Alexander Sapegin

Lucky Switcheroo: Dramatic Potency and Selectivity Improvement of Imidazoline Inhibitors of Human Carbonic Anhydrase VII

A substantial improvement of potency and selectivity of imidazoline-based inhibitors of hCA VII (a promising target for the treatment of seizures and neuropathic pain) was achieved by simply switching the position of the benzenesulfonamide moiety from N1 (as in the earlier reported series) to C2. Selectivity indices vs the off-target isoforms (hCA I, I, I and IV) greater than 100 were reached, which is exceedingly rare for hCA VII inhibitors. The drastic profile improvement of the new series has been rationalized by an additional hydrogen bonding with the nonconserved Q69 residue in the active site of hCA VII (absent in the other three isoforms studied), which also results in a favorable accommodation of the inhibitors lipophilic periphery in the nearby hydrophobic pocket. The robustness of the docking simulations was tested and confirmed by molecular dynamics simulations.

Unprotected primary sulfonamide group facilitates ring-forming cascade en route to polycyclic [1,4]oxazepine-based carbonic anhydrase inhibitors

4-Chloro-3-nitrobenzenesulfonamide reacted cleanly at room-temperature with a range of bis-electrophilic phenols bearing an NH-acidic functionality (secondary carboxamide or pyrazole) in the ortho-position. This produced a novel class of [1,4]oxazepine-based primary sulfonamides which exhibited strong inhibition of therapeutically relevant human carbonic anhydrases. 2-Chloronitrobenzene did not enter a similar cyclocondensation process, even under prolonged heating. Thus, the primary sulfonamide functionality plays a dual role by enabling the [1,4]oxazepine ring construction and acting as a enzyme prosthetic zinc-binding group when the resulting [1,4]oxazepine sulfonamides are employed as carbonic anhydrase inhibitors.

Non-covalent interactions observed in nevirapinium pentaiodide hydrate which include the rare I4–I−···O=C halogen bonding

Abstract In the course of screening for novel crystalline forms of antiviral drug nevirapine, co-crystallization of the latter with molecular iodine was attempted. This resulted in the formation of a hydrate salt form composed of the protonated nevirapinium cation and pentaiodide anion. In the X-ray structure of NVPH+I5−·H2O, halogen and hydrogen bonding interactions were identified and studied by DFT calculations and topological analysis of the electron density distribution within the framework of QTAIM method at the B3LYP/DZP-DKH and M06/DZP-DKH levels of theory. Estimated energies of these contacts are 1.3–9.4 kcal/mol.

Rare Medium-Sized Rings Prepared via Hydrolytic Imidazoline Ring Expansion (HIRE)

The hydrolytic imidazoline ring expansion (HIRE) methodology was extended to readily available tetracyclic [1,4]thiazepines as well as sulfoxide and sulfone analogs thereof. The reactions resulted in the facile formation of a rare medium-sized [1,4,7]thiazecine ring system that has an emerging utility in bioactive compound design. Comparing the HIRE rates for representative compounds in the three groups of substrates allowed drawing some generalizations about the substituent effects on the course of the reaction.