The crystal structure of the title compound (C27H45NO2) has been determined by X‐ray crystallographic techniques. The compound crystallizes in the monoclinic space group P21 with unit cell parameters a = 12.143(2), b =10.835(2), c = 19.747(4) Å, b = 101.29(1)°. The structure has been solved by direct methods and refined to R=0.064. There are two crystallographically independent molecules, I and II, in the asymmetric unit. In both the molecules, rings A, B and C are conformationally very similar, however pronounced differences are observed in the D ring which assumes a distorted envelope conformation in molecule I and a distorted half‐chair conformation in molecule II. The A/B ring junction is quasi‐trans while ring systems B/C and C/D are trans fused in both the molecules I and II. Two bifurcated intramole‐cular hydrogen bonds have been observed. Molecules are held together by intermolecular C‐H...O hydrogen bonds.
New Delhi metallo-β-lactamase-1 (NDM-1), expressed in different Gram-negative bacteria, is a versatile enzyme capable of hydrolyzing β-lactam rings containing antibiotics such as penicillins, cephalosporins, and even carbapenems. Multidrug resistance in bacteria mediated by NDM-1 is an emerging threat to the public health, with an enormous economic burden. There is a scarcity in the availability of specific NDM-1 inhibitors, and also a lag in the development of new inhibitors in pharmaceutical industries. In order to identify novel inhibitors of NDM-1, we screened a library of more than 20 million compounds, available at the MCULE purchasable database. Virtual screening led to the identification of six potential inhibitors, namely, MCULE-1996250788-0-2, MCULE-8777613195-0-12, MCULE-2896881895-0-14, MCULE-5843881524-0-3, MCULE-4937132985-0-1, and MCULE-7157846117-0-1. Furthermore, analyses by molecular docking and ADME properties showed that MCULE-8777613195-0-12 was the most suitable inhibitor against NDM-1. An analysis of the binding pose revealed that MCULE-8777613195-0-12 formed four hydrogen bonds with the catalytic residues of NDM-1 (His120, His122, His189, and Cys208) and interacted with other key residues. Molecular dynamics simulation and principal component analysis confirmed the stability of the NDM-1 and MCULE-8777613195-0-12 complex. The in vitro enzyme kinetics showed that the catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics decreased significantly in the presence of MCULE-8777613195-0-12, due to poor catalytic proficiency (kcat) and affinity (Km). The IC50 value of MCULE-8777613195-0-12 (54.2 µM) was comparable to that of a known inhibitor, i.e., D-captopril (10.3 µM). In sum, MCULE-8777613195-0-12 may serve as a scaffold to further design/develop more potent inhibitors of NDM-1 and other β-lactamases.
Synthesis of Steroidal Spirothiazolidinones-[via reaction of steroidal ketones with β-mercaptoacetic acid]. -(SHAFIULLAH; SIDDIQUI, I. H.; ANSARI, S. A.; KHAN, E. H.; SHAFI, SHEEBA; J. Indian Chem. Soc. 77 (2000) 4, 215-216; Steroid Res. Lab.,
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