A series of novel 1-aryl-3-methyl-1H,3H-thiazolo[3,4-a]benzimidazoles, TBZ analogues, were synthesized and investigated as anti-human immunodeficiency virus (HIV) agents in order to study the effects of structural modifications on antiviral activity and cytotoxicity. They were proved to inhibit significantly HIV-1 replication in vitro without showing inhibitory activity on HIV-2 or simian immunodeficiency virus. Their potency was influenced by the presence of suitable substituents in the phenyl ring at C-1 as well as by their stereochemical characteristics. In fact, the most active compound of the series was the trans-1-(2,6-difluorophenyl)-3-methyl-1H,3H-thiazolo[3,4-a]benzimidazole, in which the butterfly-like conformation is stabilized by two intramolecular hydrogen bonds between the fluorine atoms and H-1 and H-3. This was made possible by the trans arrangement of C-1 and C-3 substituents, as shown by X-ray and NMR analysis.
ArticoM (1996) Non-nucleoside anti-HIV-1 reverse transcriptase inhibitors (NNRTIs): a chemical survey from lead compounds to selected drugs for clinical trials. Il Farmaco51:305–331.
2.
BuckheitRWHollingsheadMGGermany-DeckerJWhiteELMcMahonJBAllenLBRossLJDeckerWDWestbrookLShannonWMWeislowOBaderJP & BoydMR (1993) Thiazolobenzimidazole: biological and biochemical anti-retroviral activity of a new nonnucleoside reverse transcriptase inhibitor. Antiviral Research21:247–265.
3.
ChimirriAGrassoSMonforteAMMonforteP & ZappalàM (1991a) Anti-HIV agents I. Synthesis and anti-HIV evaluation of novel 1H,3H-thiazolo[3,4-a]benzimidazoles. Il Farmaco46:817–823.
4.
ChimirriAGrassoSMonforteAMMonforteP & ZappalàM (1991b) Anti-HIV agents II. Synthesis and in vitro anti-HIV activity of novel 1H,3H-thiazolo[3,4-a]benzimidazoles. Il Farmaco46:925–933.
5.
ChimirriAGrassoSMonforteAMMonforteP & ZappalàM (1994) Anti-HIV agents. III. Synthesis and in vitro anti-HIV activity of novel 1H,3H-thiazolo[3,4-a]imidazo[4,5-b]pyridines. Il Farmaco49:345–348.
6.
ChimirriAGrassoSMolicaCMonforteAMMonforteP & ZappalàM (1996) Anti-HIV agents. IV. Synthesis and in vitro anti-HIV activity of novel 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazoles. Il Farmaco51:279–282.
7.
ChimirriAGrassoSMolicaCMonforteAMMonfortePZappalàMBrunoGNicolòFWitvrouwMJonckeereHBalzariniJ & De ClercqE (1997a) Structural features and anti-human immunodeficiency virus (HIV) activity of the isomers of 1-(2′,6′-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor. Antiviral Chemistry and Chemotherapy8:363–370.
8.
ChimirriAGrassoSMonforteAMMonfortePRaoA & ZappalàM (1997b) Anti-HIV agents. V. Synthesis, structure and in vitro anti-HIV activity of novel 1H,3H-naphtho[2′,3′:4,5]imidazo[1,2-c]thiazoles. Il Farmaco52:673–677.
9.
De ClercqE (1995a) Antiviral therapy of human immunodeficiency virus infections. Clinical Microbiology Reviews8:200–239.
10.
De ClercqE (1995b) Towards improved anti-HIV chemotherapy: therapeutic strategies for intervention with HIV infection. Journal of Medicinal Chemistry38:2491–2517.
11.
De ClercqE (1996) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infections: strategies to overcome drug resistance development. Medicinal Research Reviews16:125–157.
12.
DiamondR (1969) Profile analysis in single crystal diffractometry. Acta Crystallographica Section A25:43–55.
13.
DingJDasKMoereelsHKoymansLAndriesKJanssenPAJHughesSH & ArnoldE (1995) Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nature Structural Biology2:407–415.
14.
EvansTA & SeddonKR (1997) Hydrogen bonding in DNA – a return to the status quo. Chemical Communications2023–2024.
15.
KopfmannG & HuberR (1968) A method of absorption correction by X-ray intensity measurements. Acta Crystallographica Section A24:348–351.
16.
MonfortePMonforteAMZappalàMRomeoGGrassoS & ChimirriA (1993) 1-Phenyl substituted 1H,3H-thiazolo[3,4-a]benzimidazoles: process for their preparation, and pharmaceutical compositions containing them. US Patent 5.217.984.
17.
NardelliM (1983) PARST: a system of FORTRAN routines for calculating molecular structure parameters from results of crystal structure analyses. Computional Chemistry7:95–98.
18.
NardelliM (1995) PARST: a system of computer routines for calculating molecular parameters from results of crystal structure analysis. Journal of Applied Crystallography28:659.
19.
PauwelsRBalzariniJBabaMSnoeckRScholsDHerdewijinPDesmyterJ & De ClercqE (1988) Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. Journal of Virological Methods20:309–321.
20.
SheldrickGM (1991) SHELXTL-Plus, version 4.2. Madison: Siemens Analytical X-ray Instruments.
21.
SheldrickGM (1997). SHELXL-97. Program for the refinement of crystal structures. Madison: Siemens Analytical X-ray Instruments.
22.
SpenceRAKatiWMAndersonKS & JohnsonKA (1995) Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Science267:988–993.
23.
WitvrouwMScholsDAndreiGSnoeckRHosoyaMPauwelsRBalzariniJ & De ClercqE (1991) Antiviral activity of low-MW dextran sulfate (derived from dextran MW 1000) compared to dextran sulfate samples of higher MW. Antiviral Chemistry and Chemotherapy2:171–179.
