Alba Chimirri

Discovery of 2,3-diaryl-1,3-thiazolidin-4-ones as potent anti-HIV-1 agents

Design, synthesis and anti-HIV activity of a series of 2,3-diaryl-1,3-thiazolidin-4-ones are reported. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations thereby acting as non-nucleoside HIV-1 RT inhibitors (NNRTIs). SAR studies evidenced that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus largely influenced the in vitro anti-HIV activity of this new class of potent antiviral agents.

Design, Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies of 2,3-Diaryl-1,3-thiazolidin-4-ones as Potent Anti-HIV Agents

Starting from 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs), we performed the design, synthesis, and the structure-activity relationship studies of a series of 2,3-diaryl-1,3-thiazolidin-4-ones. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations with minimal cytotoxicity, thereby acting as nonnucleoside HIV-1 RT inhibitors (NNRTIs). Computational studies were used to delineate the ligand-RT interactions and to probe the binding of the ligands to HIV-1 RT.

Pharmacophore-Based Discovery of Small-Molecule Inhibitors of Protein–Protein Interactions between HIV-1 Integrase and Cellular Cofactor LEDGF/p75

The cellular protein lens epithelium‐derived growth factor, or transcriptional coactivator p75 (LEDGF/p75), plays a crucial role in HIV integration. The protein–protein interactions (PPIs) between HIV‐1 integrase (IN) and its cellular cofactor LEDGF/p75 may therefore serve as targets for the development of new anti‐HIV drugs. In this work, a structure‐based pharmacophore model for potential small‐molecule inhibitors of HIV‐1 IN–LEDGF/p75 interaction was developed using the LigandScout software. The 3D model obtained was used for virtual screening of our in‐house chemical database, CHIME, leading to the identification of compound CHIBA‐3002 as an interesting hit for further optimization. The rational design, synthesis and biological evaluation of four derivatives were then carried out. Our studies resulted in the discovery of a new and more potent small molecule (7, CHIBA‐3003) that is able to interfere with the HIV‐1 IN–LEDGF/p75 interaction at micromolar concentration, representing one of the first compounds to show activity against these specific PPIs. Docking simulations were subsequently performed in order to investigate the possible binding mode of our new lead compound to HIV‐1 IN. This study is a valid starting point for the identification of anti‐HIV agents with a different mechanism of action from currently available antiviral drugs.

5H-[1,2,4]Oxadiazolo[5,4-d][1,5]benzothiazepines as anticonvulsant agents in DBA/2 mice

Summary A series of 3 a ,4-dihydro-5 H -[1,2,4]oxadiazolo[5,4- d ][1,5]benzothiazepines have been synthesized by 1,3-dipolar cycloaddition reaction of benzonitriloxide to the C N double bond of 1,5-benzothiazepine derivatives, and the stereochemical features of compounds obtained have been determined by NMR spectroscopy. The results of evaluation of their activity in preventing seizures induced by audiogenic stimulation in DBA/2 mice are also reported and discussed. The 5-(4-bromophenyl)-1,3-diphenyl derivative 3b , the most active compound of the series, is over 20 times more active than the parent benzothiazepine 1b and shows an activity comparable to clobazam and better than desmethylclobazam.

GYKI 52466 and related 2,3-benzodiazepines as anticonvulsant agents in DBA/2 mice.

The behavioural and anticonvulsant effects of several 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones (2,3-BZs) and of 11b-aryl-7,11-dihydro-3-phenyl[1,2,4]oxadiazolo[5,4-a][2,3]benz odiazepin-6-ones (2,3-OBZs) were studied after intraperitoneal (i.p.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The seizures were evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a hemispheric Perspex dome. The 2,3-benzodiazepines studied after 30 min pretreatment were generally less potent than the related derivative 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) except 3,5-dihydro-7,8-dimethoxy-1-phenyl-4H-2,3-benzodiazepin-4-one (2,3-BZ-2) and 2,3-BZ-2M (3-methyl derivative of 2,3-BZ-2) which showed comparable activity. Thirty minutes after i.p. administration of 2,3-benzodiazepines, the rank order of potency for anticonvulsant activity against clonus was 2,3-BZ-2 > GYKI 52466 > 2,3-BZ-2M > 2,3-BZ-1 > 2,3-BZ-3, > 2,3-OBZ-1, > 2,3-OBZ-2 2,3-OBZ-3. The intracerebroventricular (i.c.v.) injection of aniracetam on it own (12.5 - 100 nmol/mouse) had no convulsant activity, but it reversed the anticonvulsant effects of some 2,3-benzodiazepines. In particular, the pharmacological actions of GYKI 52466, 2,3-BZ-2 and 2,3-BZ-2M, which proved to be the most potent 2,3-benzodiazepine derivatives as anticonvulsants, were significantly reduced by an i.c.v. pretreatment with aniracetam (50 nmol/mouse). Concomitant treatment with aniracetam (50 nmol/mouse) shifted to the right the dose-response curves and significantly increased the ED50 values for GYKI 52466, 2,3-BZ-2 and 2,3-BZ-2M. After 30 min pretreatment 2,3-BZ-2 showed a similar potency to GYKI 52466 in antagonizing seizures induced by i.c.v. administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), thus suggesting a clear involvement of AMPA receptors in the anticonvulsant activity of these compounds. In addition, 2,3-BZ-2 and 2,3-BZ-2M showed anticonvulsant properties longer lasting than GYKI 52466.

Molecular Dynamics Studies of the Wild-Type and Double Mutant HIV-1 Integrase Complexed with the 5CITEP Inhibitor: Mechanism for Inhibition and Drug Resistance

The human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the life cycle of the virus and is an attractive target for the development of new drugs useful in acquired immunodeficiency syndrome multidrug therapy. Starting from the crystal structure of the 5CITEP inhibitor bound to the active site in the catalytic domain of the HIV-1 IN, two different molecular dynamics simulations in water have been carried out. In the first simulation the wild-type IN was used, whereas in the second one the double mutation T66I/M154I, described to lead to drug resistance, was introduced in the protein. Compelling differences have been observed in these two structures during analyses of the molecular dynamics trajectories, particularly in the inhibitor binding modes and in the conformational flexibility of the loop (residues 138-149) located near the three catalytic residues in the active site (Asp(64), Asp(116), Glu(152)). Because the conformational flexibility of this region is important for efficient biological activity and its behavior is quite different in the two models, we suggest a hypothetical mechanism for the inhibition and drug resistance of HIV-1 IN. These results can be useful for the rational design of more potent and selective integrase inhibitors and may allow for the design of inhibitors that will be more robust against known resistance mutations.

Synthesis and anti-hIV activity of 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole structurally-related 1,2-substituted benzimidazoles.

The synthesis of 1,2-substituted benzimidazoles is reported. These novel derivatives share chemical similarities with 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles, a class of HIV-1 NNRTIs studied widely. All compounds prepared were tested in MT-4 cells to explore their potential anti-HIV activity and were found to be less potent than 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole (TBZ).

AMPA receptor antagonists as potential anticonvulsant drugs.

Over the last years alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathological processes. Efforts targeting AMPAR have been focused on identification of ligands as potential therapeutic agents useful in the prevention and treatment of a variety of neurological and non-neurological diseases. In particular, extensive work was addressed to the discovery of selective antagonists some of which proved to be potent anticonvulsant agents.

Synthesis and anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-(thi)one derivatives

Several 2,3-diaryl-1,3-thiazolidine-4-thione derivatives and 2,3-diaryl-1,3-thiazolidin-4-ones bearing a methyl group at C-5 position have been synthesized and tested as anti-HIV agents. The results of the in vitro tests showed that some of them proved to be effective inhibitors of HIV-1 replication.

Synthesis and anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-ones

Several 1,3-thiazolidin-4-ones bearing a 2,6-dihalophenyl group at C-2 and a variously substituted phenyl ring at N-3 have been synthesized and tested as anti-HIV agents. The results of the in vitro tests showed that some of them proved to be effective inhibitors of HIV-1 replication.