Asymmetric Synthesis of <i>cis</i>-Aminocyclopentenols, Building Blocks for Medicinal Chemistry

A highly efficient one-pot multistep process involving an asymmetric Pd­(II)-catalyzed Overman rearrangement and a Ru­(II)-catalyzed ring-closing metathesis reaction has been developed for the preparation of (<i>R</i>)- or (<i>S</i>)-aminocyclopenta-2-enes. The rapid strategy employed and the relatively mild conditions of the one-pot process allowed the multigram synthesis of the carbocycles in high enantiomeric excess (92% ee). The synthetic utility of these compounds was demonstrated by the stereoselective incorporation of hydroxyl groups, generating <i>cis</i>-4- and <i>cis</i>-5-aminocyclopenta-2-en-1-ols, important building blocks for medicinal chemistry

Toward novel inhibitors against KdsB: a highly specific and selective broad-spectrum bacterial enzyme

<p>KdsB (3-deoxy-manno-octulosonate cytidylyltransferase) is a highly specific and selective bacterial enzyme that catalyzes KDO (3-Deoxy-D-mano-oct-2-ulosonic acid) activation in KDO biosynthesis pathway. Failure in KDO biosynthesis causes accumulation of lipid A in the bacterial outer membrane that leads to cell growth arrest. This study reports a combinatorial approach comprising virtual screening of natural drugs library, molecular docking, computational pharmacokinetics, molecular dynamics simulation, and binding free energy calculations for the identification of potent lead compounds against the said enzyme. Virtual screening demonstrated 1460 druglike compounds in a total of 4800, while molecular docking illustrated Ser13, Arg14, and Asp236 as the anchor amino acids for recognizing and binding the inhibitors. Functional details of the enzyme in complex with the best characterized compound-226 were explored through two hundred nanoseconds of MD simulation. The ligand after initial adjustments jumps into the active cavity, followed by the deep cavity, and ultimately backward rotating movement toward the initial docked site of the pocket. During the entire simulation period, Asp236 remained in contact with the ligand and can be considered as a major catalytic residue of the enzyme. Radial distribution function confirmed that toward the end of the simulation, strengthening of ligand-receptor occurred with ligand and enzyme active residues in close proximity. Binding free energy calculations via MM(PB/GB)SA and Waterswap reaction coordinates, demonstrated the high affinity of the compound for enzyme active site residues. These findings can provide new avenues for designing potent compounds against notorious bacterial pathogens.</p

Rmsd (left) and rmsf (right) plots for MurF enzyme and compound complex.

Rmsd (left) and rmsf (right) plots for MurF enzyme and compound complex.</p

Molecular ion and daughter ion peaks as obtained through GC-MS.

(DOCX)</p

Binding free energies reported by MMGBSA and MMPBSA methods for the MurF-compound complex.

Binding free energies reported by MMGBSA and MMPBSA methods for the MurF-compound complex.</p

S1 Graphical abstract -

(TIF)</p

Antibacterial activity of bacterial crude extracts of medicinal important plant (<i>Fagonia indica</i>) against Gram- positive and Gram- negative human pathogenic strains.

Each bacterial extract was analyzed individually in triplicate (n = 1 × 3) where (mean ± SD) are average of each value.</p

Docking scores of the compounds with respect MurF receptor.

Docking scores of the compounds with respect MurF receptor.</p

Antibacterial assay of secondary metabolites against <i>Staphylococcus epidermis</i>, <i>Staphylococcus aureus</i>, <i>Staphylococcus caseolyticus</i>, Methicillin resistance <i>Staphylococcus aureus</i>, <i>Enteriobactor cloacae</i> and <i>Acinetobacter baumannii</i>.

(P.C) represent the positive control (Ampicillin, Meropenem) while (N.C) represent the negative control (DMSO) zones of inhibition. (DOCX)</p

Fig 1 -

(A-E) Total ion chromatogram (TIC) of the methanolic extract of endophytic bacteria of Fagonia indica, represents the GC-MS profile of the identified compounds. Where (A) represent S. maltophilia, (B) B. tequilensis, (C) P cypripedii, (D) E. cloacae, and (E) B. subtilis.</p