Dual Antitubercular and Antileishmanial Profiles of Quinoxaline Di-N-Oxides Containing an Amino Acidic Side Chain.

We present a new category of quinoxaline di-N-oxides (QdNOs) containing amino acid side chains with dual antituberculosis and antileishmanial activity. These compounds were synthesized by combining a regioselective 2,5-piperazinedione opening and a Beirut reaction and were screened for their activity against Mycobacterium tuberculosis and the promastigote and amastigote forms of representative species of the Leishmania genus. Most QdNOs exhibited promising antitubercular activity with IC50 values ranging from 4.28 to 49.95 µM, comparable to clinically established drugs. Structure-activity relationship analysis emphasized the importance of substituents on the aromatic ring and the side chain. Antileishmanial tests showed that some selected compounds exhibited activity comparable to the positive control miltefosine against promastigotes of Leishmania amazonensis and Leishmania donovani. Notably, some compounds were found to be also more potent and less toxic than miltefosine in intracellular amastigote assays against Leishmania amazonensis. The compound showing the best dual antitubercular and leishmanicidal profile and a good selectivity index, 4h, can be regarded as a hit compound that opens up new opportunities for the development of integrated therapies against co-infections.

Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into ß-functionalized α-ketoamides.

A sequential three-component process is described, starting from 3-arylmethylene-2,5-piperazinediones and involving a one-pot sequence of reactions achieving regioselective opening of the 2,5-diketopiperazine ring and diastereoselective generation of an aziridine ring. This method allows the preparation of N-unprotected, trisubstituted aziridines bearing a peptide side chain under mild conditions. Their transformation into ß-trifluoroacetamido-α-ketoamide and α,ß-diketoamide frameworks was also achieved in a single step.

Privileged scaffolds in synthesis: 2,5-piperazinediones as templates for the preparation of structurally diverse heterocycles.

2,5-Piperazinediones (2,5-diketopiperazines, DKPs) can be viewed as privileged building blocks for the synthesis of heterocyclic systems. This tutorial review aims at underscoring the large number and structural variety of nitrogen heterocycles that are available by suitable manipulation of DKP starting materials, including many bioactive compounds and natural products.

1,3-dipolar cycloadditions from tricyclic hemiaminals. Synthesis of the quinocarcin core through catalyst-free generation of azomethine ylides.

The generation of azomethine ylides from the readily accessible hemiaminals 3 and 8 or from iminium salt 10 was studied. Compounds 8 gave anti- and syn-cycloadducts containing the quinocarcin core through a catalyst-free dehydration process.

Cytotoxicity of new pyrazino[1,2-b]isoquinoline and 6,15-iminoisoquino[3,2-b]3-benzazocine compounds.

Looking for optimised analogues of compound 2 that might be useful in colon cancer therapy, we here explore the in vitro cytotoxicity against MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma and HT-29 human colon carcinoma cell lines of several analogues and derivatives. The effect of the R2-substituent and/or the introduction of an arylmethyl side-chain at C-3, as well as the presence of a double bond in the skeleton or a methoxy group at C-1 have been investigated. New 6,15-iminoisoquino[3,2-b]3-benzazocine compounds, related to the saframycin family, in which the C(7)-N(8)-C(9)-substructure contains a lactam function, a fused oxazolidine or an aminonitrile function were also studied, and many of them showed low micromolar GI50 values.

Recent synthetic approaches to 6,15-iminoisoquino[3,2-b]3-benzazocine compounds.

Saframycins, safracins, renieramycins, cribrostatins, and esteinascidins are 6,15-iminoisoquino[3,2-b]3-benzazocine compounds that constitute the largest subgroup among the antitumor antibiotics belonging to the tetrahydroisoquinoline family. Their structural complexity has led to widespread synthetic attention to obtain them in both racemic and enantiopure forms. Publication in 1996 of the first total synthesis of ecteinascidin 743 by Corey's group was an important milestone, but the development of preparative protocols for these structures has continued, offering new possibilities to exploit the biological activity of the above-mentioned natural products and their analogues. This minireview is intended to update this progress following a methodological rather than a chronological organization. Besides of a brief description of the different strategies evolved from retrosynthetic analyses, which have been organized according to the order of bonding events that will link the precursors, semisynthetic approaches and a brief account of the total syntheses of ecteinascidin 743, have been analyzed.

Synthesis and cytotoxic activity of pyrazino[1,2-b]-isoquinolines, 1-(3-isoquinolyl)isoquinolines, and 6,15-iminoisoquino[3,2-b]-3-benzazocines.

A series of pyrazino[2,1-b]isoquinoline and 6,15-iminoisoquino[3,2-b]-3-benzazocine compounds related to renieramycins, cribrostatin 4, and phthalascidin was synthesized and their in vitro cytotoxic activities were evaluated against three human cancer cell lines. Pyrazino[2,1-b]isoquinolines, 6,15-iminoisoquino[3,2-b]-3-benzazocines, and other more complex octacyclic compounds have been obtained and derived to precursors of iminium ion species. Hydrogenolysis of the lactam function in pentacyclic compounds gave 1-(3-isoquinolyl)isoquinolines. The micromolar cytotoxic activity of representative structures was apparently uninfluenced by the ability to generate intermediates which would permit covalent bonding to DNA.