- Development and pilot-scale demonstration of a process for inhibitors of the HIV nucleocapsid protein, NCp7
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A manufacturing process to prepare two antiretroviral agents that denature the HIV-1 nucleocapsid protein (NCp7) has been developed and demonstrated on a pilot scale. 2,2′-Dithiobis-(benzoyl chloride) (4), prepared from commercially available 2,2′-dithiobis(benzoic acid) (3), was coupled directly with L-isoleucine to give the potential anti-HIV compound [S-(R*,R*)]-2-{[2-[[2-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl] dithio]-benzoyl]amino}-3-methylpentanoic acid (2) thereby eliminating the α-amino acid protection and deprotection steps used in the original synthesis. Compound 2 was oxidized by bromine to a second potential anti-HIV compound [S-(R*,R*)]-3-methyl-2-(3-oxo-3H-benzo[d]isothiazol-2-yl)pentanoic acid (1). The intermediacy of the hydrobromide salt of 1 provided an effective purity control in the production of the pharmaceutical agent. Cost, operational, safety, environmental, and equipment considerations were taken into account during the course of development.
- Fiore, Phillip J.,Puls, Timothy P.,Walker, Jonathan C.
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- Isothiazolones
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Isothiazolones having the general structure STR1 where A is a monocyclic or bicyclic ring which may contain up to 3 heteroatoms selected from O, S, and N; R1 and R2 are substituent groups such as alkyl, alkoxy, hydroxy, nitro, cyano, amino, and carboxy; and R5 is alkyl, cycloalkyl, phenyl, and Het. The isothiazolones are useful as anti-retroviral agents, anti-inflammatory agents, and anti-atherosclerotic agents.
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- Biophysical characterization of zinc ejection from HIV nucleocapsid protein by anti-HIV 2,2'-dithiobis[benzamides] and benzisothiazolones
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HIV nucleocapsid protein (NCp7) has been suggested as a possible target for 2,2'-dithiobis[benzamide] and benzisothiazolone agents that inhibit viral replication in infected cells (Rice et al. Science 1995, 270, 1194-1197). The solution behavior of these
- Loo, Joseph A.,Holler, Tod P.,Sanchez, Joseph,Gogliotti, Rocco,Maloney, Lisa,Reily, Michael D.
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p. 4313 - 4320
(2007/10/03)
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