 and <68 µg/mL) against the Gram-positive bacteria S. aureus and S. epidermidis , respectively. While hybrid 9a exhibited significant antifungal efficacy against C. albicans (IC 50 <184 µg/mL), surpassing Flucytosine. Also, the targeting hybrids exhibited different levels of effectiveness in inhibiting DNA gyrase. Hybrid 9a showed the highest potency, followed closely by 7a (IC 50 5.19±0.12 and 6.05±0.23 µM, respectively) against Novobiocin. Moreover, the docking study demonstrates the interaction between the newly synthesized hybrids and the 4URO protein, a critical target for therapeutic intervention. Additionally, the Swiss ADME analysis of hybrids 5a and 5b has been displayed because of their exceptional combination of physicochemical features and bioavailability ratings.