ABSTRACT
In this study, synthesis and docking studies of a series of new benzimidazole derivatives linked to substituted pyrimidines either through the methylenethio linkage or its bioisosteric methylene amino bridge were carried out. All the synthesized compounds were evaluated for their hepatitis C virus (HCV) RNA replication-inhibitory activity. Compounds 4d, 4f, and 4h were found to be more potent than VX-950 (IC50/90 of 4d=0.123/0.321, 4f=0.145/0.345, 4h=0.129/0.432, VX-950=0.20/0.45 µM, respectively) and 6d (IC50/90=0.116/0.452 µM) displayed activity very similar to that of the standard. Compounds 4d, 4f, 4h, and 6d were potent HCV RNA replication inhibitors and are good drug candidates for further investigations.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Hepacivirus/genetics , Models, Molecular , RNA, Viral/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzimidazoles/chemistry , Cell Line , Hepacivirus/physiology , Humans , RNA, Viral/biosynthesis , Virus ReplicationABSTRACT
In continuation of our previous work, a novel series of steroid derivatives were synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic properties were evaluated. Twenty-one heterocyclic derivatives containing a cyanopyrane ring fused to a steroidal moiety were conveniently synthesized and screened for their antagonistic, antiandrogen and prostate anticancer activities comparable to that of bicalutamide as the reference control. Some of the compounds exhibited better antagonistic, antiandrogen and prostate anticancer activities than the reference controls. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). Synthetic steroidal structures fused to a substituted cyanopyrane ring seem to be a promising approach in the search for novel leads for potent antagonistic, antiandrogen and prostate anticancer agents.
Subject(s)
Androgen Receptor Antagonists/chemistry , Androgen Receptor Antagonists/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Steroids/chemistry , Steroids/pharmacology , Androgen Receptor Antagonists/chemical synthesis , Androgen Receptor Antagonists/toxicity , Anilides/toxicity , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/toxicity , Humans , Male , Nitriles/toxicity , Prostatic Neoplasms , Receptors, Androgen/chemistry , Receptors, Androgen/metabolism , Steroids/chemical synthesis , Steroids/toxicity , Structure-Activity Relationship , Tosyl Compounds/toxicityABSTRACT
Condensation of 3beta-hydroxy-16-[(4-chlorophenyl)methylene]androst-5-en-17-one (1) with hydrazine hydrate in acetic acid afforded N-acetyl pyrazoline derivative 2, while condensation of 1 with semicarbazide afforded compound 3. Also, compound 1 was treated with hydrazine hydrate in absolute methanol or ethanol to afford the corresponding alpha-methoxy (4) and alpha-ethoxy (5) derivatives, which were cyclized with etherated boron trifluoride to the pyrazoline derivative 6. The latter could be prepared directly by refluxing 1 with hydrazine hydrate in dioxane. Oxidation of compound 6 with Oppenour or Moffat oxidizing agents yielded 3-oxo-derivatives 7 and 8, respectively. On the other hand, condensation of compound 1 with substituted hydrazines, gave the corresponding 3beta-hydroxyandrostenopyrazolines 9a,b, which were oxidized using the Moffat method to give 3-oxo-androstenopyrazolines 10a,b, which were condensed with ethylene triphenyl-phosphorane in DMSO to yield 3-ethylene androstenopyrazolines 11a,b. Dehydrogenation of 9a,b with Wettestein oxidation afforded Delta4,6-diene-3-one analogues 12a,b, which were treated with chloranil to yield Delta(4,6,8(14))-tri-ene-3-one analogues 13a,b. Oppenour oxidation of 9a,b afforded Delta4-ene-3-one analogues 14a,b, which were treated with dichlorodicyanoquinone (DDQ) in dioxane to give Delta1,4,6-triene-3-one analogues 15a,b. Pharmacological screening showed that many of these compounds inhibit 5alpha-reductase activity.
