Synthesis, metabolism and structure-mutagenicity relationships of novel 4-nitro-(imidazoles and pyrazoles) in Salmonella typhimurium.

A new series of 4-nitro-(imidazoles and pyrazoles) were synthesized as novel antimycotics and tested for their activation to mutagenic forms using Salmonella typhimurium TA98 and TA100, in the presence and in the absence of metabolic activation. TA100NR, TA100/1,8-DNP6, YG1026 and YG1029 strains were employed to identify a specific metabolic reaction which governs the mutagenic potency. Derivatives in the pyrazole group were generally found to be non mutagenic and active imidazoles were weak-direct-acting mutagens. For most of the compounds the mutagenic responses in TA98 were absent or 12- to 22-fold lower compared to TA100. The presence of a methyl or a benzylic group on the imidazole ring and substituents on the N1 and N3 positions were determinant for mutagenicity. Metabolism by bacterial enzyme systems was important to the expression of genotoxicity. Active compounds showed no mutagenicity toward the strain defective in classical nitroreductase and increased mutagenicity, from 2- to 7-fold depending on the test compound, toward the corresponding overproducing bacteria. On the other hand, compounds displayed reduced mutagenicity to the O-acetyltransferase strain without having increased activity in the corresponding overproducing bacteria, YG1029.

Synthesis and antiviral assays of some 2-substituted benzimidazole-N-carbamates.

Some 2-substituted benzimidazole-N-carbamates were synthesized and tested in vitro for antiviral activity. Two derivatives were active at noncytotoxic concentrations. The results confirmed the importance of the substituents at the 2-position of benzimidazole; an isopropylcarboxamide group led to the best activity.

Synthesis and antimicrobial assays of 3-diazoindole-2-carboxamides.

Some 3-diazoindole-2-carboxamides have been synthesized and their antimicrobial activity have been tested. Antimicrobial activity was practically lacking.

Synthesis and antiviral assays of some benzimidazole nucleosides and acyclonucleosides.

Some benzimidazole nucleosides and acyclonucleosides were synthesized and tested in vitro as antiviral agents. None of them showed significant activity. Replacement of the benzenesulphonyl group at N-1 with the ribofuranosyl moiety or with the acyclovir side-chain was deleterious.

Some new 3-methoxy-5-methyl-1,4-substituted pyrazoles.

A series of 3-methoxypyrazole derivatives was synthesized and tested as antifungal agents. The substituents were chosen on the base of their lipophylicity and for their presence in well-known antifungal drugs. The compounds displayed no significant activity in vitro.

Synthesis and antimicrobial activity of new diazoimidazole derivatives containing an N-acylpyrrolidine ring.

A series of 4-diazoimidazole-5-carboxamides bearing in position 2 lipophilic substituents was synthesized and their antimicrobial activity was evaluated in vitro against pathogenic Gram-positive, Gram-negative bacteria and fungi. Some compounds presented antifungal activity, particularly two derivatives (1g and 1h) showed good MIC values (10-50 microg/ml) against both moulds and yeasts.

Some new quinoline-based mono and dicarboxylic acids.

Some quinoline-based mono- and dicarboxylic acids structurally related to kynurenic acid have been synthesized and screened as antagonists of neurotransmission of NMDA, AMPA and KA excitatory amino acid receptors. Higher affinity for NMDA receptor was pointed out in the short series, but all the compounds, even those with key structural features of glutamic acid showed no significant activity.

Synthesis and antimicrobial activity of some N-monosubstituted 2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamides.

A short series of N-monosubstituted (aryl, aminoacyl, dipeptidyl)-2-(2-aminothiazol-4-yl)-(Z) -2-methoxyiminoacetamides was synthesized and tested for antimicrobial activity. A few members showed a somewhat interesting inhibitory action against Cryptococcus neoformans (MIC = 150 micrograms/ml).

Synthesis and antimicrobial activity of N, N-dialkyl-2-substituted-5-diazo-imidazole-4-carboxamides.

A series of 2-substituted-5-diazoimidazole-4-carboxamides has been synthesized, and their antimicrobial activity has been tested in vitro. Some of the compounds show antifungal activity related to the presence of small groups on the 4-carbox-amido moiety, while the presence of substituents in position 2 was detrimental.

Synthesis and antimycotic activity of some benzyloxyimino compounds.

Some benzyloxyimio compounds, related to oxiconazole and having a 1H-indole or 1H-benzimidazole moiety, have been synthesized and tested in vitro for their antimycotic activity against Candida tropicalis and C. albicans. The most active was showed to be 0-(2,4-dichlorobenzyl)-1-benzyl-5-nitro-1H-benzimidazole-2-carboxaldehyd e oxime (MIC: 25 micrograms/ml against both microorganisms). A structural feature important for the biological activity of the series appears to be presence of a benzimidazole nucleus substituted by an electron withdrawing group.

Synthesis and antimicrobial activity of some new benzodifurans and phenanthrolines.

A short series of di-functionalized benzodifurans and phenanthrolines were synthesized for in vitro antimicrobial activity. Dicarboxaldehydes, chiefly those with a phenanthroline supporting moiety, proved to be most effective, showing significant fungal growth inhibition.

Polo-like kinases inhibitors.

Polo-like kinases (PLKs) are a family of serine/threonine kinases that play crucial roles in multiple stages of mitosis. PLK1 is the most studied member of the family. It is overexpressed in a wide spectrum of cancer types and is a promising target in oncology. Most of PLK1 inhibitors are ATP-competitive. Despite the structural similarities among various kinases, several inhibitors are selective. Some areas of the PLK1 active site are important for selectivity against other kinases. These include a small pocket formed by Leu 132 in the hinge region, a bulky phenylalanine and a small cysteine at the bottom and in the roof of the ATP pocket, respectively, and an unusual concentration of positively charged residues in the solvent-exposed region. Many ATP-competitive inhibitors are heterocyclic systems able to interact with the unique features of the PLK1 binding site. Other inhibitors target regions outside the ATP pocket, such as the substrate binding domain or a hydrophobic pocket, formed when the kinase is in the inactive conformation. An alternative approach to obtain specificity and to overcome drug resistance often associated with kinase inhibitors is the inhibition of the polo-box domain (PBD) of PLK1. The PBD is unique for the family of PLKs and is essential for PLK functions; so it is a useful target for the development of selective and potent inhibitors for clinical uses. In this review some PLK inhibitors are reported, focusing on chemical structures, structure-activity-relationships (SAR) and biological activities. The great potential of these compounds could open promising perspectives. Moreover, a combination of polo-like kinases inhibitors with other anticancer drugs might offer new opportunities for cancer therapy.

Irreversible protein kinase inhibitors.

Targeting cancer with small molecule irreversible inhibitors of kinases represents an emerging challenge in drug discovery. Irreversible inhibitors bind to kinase active site in a covalent and irreversible form, most frequently by reacting with a nucleophilic cysteine residue, located near the ATP binding pocket. The most common mechanism is the Michael reaction, that refers to the addition of a nucleophile, such as cysteine, to an α,ß unsaturated carbonyl. The nucleophile reacts at the electrophilic ß-position to form an adduct; as a result the inhibitor irreversibly blocks binding of ATP to the kinase, rendering the kinase inactive. Different cysteine-reactive groups have been evaluated, an acrylamide or a substituted acrylamide moiety are the Michael acceptors of choice. There are some advantages for the irreversible kinase inhibition. These compounds are highly selective because they target a specific cysteine and only a limited number of kinases has a cysteine at the corresponding position. Another advantage is that covalent bond formation can overcome competition with the high endogenous concentration of ATP. A further motivation for designing irreversible inhibitors is their longer duration of action respect to conventional inhibitors. In fact, once bound to enzyme, these compounds do not readily dissociate and the inhibition continues even after the inhibitor leaves the circulation. Moreover, these inhibitors have the potential to overcome and prevent the emergence of acquired resistance conferred by mutations. In this review examples of irreversible inhibitors are reported, focusing on chemical structures, SAR and biological activities. The great potential of these compounds could open new and promising perspectives for a broader application of this approach.

Non-ATP competitive protein kinase inhibitors.

Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties.

Synthesis and antiviral activity of some N-benzenesulphonylbenzimidazoles.

Some N-sulphonylated benzimidazoles were synthesized as potential antiviral agents. Compound 16b and, to a lesser extent, 19b showed activity against two RNA viruses at micromolar concentrations.