Sintesi e valutazione biologica di nuovi "lead compounds" per la terapia antitubercolare. Derivati del 2-(benzotriazol-1(2)-il)-3- acrilonitrile e delle chinossaline 1,4-diossido

L'insorgenza sempre più elevata di ceppi di M. tuberculosis chemioresistenti ai farmaci abitualmente impiegati in terapia (MDR) ha spronato la ricerca di nuovi "lead compounds" per lo sviluppo di molecole che, agendo con meccanismo diverso da quello dei farmaci attualmente impiegati in terapia, possano contribuire a superare il problema della farmacoresistenza. In quest'ambito le nostre ricerche si sono orientate verso due differenti direzioni. La prima prende lo spunto dai risultati ottenuti in passato da vari gruppi di ricerca con alcuni derivati di sintesi di sistemi eterociclici aromatici quali benzimidazolo, benzotiazolo, benzoisotiazolo e benzofurano, che avevano dimostrato attività  antimicobatterica in vitro soprattutto nei confronti di ceppi MDR. La seconda linea di ricerca si è basata sulla nota attività  antibatterica e soprattutto antimicotica della chinossalina 1,4-diossido, con la consapevolezza che spesso l'attività  antimicobatterica è associata a quella antifungina

Imidazolo [1,2-a] e 1,2,4-triazolo[4,3-a] chinossaline analoghe degli antifolici metotrexato e trimetrexato

Abbiamo progettato una nuova serie di chinossaline, nelle quali l’anello pirrolico è stato sostituito con un’anello imidazolico o con uno triazolico lasciando nelle posizioni 2, 5, 6, 7 e 8 dell’anello chinossalinico gli stessi sostituenti precedentemente esaminati. Di questi composti verranno descritti la sintesi e i risultati farmacologici relativi alla loro attività

Antitumor Agents. 1. Synthesis, Biological Evaluation, and Molecular Modeling of 5H-Pyrido[3,2-a]phenoxazin-5-one, a Compound with Potent Antiproliferative Activity

The iminoquinone is an important moiety of a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, powerful, highly toxic, natural antibiotics that target DNA as intercalating agents. A series of polycyclic iminoquinonic compounds, 2-amino-3H-phenoxazin-3-one (1), 2-amino-1,9-diacetyl-3H-phenoxazin-3-one (2), 2-acetylamino- 3H-phenoxazin-3-one (3), 3H-phenoxazin-3-one (4), 5H-pyrido[3,2-a]phenoxazin-5-one (5), and 5H-pyrido[3,2-a]phenothiazin-5-one (6), strictly related to the actinomycin chromophore, were synthesized for developing new anticancer intercalating drugs. The antiproliferative activity of these compounds, evaluated against representative human liquid and solid neoplastic cell lines, showed that 5 and its isoster 6 were the most active compounds inhibiting cell proliferation in a submicromolar range. Compound 5 was also evaluated against KB subclones (KBMDR, KB7D, and KBV20C), which overexpress the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. All the above KB subclones did not show altered sensitivity to the antiproliferative activity of 5. UV-vis and 1H NMR spectroscopy experiments support the phenoxazinone 5/DNA binding. Molecular mechanics methods were used to build a three-dimensional model of the 5/[d(GAAGCTTC)]2 complex. Electrostatic interactions between the hydrogen of the positively charged pyridine nitrogen of 5 and the negatively charged oxygen atoms (O4¢ and O5¢) of the cytosine C5 residue together with stacking forces contribute to the high antiproliferative activity. The metal(II)-assisted synthesis procedure of 5 is described, and the formation mechanism is proposed

Synthesis and Biological Evaluation of Triazolo[4,5-<I>g</I>]quinolines, Imidazo[4,5-<I>g</I>]quinolines and Pyrido[2,3-<I>g</I>]quinoxaline. Part II

Synthesis of triazolo[4,5-g]quinolines, imidazo[4,5-g]quinolines and pyrido[2,3-g]quinoxaline has been described. Antimycobacterial, antibacterial and antimycotic activity were also reported. Compounds (14) and (IIb) exhibited an interesting antimycobacterial activity (against M. tuberculosis and M. smegmatis)

New 6-nitroquinolones: synthesis and antimicrobial activities

Pursuing our searches on quinolonecarboxylic acids we used a simple three-step one pot procedure to synthesize novel 1,7-disubstituted-6-nitroquinolones. The new derivatives were tested against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) as well as against both gram-positive and gram-negative bacteria. In vitro assays showed some derivatives were endowed with good inhibiting activities against tested mycobacteria. Some derivatives were also found more potent than ciprofloxacin and ofloxacin (used as reference drugs) against gram-positive bacteria

Synthesis and in vitro antimycobacterial activity of novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone analogues of PNU-100480

Pursuing our search program for new antitubercular drugs we decided to explore the potentiality of oxazolidinone moiety by synthesizing novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone analogues of PNU-100480. The new derivatives were tested against atypical mycobacteria as well as against drug resistant Mycobacterium tuberculosis and some of them exhibited a fairly good activity against Mycobacterium avium complex (MAC

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson’s Disease

The search for new disease-modifying drugs for Parkinson’s disease (PD) is a slow and highly expensive process, and the repurposing of drugs already approved for different medical indications is becoming a compelling alternative option for researchers. Genetic variables represent a predisposing factor to the disease and mutations in leucine-rich repeat kinase 2 (LRRK2) locus have been correlated to late-onset autosomal-dominant PD. The common fruit fly Drosophila melanogaster carrying the mutation LRRK2 loss-of-function in the WD40 domain (LRRK2WD40), is a simple in vivo model of PD and is a valid tool to first evaluate novel therapeutic approaches to the disease. Recent studies have suggested a neuroprotective activity of immunomodulatory agents in PD models. Here the immunomodulatory drug Pomalidomide (POM), a Thalidomide derivative, was examined in the Drosophila LRRK2WD40 genetic model of PD. Mutant and wild type flies received increasing POM doses (1, 0.5, 0.25 mM) through their diet from day 1 post eclosion, until postnatal day (PN) 7 or 14, when POM’s actions were evaluated by quantifying changes in climbing behavior as a measure of motor performance, the number of brain dopaminergic neurons and T-bars, mitochondria integrity. LRRK2WD40 flies displayed a spontaneous age-related impairment of climbing activity, and POM significantly and dose-dependently improved climbing performance both at PN 7 and PN 14. LRRK2WD40 fly motor disability was underpinned by a progressive loss of dopaminergic neurons in posterior clusters of the protocerebrum, which are involved in the control of locomotion, by a low number of T-bars density in the presynaptic bouton active zones. POM treatment fully rescued the cell loss in all posterior clusters at PN 7 and PN 14 and significantly increased the T-bars density. Moreover, several damaged mitochondria with dilated cristae were observed in LRRK2WD40 flies treated with vehicle but not following POM. This study demonstrates the neuroprotective activity of the immunomodulatory agent POM in a genetic model of PD. POM is an FDA-approved clinically available and well-tolerated drug used for the treatment of multiple myeloma. If further validated in mammalian models of PD, POM could rapidly be clinically tested in humans