Synthesis and Antibacterial Evaluation of Rhodanine and Its Related Heterocyclic Compounds against S. aureus and A. baumannii

Abstract

Antimicrobial resistance is a serious challenge to modern medicine. Besides imposing high financial burden, multidrug resistant infections are directly responsible for high morbidity and mortality. Even though a number of antibiotics are currently available to treat infections caused by ESKAPE organisms, more and more bacterial strains are becoming resistant to these drugs. Prevailing circumstances pose an urgent unmet need for the development of newer antimicrobials to treat the infections caused by MDR organisms. Rhodanine and structurally related 5‐membered heterocycles possess wide range of pharmacological activities. A number of these derivatives have shown good to potent inhibition against various microorganisms. They are reported to alter the function of DNA gyrase B, metallo‐β‐lactamases, penicillin binding protein (PBP), Mur ligases, RNA polymerase, Enoyl ACP reductases, 1‐deoxy‐d‐xylulose‐5‐phosphate reductoisomerase. etc which are vital in bacterial growth, survival and replication. In this study, we have generated a library of Rhodanine and related 5 membered heterocyclic derivatives and screened them against a panel of pathogens. Among all the compounds, 2a–i, 3a–b, 3g, 4, 6b–c, 6e, 6g, 12a–b and 14b–c have demonstrated good to moderate inhibition against S. aureus (MIC 0.125–8 μg/mL). Further, compound 17b demonstrated moderate activity against A. baumannii (MIC 8 μg/mL). In addition, compounds 2a, 2e, 4, 6c, 6g and 14b have shown good to mild inhibition against MDR S. aureus including VRSA (MIC 0.5–16 μg/mL) with good selectivity index 20–1600. In addition, compound 2e inhibited the growth gradually after 6 h in time kill kinetic studies and not antagonized with the tested FDA approved drugs.

N-Derivatives of (Z)-Methyl 3-(4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylates as Antimicrobial Agents—In Silico and In Vitro Evaluation

“…All compounds have been assessed for their ADMET profile in ADMET Predictor version 10.4 provided by the Simulation Plus software package [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ...…”

“…So far, many indole-based rhodanine derivatives ( Figure 3 ) have been proposed [ 6 , 41 , 45 , 46 , 47 , 48 , 49 ] as antimicrobial agents, some of which possess high efficacy in treating multi-drug resistant pathogens [ 6 , 41 , 47 , 48 , 49 ]. Therefore, it is noteworthy that the combination of indole and rhodanine scaffolds into new chemical entities could be a promising strategy for antimicrobial therapies.…”

Design, synthesis, and structure–activity studies of new rhodanine derivatives as carbonic anhydrase II, IX inhibitors

“…[16,17] Many bioactive compounds of natural and synthetic origin (I-V) (Figure 1) containing Rhodanine core have become therapeutically important, viz., PDE4 inhibitors, [18] antiviral, [19] anticancer, and antibacterial agents. [20] Rhodanines and their structurally related compounds are being explored as the nonsulfonamide class of carbonic anhydrase inhibitors. Arif et al synthesized morpholine-linked benzylidene Rhodanine derivatives (VI) through a one-pot, four-component reaction possessing good CAII inhibition.…”

Rhodanine‐Incorporated Indole Derivatives as Pharmacologically Vital Hybrids

“…Among all the synthesized analogues, indole ring‐containing compounds 142 and 143 displayed moderate antibacterial activity against these two strains with MIC values of 8 and <64 μg/mL, respectively. From the SAR investigation, a change in the position of the double bond from C‐3 (142) to C‐2 (143) enhanced the antibacterial activity [36] …”

“…From the SAR investigation, a change in the position of the double bond from C-3 (142) to C-2 (143) enhanced the antibacterial activity. [36] Horishny et al synthesized indole-incorporated rhodanine derivatives 144-155 and evaluated them for their antibacterial and antifungal activities (Figure 23). All the tested analogues displayed better potency than ampicillin against all the bacteria.…”