title: In vitro anti-HIV-1 activity of salicylidene acylhydrazide compounds.
abstract: Salicylidene acylhydrazide compounds have been shown to inhibit bacterial pathogens, including Chlamydia and Neisseria gonorrhoeae. If such compounds could also target HIV-1, their potential use as topical microbicides to prevent sexually transmitted infections would be considerable. In this study, the in vitro anti-HIV-1 activity, cytotoxicity and mechanism of action of several salicylidene acylhydrazides were determined. Inhibitory activity was assessed using TZM-bl cells and primary peripheral blood mononuclear cells (PBMCs) as targets for HIV-1 infection. Antiviral activity was measured against cell-free and cell-associated virus and in vaginal fluid and semen simulants. Since the antibacterial activity of salicylidene acylhydrazides is reversible by Fe(2+), the ability of Fe(2+) and other cations to reverse the anti-HIV-1 activity of the compounds was determined. Real-time PCR was also employed to determine the stage affected in the HIV-1 replication cycle. Four compounds with 50% inhibitory concentrations against HIV-1 of 1-7 μM were identified. In vitro toxicity varied but was generally limited. Activity was similar against three R5 clade B primary isolates and whether the target for virus replication was TZM-bl cells or PBMCs. Compounds inhibited cell-free and cell-associated virus and were active in vaginal fluid and semen simulants. Fe(2+), but not other cations, reversed the anti-HIV-1 effect. Finally, the inhibitory effect of the compounds occurred at a post-integration step. In conclusion, salicylidene acylhydrazides were identified with in vitro anti-HIV-1 activity in the micromolar range. The activity of these compounds against other sexually transmitted pathogens makes them potential candidates to formulate for use as a broad-spectrum topical genital microbicide.
authors: Department of Medicine (Infectious Diseases), University of California, Irvine School of Medicine, 3044 Hewitt Hall, Irvine, CA 92697, USA. dnfortha@uci.edu
authors: Donald N
authors: DN
authors: Forthal
authors: Tran B
authors: TB
authors: Phan
authors: Anatoly V
authors: AV
authors: Slepenkin
authors: Gary
authors: G
authors: Landucci
authors: Hencelyn
authors: H
authors: Chu
authors: Mikael
authors: M
authors: Elofsson
authors: Ellena
authors: E
authors: Peterson
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D012634:Bodily Secretions / Q000821:virology; D002478:Cells, Cultured; D005260:Female; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D008826:Microbial Sensitivity Tests; D012545:Schiff Bases / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D006834:Hydrazines; D012545:Schiff Bases