Rita Meleddu

Synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis: Part 2. Synthesis of rigid pyrazolones

Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC=4 microg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity.

Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis

As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 microg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure-activity relationship analysis.

1,5-Diaryl-2-ethyl pyrrole derivatives as antimycobacterial agents: Design, synthesis, and microbiological evaluation

During the search of novel antitubercular drugs related to BM 212, new diarylpyrroles were designed and synthesized on the basis of a structure-activity relationship analysis of many pyrroles previously described by us. Among them, 1-(4-fluorophenyl)-2-ethyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole (2b) proved to be particularly active, with a minimum inhibitory concentration (MIC, expressed as microg/mL) and a protection index (PI) better than or comparable to those of reference compounds. Also the remaining compounds were very active, although their MIC and PI were in general lower than those of their parent 2-methyl analogues.

1,5-Diphenylpyrrole Derivatives as Antimycobacterial Agents. Probing the Influence on Antimycobacterial Activity of Lipophilic Substituents at the Phenyl Rings

Synthesis and biological evaluation of new derivatives of 1,5-bis(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM 212, 16) are reported. Variously substituted phenyl rings with different substitution pattern and lipophilicity were added to the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. The most active derivatives showed activity between 0.125-0.5 microg/mL (better than 16 and streptomycin) and protection index (64-256) higher than 16 (4) and similar to isoniazid and streptomycin (128).

Synthesis and biological evaluation of new enantiomerically pure azole derivatives as inhibitors of Mycobacterium tuberculosis

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole.

Molecular Aspects of the RT/drug Interactions. Perspective of Dual Inhibitors

The HIV-1 reverse transcriptase (RT) is one of the most attracting targets for the development of early phase infection inhibitors. Although many RT inhibitors have been approved for the treatment of HIV-1 infection, they all target the polymerase function of this enzyme. So far, no drugs are available for the inhibition of the RT associated ribonuclease H function (RNase H), which plays an essential role in the HIV replication cycle. Moreover it should be reported that many of the known RT inhibitors, targeting the polymerase function, enhance the RNase H activity, indicating that, although spatially distinct, a close relation occurs between the two functions. The aim of this review is to summarise the efforts in the design of new inhibitors either characterized by a novel mechanism of action or capable of blocking both RT associated functions, as well as pointing out the main binding features of the known RT inhibitors.

Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1: a patent survey

Introduction: Vascular adhesion protein-1 (VAP-1)/semicarbazide-sensitive amine oxidase (SSAO) is an adhesion protein involved in leukocyte trafficking and inflammatory processes, with a special amine oxidase activity. Inhibitors have been mainly developed for treating chronic inflammatory disorders. The utility of inhibitors as antiangiogenic agents in ophthalmological and oncological diseases is currently under evaluation. SSAO substrates may mimic several insulin effects, although their utility for the treatment of diabetes is still far from being fully understood. Areas covered: This paper reviews the patent literature of SSAO/VAP-1 inhibitors and substrates, for the period of 1990 – 2010. The current stage of SSAO/VAP-1-interacting agents published in patents is described, along with their chemical structures and pharmacological uses. Expert opinion: SSAO/VAP-1 is a promising anti-inflammatory target. Another important field for therapeutic application of these inhibitors may be ophthalmology, due to their antiangiogenic effects. SSAO substrates might also be of therapeutic value in the treatment of diabetes; however, more extensive research has to be undertaken to validate this approach.

3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles: a new scaffold for the selective inhibition of monoamine oxidase B.

3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles were designed, synthesized, and tested as inhibitors against human monoamine oxidase (MAO) A and B isoforms. Several compounds, obtained as racemates, were identified as selective MAO-B inhibitors. The enantiomers of some derivatives were separated by enantioselective HPLC and tested. The R-enantiomers always showed the highest activity. Docking study and molecular dynamic simulations demonstrated the putative binding mode. We conclude that these 1,3,4-oxadiazoles derivatives are promising reversible and selective MAO-B inhibitors.

Synthesis of new 3-aryl-4,5-dihydropyrazole-1-carbothioamide derivatives. An investigation on their ability to inhibit monoamine oxidase

Some differently substituted 3-aryl-4,5-dihydropyrazoles-1-carbothioamides have been synthesised with the aim to investigate their monoamine oxidase inhibitory activity. The chemical structures of the compounds have been characterized by means of their IR, (1)H NMR, (13)C NMR spectroscopic data and elemental analyses. All the active compounds showed a selective activity towards the B isoform of the enzyme, regardless of the substitution on the heterocyclic ring. The inhibition of the enzymatic activity was measured on human recombinant MAO isoforms, expressed in baculovirus infected BTI insect cells. Docking experiments were carried out with the aim to rationalize the mechanism of inhibition of the most active and selective compound.

(3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro- 1H -indol-2-one derivatives as dual inhibitors of HIV-1 reverse transcriptase

The HIV-1 Reverse Transcriptase (RT) is a validated and deeply explored biological target for the treatment of AIDS. However, only drugs targeting the RT-associated DNA polymerase (DP) function have been approved for clinical use. We designed and synthesised a new generation of HIV-1 RT inhibitors, based on the (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one scaffold. These compounds are active towards both RT-associated functions, DNA polymerase and ribonuclease H. The structure, biological activity and mode of action of the new derivatives have been investigated. In particular, the nature of the aromatic group in the position 4 of the thiazole ring plays a key role in the modulation of the activity towards the two RT-associated functions.