Enlarging the NSAIDs family: ether, ester and acid derivatives of the 1,5-diarylpyrrole scaffold as novel anti-inflammatory and analgesic agents.

The development of the coxib family has represented a stimulating approach in the treatment of inflammatory disorders, such as arthritis, and for the management of acute pains, in relation to the well-known traditional Non-Steroidal Anti-inflammatory Drugs (t-NSAIDs). Prompted by the pursuit for new cyclooxygenase-2 (COX-2) inhibitors, endowed with fine tuned selectivity and high potency, in the past years we have identified novel classes of ether, ester and acid molecules characterized by the 1,5-diarylpyrrole scaffold as potentially powerful anti-inflammatory molecules (12-66). All compounds proved to exert an in vitro inhibition profile as good as that shown by reference compounds. Compounds bearing a p-methylsulfonylphenyl substituent at C5 displayed the best issues. In particular, ester derivatives proved to perform the best in vitro profile in terms of selectivity and activity toward COX-2. The cell-based assay data showed that an increase of hindrance at the C3 side chain of compounds could translate to activity enhancement. The human whole blood (HWB) test let to highlight that submitted compounds displayed 5-10 fold higher selectivity for COX-2 vs COX-1 which should translate clinically to an acceptable gastrointestinal safety and mitigate the cardiovascular effects highlighted by highly selective COX-2 inhibitors. Finally, to assess in vivo anti-inflammatory and analgesic activity three different tests (rat paw pressure, rat paw oedema and abdominal constriction) were performed. Results showed good in vivo anti-inflammatory and analgesic activities. The issues gained with these classes of compounds represent, nowadays, a potent stimulus for a further enlargement of the NSAIDs family. In this review we describe the results obtained by our research group on this topic.

New derivatives of BM212: A class of antimycobacterial compounds based on the pyrrole ring as a scaffold.

During our investigation in the area of antimycobacterial agents, we have identified the 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212) as the lead compound for a new class of antimycobacterial pyrrole derivatives with potent in vitro activity against mycobacteria and with low cytotoxicity. We have also identified the salient structural features of BM212, while structure-activity relationships (SAR) and molecular modeling studies on pyrrole compounds allowed us to design and synthesize additional analogues. Among them, seven compounds revealed a very high activity (better than that of BM212 toward mycobacteria) and a very interesting protection index, comparable to that of reference compounds, such as isoniazid, streptomycin and rifampin.

New trends in development of antimycobacterial compounds.

The resurgence of tuberculosis and the surge of multidrug-resistant clinical isolates of Mycobacterium tuberculosis have reaffirmed tuberculosis as a primary public health concern. In this review we describe some new findings on the pharmacological status of fluoroquinolones derivatives (Gatifloxacin, Moxifloxacin and Sitafloxacin), new macrolides (Clarithromycin, Azithromycin and Roxithromycin), new rifamycin derivatives (Rifapentin, Rifabutin and Rifalazil) and new oxazolidinones (Linezolid and PNU 100480). We describe also other type of agents that are being developed as antimycobacterial drugs. Some of these are under clinical investigation, while others are considered to be promising candidates for future development. Among them, nitroimidazopyrans, new ketolides, Isoxyl (ISO), pyrroles derived from BM 212, Mefloquine and Diarylquinoline R207910 are discussed. We also describe the mechanism of drug resistance in mycobacteria, as well as new potential targets.

Building a pharmacophore model for a novel class of antitubercular compounds.

Starting from a set of 32 antitubercular compounds, for the first time a three-dimensional pharmacophore model has been derived through a computational approach based on CATALYST software. The model proved to be able to identify compounds belonging to classes of molecules already reported as antitubercular agents.

New pyrrole derivatives as antimycobacterial agents analogs of BM212.

During the course of our investigations in the field of azole antimicrobial agents, we have identified BM212 a pyrrole derivative with good in vitro activity against mycobacteria and candidae. These findings prompted us to prepare new pyrrole derivatives 2-6 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.

Antimycobacterial activity of new ortho-, meta- and para-toluidine derivatives.

Novel toluidine derivatives are described. Some of them showed an interesting in vitro activity against Mycobacterium tuberculosis, M. smegmatis, M. marinum, M. gordonae, and M. avium. Some of them were more active than Streptomycin and Isoniazid, which were used as controls, against M. avium and M. gordonae. In particular, we confirm the good activity of biphenyl derivatives.

Bactericidal activities of the pyrrole derivative BM212 against multidrug-resistant and intramacrophagic Mycobacterium tuberculosis strains.

The pyrrole derivative BM212 [1, 5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)methyl-pyrrole] was shown to possess strong inhibitory activity against both Mycobacterium tuberculosis and some nontuberculosis mycobacteria. BM212 was inhibitory to drug-resistant mycobacteria and also exerted bactericidal activity against intracellular bacilli residing in the U937 human histiocytic lymphoma cell line.

Synthesis and microbiological evaluations of (N-heteroaryl) arylmethanamines and their Schiff bases.

The synthesis as well as the antimicrobial and antiviral activities of new (N-heteroaryl)arylmethanamines and their Schiff bases are reported. None of the tested compounds shown activity against Herpes simplex virus type 2 and against Gram positive and Gram negative bacteria. Weak or moderate activity on poliovirus Sabin type 1, on reverse transcriptase and against Cryptococcus neoformans was shown by some of the tested compounds. Viceversa several synthesized compounds exhibited a moderate or good activity against strains of Candida albicans, while only some of the tested compounds were found moderately active against strains of Candida sp. Instead numerous new compounds 3 or 4 were active as control against isolates of plant pathogenic fungi. The obtained results are discussed on the basis of structure-activity relationships.

Research on antibacterial and antifungal agents. XII--Synthesis and antimicrobial activity of some Mannich bases of diarylpyrroles.

The synthesis and antimicrobial activity of some Mannich bases of diarylpyrroles are reported. The obtained data show that activity is closely connected to molecular basicity. Results are discussed on the basis of structure activity relationships.

Antifungal agents, Part 11. Biphenyl analogues of naftifine: synthesis and antifungal activities.

A series of naftifine analogues having the biphenyl instead of the naphthyl moiety have been synthesized in a search devoted to study bioanalogues of clinically efficacious antifungal agents. The new derivatives were tested against Candida albicans by the direct contact method. They were also assayed against Gram-positive and Gram-negative bacteria and against some isolates of plant pathogenic fungi. Derivatives 8a, 8c, and 9a were found to be active against Candida albicans, derivative 5a was active against E. coli, a very resistant species to antimycotic agents, and derivatives 8a and 8b inhibited the plant pathogenic Rhizoctonia solani.

Study of the Mannich reaction: beta-amino-methylation of N-aryl and N-azaheteroaryl-substituted 2,5-dimethylpyrroles, compounds with potential biological activity.

Owing to the increasing need of drugs for the treatment of a variety of fungal and bacterial opportunistic infections, a study has been started with the aim of synthesizing structures amenable to a number of easily-to-perform structural modifications in order to meet the requirement of bypassing resistance phenomena. This paper reports on the synthesis of several N-(alpha-azaheteroaryl)-substituted 2,5-dimethyl-pyrroles bearing in one beta-position (or in both beta-positions) aminomethyl groups, introduced via a Mannich reaction. Electronic and steric effects by the N-(azaheteroaryl) substituents and the 2- and 5-methyl groups on the course of the Mannich reaction are discussed along with the results of in vitro tests against many Candida species, some bacteria, and several pathogenic plant fungi.

Antifungal agents. 7. Dichlorophenylpyrrylimidazolylmethane derivatives: synthesis and antifungal activities.

The synthesis and antifungal activities of some dichlorophenyl-1H-pyrrol-2-yl-1H-imidazol-1-ylmethane derivatives substituted at pyrrole nitrogen are reported. When tested against Candida albicans and Candida spp., some derivatives were found to be from two to four times less active than miconazole, bifonazole and ketoconazole, used as standard controls.

Antifungal agents, II: Synthesis and antifungal activities of aryl-1H-pyrrol-2-yl-1H-imidazol-1-yl-methane derivatives with unsaturated chains.

The synthesis and antifungal activities of aryl-1H-pyrrol-2-yl-1H-imidazol-1-yl-methanes having allyl, crotyl, and acrylate chains linked to the N-pyrrole atom and substituted at phenyl ring by Cl, F, CH3, and NO2 groups are reported. In vitro tests against Candida albicans and Candida spp. showed 2,4-dichlorophenyl-1-allyl-1H-pyrrol-2-yl-1H-imidazol-1-yl-methane to be the most potent derivative with activities comparable to those of ketoconazole and slightly inferior to those of bifonazole and miconazole. Some structure-activity relationships are discussed.

Chemotherapeutic agents with an imidazole moiety. III. Synthesis and microbiological activity of new 1,4-diarylimidazole and 1,4-pyrrolimidazolphenylene derivatives.

New 1,4-diarylimidazole and 1,4-pyrrolimidazol-phenylene derivatives were prepared in attempt to deepen S.A.R. study on chemotherapeutic agents with an imidazole moiety. Antimicrobial data in comparison with antifungal antibiotic pyrrolnitrin showed that all tested compounds are practically inactive against blastomycetes but some derivatives exhibited selective activity against strains of gram-negative bacteria. The results obtained are discussed on the basis of structure-activity relationships.

Research on antibacterial and antifungal agents. IX--Synthesis and microbiological activity of new N-arylpyrroles.

The synthesis and antiblastomycete activity of new N-arylpyrrole derivatives are reported. Antimicrobial data in comparison with those obtained with pyrrolnitrin and miconazole showed that all tested compounds possess weak or poor activity. The obtained results are discussed on the basis of structure-activity relationships.

Antimicrobial activity of a new derivative: N-(4-chlorobenzyl)-2-(1H-imidazol-1-ylmethyl)benzenamine.

The activity of a new antifungal agent, an imidazolylmethylaniline derivative (XX H), synthesized by the authors, has been studied in vitro and in vivo. Antimicrobial data, in comparison with miconazole, ketoconazole and bifonazole, show antimicotic activity. The results are discussed on the basis of structure-activity relationships.

[Substances with antibacterial and antifungal activity. VI. Synthesis and microbiologic activity of new derivatives of 1,5-diarylpyrrole and 1,4-pyrrolphenylene]. / Richerche su sostanze ad attività antibatterica ed antifungina. Nota VI--Sintesi ed attività microbiologica di nuovi derivati dell'1,5-diarilpirrolo ed 1,4-pirrolfenilene.

New 1,5-diarylpyrrole and 1,4-pyrrolphenylene derivatives were prepared to study influence on the microbiological activity of an unsubstituted pyrrole nucleus or of a double identical molecular structure. Antimicrobial data in comparision with antifungal antibiotic pyrrolnitrin showed that all tested compounds exhibited very poor antifungal and antibacterial activity. Only some derivatives showed a selective activity against strains of Candida sp. and against strains of gram-positive or gram-negative bacteria.

[Substances with antibacterial and antifungal activity. VII. Synthesis and microbiologic activity of new derivatives of 1,5-diarylpyrrole]. / Ricerche su sostanze ad attività antibatterica ed antifungina. Nota VII--Sintesi ed attività microbiologica di nuovi derivati dell'1,5-diarilpirrolo.

The synthesis and antifungal activities of new 1,5-diarylpyrrole derivatives are reported. Antimicrobial data in comparison with pyrrolnitrin show that N-methylpiperazinylamides exhibit very poor activity against Candida albicans and Candida sp. while acid and ester derivatives are inactive. Vice-versa many acid or amide derivatives show interesting antibacterial activity. The results obtained are discussed on the basis of structure-activity relationships.

[A substance with antibacterial and antifungal activity. IV. Synthesis and microbiological activity of new 1,5-diarylpyrrole derivatives]. / Ricerche su sostanze ad attività antibatterica ed antifungina. Nota IV--Sintesi ed attività microbiologica di nuovi derivati 1,5-diarilpirrolici.

The synthesis and antifungal activities of new 1,5-diarylpyrrole derivatives are reported. Antimicrobial data in comparison with pyrrolnitrin show that only carboxamide derivatives exhibit satisfactory antifungal activity. By contrast all tested compounds show very poor antibacterial activity. The displacement of NO2 group from para to meta or ortho position of the aryl at C5 of the pyrrole ring affects the antimicrobial activity.

[A substance with antibacterial and antifungal activity. V. Synthesis and microbiological activity of new derivatives of 1,5-diarylpyrrole]. / Ricerche su sostanze ad attività antibatterica ed antifungina. Nota V--Sintesi ed attività microbiologica di nuovi derivati 1,5-diarilpirrolici.

The synthesis and antifungal activities of new 1,5-diarylpyrrole derivatives are reported. The N-methylpiperazinyl substituent must be regarded as fundamental to activity. Furthermore the presence of substituents on the para position of the two phenyl rings and the presence of halogen atoms can be considered strengthening factors to microbiological activity. The results obtained are discussed on the basis of structure-activity relationship.