BIOMAT Database Logo BIOMAT Database Logo

Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-one (TIBO) derivatives. 1991

M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
Janssen Research Foundation, Spring House, Pennsylvania 19477.

A series of 6-substituted 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-ones (9) have been synthesized and tested for their ability to inhibit the replication of the HIV-1 virus in MT-4 cells. Two synthetic methods are described, one of which allows the synthesis of single enantiomers of the final products. A structure-activity study was done within the series of compounds to determine the optimum group for the 6-position substitution and to determine whether the activity was enantiospecific at the 5-position, which was substituted with a methyl group. The best analogue, 9jj, inhibited HIV-1 with an IC50 of 4 microM, which is comparable to the activity level of DDI, a 2',3'-dideoxynucleoside-type structure undergoing clinical trials as an anti-AIDS therapy.

UI MeSH Term Description Entries
D002621 Chemistry A basic science concerned with the composition, structure, and properties of matter; and the reactions that occur between substances and the associated energy exchange.
D006678 HIV Human immunodeficiency virus. A non-taxonomic and historical term referring to any of two species, specifically HIV-1 and/or HIV-2. Prior to 1986, this was called human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). From 1986-1990, it was an official species called HIV. Since 1991, HIV was no longer considered an official species name; the two species were designated HIV-1 and HIV-2. AIDS Virus,HTLV-III,Human Immunodeficiency Viruses,Human T-Cell Lymphotropic Virus Type III,Human T-Lymphotropic Virus Type III,LAV-HTLV-III,Lymphadenopathy-Associated Virus,Acquired Immune Deficiency Syndrome Virus,Acquired Immunodeficiency Syndrome Virus,Human Immunodeficiency Virus,Human T Cell Lymphotropic Virus Type III,Human T Lymphotropic Virus Type III,Human T-Cell Leukemia Virus Type III,Immunodeficiency Virus, Human,Immunodeficiency Viruses, Human,Virus, Human Immunodeficiency,Viruses, Human Immunodeficiency,AIDS Viruses,Human T Cell Leukemia Virus Type III,Lymphadenopathy Associated Virus,Lymphadenopathy-Associated Viruses,Virus, AIDS,Virus, Lymphadenopathy-Associated,Viruses, AIDS,Viruses, Lymphadenopathy-Associated
D000998 Antiviral Agents Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D001570 Benzodiazepinones
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014779 Virus Replication The process of intracellular viral multiplication, consisting of the synthesis of PROTEINS; NUCLEIC ACIDS; and sometimes LIPIDS, and their assembly into a new infectious particle. Viral Replication,Replication, Viral,Replication, Virus,Replications, Viral,Replications, Virus,Viral Replications,Virus Replications
D055598 Chemical Phenomena The composition, structure, conformation, and properties of atoms and molecules, and their reaction and interaction processes. Chemical Concepts,Chemical Processes,Physical Chemistry Concepts,Physical Chemistry Processes,Physicochemical Concepts,Physicochemical Phenomena,Physicochemical Processes,Chemical Phenomenon,Chemical Process,Physical Chemistry Phenomena,Physical Chemistry Process,Physicochemical Phenomenon,Physicochemical Process,Chemical Concept,Chemistry Process, Physical,Chemistry Processes, Physical,Concept, Chemical,Concept, Physical Chemistry,Concept, Physicochemical,Concepts, Chemical,Concepts, Physical Chemistry,Concepts, Physicochemical,Phenomena, Chemical,Phenomena, Physical Chemistry,Phenomena, Physicochemical,Phenomenon, Chemical,Phenomenon, Physicochemical,Physical Chemistry Concept,Physicochemical Concept,Process, Chemical,Process, Physical Chemistry,Process, Physicochemical,Processes, Chemical,Processes, Physical Chemistry,Processes, Physicochemical

Related Publications

M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase.
March 2005, Journal of medicinal chemistry,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
Molecular docking studies on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone (TIBO) derivatives as HIV-1 NNRT inhibitors.
February 2008, Journal of computer-aided molecular design,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
Solid-phase synthesis of tetrahydro-1,4-benzodiazepin-2-one derivatives.
January 2000, Molecular diversity,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
Synthesis and pharmacological activity and some derivatives of 1-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one.
May 1978, Journal of medicinal chemistry,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives.
February 1991, Proceedings of the National Academy of Sciences of the United States of America,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
Allosteric inhibition of human immunodeficiency virus type 1 reverse transcriptase by tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione compounds.
January 1992, Molecular pharmacology,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
A novel one-pot pseudo-five-component synthesis of 4,5,6,7-tetrahydro-1H-1,4-diazepine-5-carboxamide derivatives.
May 2008, The Journal of organic chemistry,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
Synthesis and study of anti-HIV-1 RT activity of 5-benzoyl-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one derivatives.
June 2017, Bioorganic chemistry,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5, 1- jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150).
January 1993, Molecular pharmacology,
M J Kukla, and H J Breslin, and R Pauwels, and C L Fedde, and M Miranda, and M K Scott, and R G Sherrill, and A Raeymaekers, and J Van Gelder, and K Andries
Data mining using template-based molecular docking on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone (TIBO) derivatives as HIV-1RT inhibitors.
November 2008, Journal of molecular modeling,
Copied contents to your clipboard!