IT202100020582A1 - Composti a struttura benzo[a]carbazolica per uso nella prevenzione e/o nel trattamento di malattie infettive - Google Patents
Composti a struttura benzo[a]carbazolica per uso nella prevenzione e/o nel trattamento di malattie infettive Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
Descrizione del brevetto per invenzione industriale avente per titolo: ?COMPOSTI A STRUTTURA BENZO[A]CARBAZOLICA PER USO NELLA PREVENZIONE E/O NEL TRATTAMENTO DI MALATTIE INFETTIVE?
Campo tecnico dell?invenzione
L?invenzione riguarda l?uso di composti a struttura benzo[a]carbazolica nella prevenzione e/o nel trattamento di malattie infettive.
Stato della tecnica
Le terapie esistenti per trattare le malattie infettive sono sempre pi? inefficaci a causa dello sviluppo di resistenza da parte dei microorganismi ai farmaci usati sia nella prevenzione che nel trattamento delle malattie. Inoltre si assiste al propagarsi di gravi infezioni causate da nuovi virus quali il nuovo coronavirus denominato SARS-CoV-2 che causa la malattia COVID-19.
Pertanto, sussiste la necessit? di individuare nuovi agenti anti-infettivi.
WO2019/049024 descrive composti a struttura benzo[a]carbazolica aventi attivit? antitumorale.
Si ? ora trovato che tali composti sono in grado di inibire l?infezione o la reinfezione da agenti patogeni quali batteri, virus, funghi o protozoi.
Elenco e breve descrizione delle figure
La Figura 1 mostra l?analisi di Chlamydia Trachomatis su pellet 24 ore dopo la reinfezione.
La Figura 2 mostra i dosaggi MTT a 24, 48 e 72 ore dopo la somministrazione dei composti alle concentrazioni indicate.
La Figura 3 mostra l?espressione di mediatori immunitari nei supernatanti delle cellule HeLa.
Sommario dell?invenzione
L?invenzione si riferisce all?uso di composti a struttura benzo[a]carbazolica di formula (I), descritti anche nella domanda di brevetto n. WO2019/049024, nella prevenzione e/o nel trattamento di malattie infettive causate da agenti patogeni quali batteri, virus, funghi o protozoi.
I composti dell?invenzione agiscono con meccanismo d?azione non diretto sull?agente infettante, ma direttamente sulla cellula ospite infettata, impedendo l?inattivazione del fattore di trascrizione P53 che controlla la risposta cellulare allo stress inducendo l?arresto del ciclo cellulare o apoptosi. I composti dell?invenzione infatti impediscono l?inattivazione di P53 mediata da proteine oncogeniche quali MDM2 (e/o MDM4). Nelle cellule infettate, i composti dell?invenzione si legano al sito di binding su MDM2 per il gene P53 ed impediscono l?accoppiamento MDM2-P53. Questo consente di stabilizzare i livelli di proteina P53, riducendo la degradazione mediata dal legame MDM2-P53, inoltre induce anche un notevole aumento della trascrizione di P53. Sorprendentemente si ha un potente effetto di arresto permanente del ciclo cellulare con effetto apoptotico in grado di impedire la propagazione dell?infezione, con l?aumento dei livelli di P53 libero a livello della cellula infetta. Le i composti dell?invenzione non hanno mostrato alcuna attivit? antibatterica quando testate direttamente su una coltura di Staphylococcus Aureus. Pertanto, questi composti non agendo sull?agente infettante ma sulle cellule infettate dell?ospite, non danno effetti di resistenza alla terapia, tipici delle varie classi di antibatterici, antivirali, antifungini o antiprotozoari.
Inoltre, i composti dell?invenzione possono essere usati in combinazione con altre classi di farmaci nelle infezioni da patogeni di varia natura ed anche nella marcatura di cellule e tessuti infettati da patogeni in diagnostica medica.
Descrizione dettagliata dell?invenzione
Oggetto della presente invenzione sono composti di formula (I):
in cui
m ? 0 o un intero variabile da 1 a 2;
X ? scelto nel gruppo comprendente -CH(R3)- dove R3 ? H o (C1-C6)-alchile; -O-; -S(=O)n- dove n ? 0 o un intero variabile da 1 a 2; -C=(N-R4)- dove R4 ? ?OH, ?O-(CH2)p-CO-NR5R6 ciascuno di R5 e R6 ? indipendentemente H o (C1-C6)alchile e p ? un intero variabile da 1 a 4 oppure ?O-(CH2)p-COO(C1-C6)-alchile; -C(=O)-; o -NH-SO2-;
R1 ? scelto nel gruppo comprendente idrogeno; alogeno; -NO2; (C1-C6)-alchile opzionalmente sostituito da alogeno; oppure ?O-(CH2)p-CO-NR5R6 come sopra definito;
R2 ? H o (C1-C6)-alchile, preferibilmente H;
Q ? un sostituente avente una struttura betalattamica di formula I?, I?? o I???,
dove q ? 0 o un intero variabile da 1 a 2;
Q? ? scelto nel gruppo comprendente -O(C1-C6)alchile; -O(CH2)r-fenile, dove r ? un intero variabile da 1 a 4, preferibilmente 1 e il fenile ? opzionalmente sostituito da alogeno, (C1-C6)alchile, -OR2, dove R2 ? come sopra definito; -OCO(C1-C6)alchile; -N(R2)2, dove ciascuno di R2 ? indipendentemente come sopra definito; NHCO(C1-C6)alchile; NHCOO(C1-C6)alchile; NHCOO-(CH2)s-fenile, dove s ? 0 o un intero variabile da 1 a 2 e fenile ? opzionalmente sostituito da alogeno, (C1-C6)alchile, -OR2, dove R2 ? come sopra definito; -NH-O-R2,dove R2 ? come sopra definito; N(R2)-O-R2 dove ciascuno di R2 ? indipendentemente come sopra definito; e NH-OCO(C1-C6)alchile;
Z ? H, -(C1-C6)alchile, -(CH2)t-O-CO-(C1-C6)alchile, dove t ? un intero variabile da 1 a 4;
W ? scelto nel gruppo comprendente H; -(C1-C6)alchile opzionalmente sostituito da alogeno; -(CH2)t-O-CO-(C1-C6) alchile dove t ? un intero da 1 a 4, preferibilmente 1; alogeno; -NO2; ?O-(CH2)p-CO-NR5R6 come sopra definito; oppure ?CH2-CO-NH-CHR7-CONH-R2 dove R2 ? come sopra definito e R7 ? ?(CH2)w-NH-CO-Q? dove w ? un intero variabile da 1 a 4 e Q? ? come sopra definito;
e loro sali farmaceuticamente accettabili,
per l?uso nella prevenzione e/o nel trattamento di malattie infettive.
Con il termine (C1-C6)alchile si intende una catena alchilica lineare o ramificata contenente da 1 a 6 atomi di carbonio. Le catene alchiliche contenenti da 1 a 4 atomi di carbonio (C1-C4)alchile sono preferite, quali metile, etile, n- propile, iso-propile, n-butile, iso-butile o tert-butile.
Con il termine alogeno si intende fluoro, cloro, bromo o iodio. Alogeni preferiti sono fluoro, cloro e bromo.
Nel caso i composti dell?invenzione contengano gruppi salificabili, si intendono compresi nell?ambito dell?invenzione i sali con basi o acidi organici o inorganici farmaceuticamente accettabili.
Per sali farmaceuticamente accettabili si intendono sali di acidi o basi inorganiche od organiche.
Un sale del composto pu? presentare vantaggi dovuti a una o pi? propriet? fisiche, quali un?aumentata stabilit? farmaceutica a differenti temperature ed umidit? o migliorata solubilit? in mezzo acquoso od oleoso.
In generale questi sali possono essere preparati con metodi convenzionali facendo reagire un composto della presente invenzione con un acido o una base appropriati.
Sali farmaceuticamente accettabili dei composti della presente invenzione possono essere preparati da un acido inorganico o organico. Esempi di acidi inorganici utilizzabili nella preparazione dei sali sono: cloridrico, bromidrico, iodidrico, nitrico, solforico, fosforico. Acidi organici utilizzabili nella preparazione dei sali sono: formico, acetico, trifluoroacetico, propionico, ecc.
Basi farmaceuticamente accettabili per formare i sali dei composti della presente invenzione possono essere inorganiche od organiche. I sali metallici preferiti possono essere con metalli alcalini o alcalino-terrosi ed altri sali con metalli fisiologicamente accettabili. I sali possono essere anche formati con alluminio, calcio, litio, magnesio, potassio, sodio e zinco. I sali organici preferiti possono essere preparati da ammine terziarie e sali di ammonio quaternari.
Sali con basi inorganiche comprendono, ad esempi, sali di sodio, potassio, calcio e idrossidi di alluminio; sali con basi organiche, comprendono, ad esempio, sali di lisina, arginina, trietilammina, dibenzilammina, piperidina e altre ammine organiche accettabili oppure sali con acidi organici possono essere ossalico, tartarico, maleico, succinico, citrico o sali con acidi inorganici possono essere acido nitrico, cloridrico, solforico, fosforico.
I composti dell?invenzione sono utilizzabili nella prevenzione e/o nel trattamento di infezioni causate da agenti patogeni quali batteri, virus, funghi o protozoi.
Fra le infezioni da batteri patogeni sono comprese quelle da batteri gram-positivi quali cocci del tipo Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Enterococci, e bacilli del tipo Clostridia, Bacillus anthracis, Corynebacterium diphtheria, Erysipelothrix rhusiopathiae, Listeria monocytogenes; sempre tra le infezioni da batteri patogeni sono comprese anche quelle da batteri gram-negativi quali Brucella, Campylobacter jejuni, Bartonella henselae, Neisseria meningitidis, Vibrio cholera, Escherichia coli, Haemophilus influenza, Spirochetes, Moraxella, Klebsiella, Enterobacter, Serratia, Legionella, Bordetella pertussis, Yersinia pestis, Pseudomonas aeruginosa, Salmonella, Proteus, Shigella, Francisella tularensis, Veillonella, Prevotella; sono anche comprese le infezioni causate da altri tipi di batteri: Clamydia Trachomatis, Rickettsia, Borellia, Mycoplasma, Legionella, Helicobacter, Mycobacteria e Nocardia.
Fra le infezioni da virus patogeni sono comprese quelle da virus appartenenti alle famiglie: Adenoviridae come Human mastadenovirus; Anelloviridae come Torque teno viruses; Astroviridae come Mamastroviruses; Caliciviridae come Norovirus, NoV (Norwalk virus) e Sapovirus (Sapporo virus); Coronaviridae come MERS-CoV, SARS-CoV, SARS-CoV-2 (COVID-19) e varianti (Pandemiche); Filoviridae come Ebolavirus; Flaviviridae come Tick-borne encephalitis virus; Herpesviridae come HSV1 ed HSV2; Orthomyxoviridae come Influenza A virus (pandemica); Papillomaviridae come Human Papilloma virus (HPV); Paramyxoviridae come Hendra henipavirus ed Nipah henipavirus; Parvoviridae; Picornaviridae come Enterovirus A (Coxsackievirus), Enterovirus B (Echovirus) ed Enterovirus C (Poliovirus), o anche Hepatovirus come Hepatovirus A ed Hepatovirus E, o anche Kobuvirus o Parechovirus; Poxviridae; Polyomaviridae come Human polyomavirus; Reoviridae come Orthoreovirus e Rotavirus A; Retroviridae come HIV; Rhabdoviridae come Rabbia.
Fra le infezioni da funghi patogeni sono comprese: Candidiasi da Candida albicans; Dermatofitosi da onychomycosis (tinea); Aspergillosi da Aspergillus; Mucormicosis da Rhizopus, Rhizomucor, e Mucor; Histoplasmosi da Histoplasma capsulatum; Blastomicosi da Blastomyces dermatitidis; Coccidioidomicosi da Coccidioides immitis; Paracoccidioidomicosi da Paracoccidioidiosi brasiliensis; Cryptococcosi da Cryptococcus neoformans o C. gattii.
Fra le infezioni da protozoi patogeni sono comprese: Amebiasi da Entamoeba histolytica; Cheratite Amebica da Acanthamoeba; Meningo encefalite amebica primaria da Naegleria fowleri; Tripanosomiasi da T. brucei gambiense and T. brucei rhodesiense o da Trypanosoma cruzi; Malattia di Changas da American Trypanosomiasis; Leishmaniosi da Leishmania; Criptosporiadi da Cryptosporidium; Giardiasi da Giardia; Malaria da Plasmodio; Toxoplasmosi da Toxoplasma gondii; Babesiosi da Babesia; Ciclosporiasi da Cystoisospora (Isospora) belli; Encefalite granulomatosa Amebica da Acanthamoeba species o da Balamuthia mandrillaris.
In particolare, i composti dell?invenzione sono utilizzabili per la prevenzione e/o il trattamento dell?infezione da coronavirus denominato SARS-CoV-2.
Composti preferiti per gli usi descritti secondo l?invenzione sono i composti di formula (I), o loro sali farmaceuticamente accettabili, in cui:
m and X sono come sopra definiti;
R1 ? scelto nel gruppo comprendente idrogeno, alogeno, -NO2, metile opzionalmente sostituito da alogeno; oppure ?O-CH2-CO-N(CH3)2;
R2 ? H;
Q ? un sostituente avente una struttura betalattamica di formula I?, I?? o I???, in cui Q? ? scelto nel gruppo comprendente -O(C1-C6)alchile, preferibilmente ?O-etile e ?O-tertbutile; oppure -O(CH2)r-fenile, dove r ? un intero variabile da 1 a 4, preferibilmente 1, e il fenile ? opzionalmente sostituito da alogeno, preferibilmente fluoro, o -O-(C1-C6)alchile, preferibilmente ?O-CH3;
Z ? H;
W ? ?CH2-CO-NH-CHR7-CONH-R2 dove R2 ? (C1-C6)-alchile e R7 ? ?(CH2)w-NH-CO-Q? dove w ? come sopra definito e Q? ? -O(C1-C6)alchile; -O(CH2)r-fenile, dove r ? come sopra definito, e il fenile ? opzionalmente sostituito da alogeno, preferibilmente fluoro, o -O-(C1-C6)alchile, preferibilmente ?OCH3.
Composti particolarmente preferiti per gli usi descritti sono i composti di formula (I) o loro sali farmaceuticamente accettabili scelti nel gruppo costituito da:
I composti dell?invenzione sono in grado di inibire MDM2 attivando efficacemente P53 nelle cellule infette che ne induce l?apoptosi, bloccando la progressione dell?infezione. Sono stati condotti degli esperimenti su modelli cellulari utilizzando i composti dell?invenzione che dimostrano in maniera inequivocabile che attraverso l?inibizione di MDM2 ? possibile bloccare l?infezione. In particolare, ? stato utilizzato il composto RM37 in un modello cellulare di cellule HeLa infettate da Clamidia. Inoltre, ? stato dimostrato che il pretrattamento con RM37 impedisce la reinfezione da Clamidia nelle cellule HeLa trattate.
I risultati ottenuti sono stati anche validati con Nutlin-3 usato come farmaco di riferimento. , Nat. Commun., 2014, 5, 5201, DOI: 10.1038/ncomms6201, hanno riportato risultati simili per Nutlin-3 nello stesso tipo di infezione utilizzata come modello sperimentale.
Inoltre, ? stato anche dimostrato che i composti dell?invenzione sono stabili nelle condizioni dei test biologici e non hanno alcun effetto antibiotico. Pertanto, si pu? escludere che i composti dell?invenzione agiscano sul batterio come antibiotici, questo permette di evitare l?instaurarsi di potenziali rischi di induzione di fenomeni di resistenza batterica.
Ulteriore oggetto dell?invenzione sono anche composizioni farmaceutiche contenenti almeno un composto della presente invenzione di formula (I) insieme ad adiuvanti e/o veicoli farmaceuticamente accettabili per l?uso nella prevenzione e/o nel trattamento delle malattie infettive sopra indicate.
La dose giornaliera di principio attivo da somministrare pu? essere una singola dose oppure pu? essere una quantit? efficace suddivisa in pi? dosi minori da somministrare nell'arco della giornata. Di solito, la dose giornaliera totale pu? essere in quantit? preferibilmente da 200 a 1000 mg, pi? preferibilmente da 50 a 400 mg. Il regime di dosaggio e la frequenza di somministrazione per il trattamento delle malattie menzionate con il composto dell'invenzione e/o con le composizioni farmaceutiche della presente invenzione saranno selezionati in base a una variet? di fattori, inclusi ad esempio et?, peso corporeo, sesso e condizioni mediche del paziente nonch? gravit? della malattia, via di somministrazione, considerazioni farmacologiche ed eventuale terapia concomitante con altri farmaci. In alcuni casi, possono essere usati livelli di dosaggio inferiori o superiori al suddetto intervallo e/o pi? frequenti, a giudizio del medico e in base allo stato della malattia.
I composti dell'invenzione possono essere somministrati per via orale, parenterale, rettale o topica, per inalazione o aerosol, in formulazioni contenenti veicoli o eccipienti farmaceuticamente accettabili.
Tali composizioni possono anche comprendere adiuvanti, come agenti umettanti emulsionanti, sospendenti, edulcoranti, aromatizzanti e simili.
Inoltre, i composti dell?invenzione possono essere utilizzati nella prevenzione e/o nel trattamento delle malattie infettive sopra indicate in combinazione con altre classi di farmaci con i quali possono esercitare azioni combinate multitarget e pertanto sono classificabili come adiuvanti chemioterapici, di origine naturale o sintetica o semisintetica. In questo ambito si possono associare ad esempio con antibiotici, antivirali, antimicotici ed antiprotozoari. Queste associazioni possono portare ad un potenziamento dell?effetto antiinfettivo agendo in contemporanea sia su target molecolari presenti esclusivamente nell?agente infettante che su target molecolari presenti nelle cellule dell?ospite che subisce l?infezione. Alcuni esempi di adiuvanti che possono essere associati ai composti di formula (I) per la chemioterapia antiinfettiva possono essere antibiotici betalattamici quali penicilline, cefalosporine, carbapenemi, monobattami, inibitori di betalattamasi, tetracicline, macrolidi, aminoglicosidi, gramicidina, polimixine, bacitracina, vancomicina, actinomicina, lincosamidi, ansamicine, streptogramine, antracicline, cloramfenicolo ed analoghi, acido fusidico, fosfomicina, mupirocina, cicloserina. Esempi di combinazioni con antibiotici sono preferibilmente le associazioni con penicilline come ampicillina, amoxicillina, piperacillina, mezlocillina; le associazioni con cefalosporine sono preferibilmente quelle con cefazolina, cefalessina, cefurossima, cefuzonam, ceftazidima, cefzopram, ceftarolina, cefempidone; le associazioni con carbapenemi sono preferibilmente quelle con tienamicina, ertapenem, meropemenem; le associazioni con monobactami sono preferibilmente quelle con aztreonam, carumonam; le associazioni con inibitori di betalattamasi sono preferibilmente quelle con acido clavulanico, sulbactam, tazobactam, avibactam; le associazioni con tetracicline sono preferibilmente quelle con tetraciclina, ossitetraciclina, clortetraciclina, doxiciclina, tigeciclina, amadaciclina, anidrotetraciclina, minociclina; le associazioni con macrolidi sono preferibilmente quelle con eritromicina, claritromicina, azitromicina, spiramicina, nistatina, anfotericina B; le associazioni con aminoglicosidi sono preferibilmente quelle con streptomicina, neomicina, gentamicina, tobramicina, amicacina, kanamicina A, B, C; le associazioni con altri antibiotici sono preferibilmente quelle con gramicidina A, gramicidina S, polimixine B ed E, bacitracina A, vancomicina, dactinomicina, lincosamina, clindomicina, rifamicina, rifampicina, daunorubicina, doxorubicina, epirubicina, idarubicina, valrubicina, cloranfenicolo, tianfenicolo, forfenicolo, griseofulvina. Secondo un aspetto preferito, le associazioni dei composti di formula (I) dell?invenzione, adiuvanti chemioterapici non antibiotici, sono preferibilmente quelle con tolnafato, tolciclato, clortrimazolo, miconazolo, econazolo, ketoconazolo, fluconazolo, itraconazolo, flucitosina, terbinafina; sulfamidici quali: sulfapiridina, sulfatiazolo, sulfadiazina, sulfamerazina, sulfadimetossina, sulfaperina, sulfafenazolo, sulfalene, sulfametossipiridazina, sulfaguanidina, nitrosulfatiazolo, succinilsulfatiazolo, ftalilsulfatiazolo, sulfametossazolo, sulfisomidina; trimetropina, pirimetamina; etambutolo, isoniazide, pirazinamide, chinina, euchina, aristochina, clorochina, idrossiclorochina, meflochina, primachina, cloroguanile, cicloguanile, pirimetamina, sulfadoxina, alofrantina; chinoloni ed analoghi quali: acido nalidissico, acido piromidico, acido pipemidico, flumechina, norfloxacina, ciprofloxacina, ofloxacina, levofloxacina, sparfloxacina, gemifloxacina, moxifloxacina, besifloxacina; nitrofurani quali: nitrofurazone, furazolidone, nimorazolo, metronidazolo; antivirali quali: aciclovir, ganciclovir, idoxouridina, ribavirina, trifluridina, vidarabina, citarabina, zidovudina, didanosina, foscarnet, zalcitabina, stavudina, lamivudina, nevirapina, saquinavir, ritonavir, indinavir, amprenavir, lopinavir, adamantina, rimatidina, zanamivir, oseltamivir, darunavir, redmesivir; interferoni quali: INF-?, INF-?, INF-?; immunostimolanti come ad esempio acido poliinosinico:policitidilico (Poli I:C); inibitori di COX2 quali ad esempio: acido acetilsalicilico, celecoxib, valdecoxib, etoricoxib, rofecoxib, lumaricoxib, parecoxib.
I seguenti esempi illustrano ulteriormente l?invenzione.
Esempi
Materiali e metodi - Coltura cellulare
Cellule HeLa sono state propagate nel mezzo di Eagle modificato da Dulbecco ad alto contenuto di glucosio (DMEM) (Euroclone) con il 10% di siero bovino fetale (FBS) (Euroclone). Le colture cellulari sono state mantenute su un cluster di coltura cellulare a 6 pozzetti (Corning) a 35 ? C e 5% CO2. Contaminazioni da micoplasma sono state escluse mediante PCR, utilizzando i primer GPO-3 e MGSO come descritto da van Kuppeveld et al. (van Kuppeveld F J M, Johansson K-E, Galama J M D, Kissing J, B?lske G, van der Logt J T M, Melchers W J G. Detection of mycoplasma contamination in cell cultures by a mycoplasma group-specific PCR. Appl Environ Microbiol. 1994;60:149?152).
Esempio 1
Infezione da Chlamydia Trachomatis
Le cellule sono state coltivate fino all'80% di confluenza su un cluster di coltura cellulare a 6 pozzetti e inoculate con C. trachomatis sierotipo D (ATCC VR-885) ad una molteplicit? di infezione (MOI) di 0,5. L?inoculo ? stato centrifugato con perle di vetro e diluito in DMEM per raggiungere il valore di MOI indicato a un volume finale di 500 ?l per pozzetto. Dopo centrifugazione a 3000 RPM per 45 min, le cellule sono state ulteriormente incubate con DMEM contenente il 10% di FBS ai tempi indicati a 35?C e 5% CO2. Allo stesso tempo, ? proseguito il trattamento delle cellule non infette, inseminate nelle stesse condizioni.
Trattamento con Nutlin3-a, RM37, RM 53.
Le cellule Hela sono state infettate come descritto sopra, 24 ore dopo l'infezione sono state trattate con Nutlin 3-A (farmaco di riferimento), RM37 (composto dell?invenzione) e RM 53 (composto comparativo) sciolti in DMSO e risospese in mezzo di crescita completo alla concentrazione finale di 5?M e 20?M, per 24 e 48 ore. Le cellule non trattate sono state sottoposte alle stesse condizioni.
Il composto RM53 di comparazione ha la seguente struttura:
Analisi della progenie infettiva
I surnatanti e i pellet di cellule HeLa, inseminati su un cluster di coltura cellulare a 6 pozzetti, infettati con Chlamydia Trachomatis serovar D e trattati con i composti come descritto, sono stati raccolti dopo 24 ore (per reinfezione 1) e 48 ore (per reinfezione 2). I pellet sono stati lisati per agitazione su vortex con perle di vetro.
I lisati sono stati diluiti in DMEM con FBS al 10% e trasferiti su cellule HeLa fresche a una diluizione finale di 1:40. Dopo centrifugazione a 3000 RPM per 45 min, le cellule sono state ulteriormente incubate con terreno completo per 24 ore a 35 ? C e 5% CO2. 24 ore dopo la reinfezione con lisati, i supernatanti e il pellet sono stati raccolti e conservati a -80 ? C per le analisi.
Le cellule non trattate sono state sottoposte alle stesse condizioni.
Isolamento del DNA
Il DNA batterico ? stato isolato dai supernatanti e pellet ed eluito in un volume finale di 50 ?L utilizzando un kit commerciale (Maxwell DNA kit, Promega). Il DNA ? stato conservato fino al momento dell'analisi a ?20 ? C.
Analisi PCR in tempo reale
La rilevazione di Chlamydia Trachomatis ? stata eseguita su DNA da pellet 24 ore dopo entrambe le reinfezioni (Reinfezione 1 e Reinfezione 2), utilizzando il kit commerciale RealLine Chlamydia Trachomatis Fla-Format (Bioron), seguendo le istruzioni del produttore.
I test PCR sono stati eseguiti utilizzando il sistema di rilevamento della sequenza ABI PRISM 7900 in tempo reale (Applied Biosystem). L'inoculo ? stato utilizzato come controllo positivo e la miscela di reazione ? stata utilizzata come controllo negativo. nella Figura 1 vengono riportati i valori di ciclo soglia (Ct). Il ciclo soglia (Ct) ? il primo numero del ciclo di una PCR in tempo reale in cui viene rilevata la fluorescenza che indica la presenza del patogeno ricercato nel campione. Pi? basso ? il valore di Ct, maggiore ? la quantit? di agente patogeno nel campione analizzato.
Nella Fig.1 ? riportata l?analisi di Chlamydia Trachomatis su pellet 24 ore dopo la reinfezione.
Reinfezione 1: cellule reinfettate con lisati 24 ore dopo la somministrazione dei composti alle concentrazioni indicate.
Reinfezione 2: cellule reinfettate con lisati 48 ore dopo la somministrazione dei composti alle concentrazioni indicate.
Esempio 2
Saggio MTT
Le cellule HeLa sono state depositate su diverse piastre di coltura a 96 pozzetti ad albero a circa 2 x 104, 1,5 x 104 e 1 x 104 per pozzetto in tre repliche e incubate per 24 ore.
Sono state aggiunte diverse concentrazioni (0,5?M, 1?M, 2,5?M, 5?M, 10?M, 20?M e 25?M) di ogni composto (Nutlin-3a, RM37, RM53) e le cellule sono state ulteriormente incubate per 24 ore, 48 ore e 72 ore a 35?C in atmosfera umidificata (5% CO2). Gli stessi esperimenti sono stati eseguiti su cellule non trattate.
Il test colorimetrico 3-(4,5-dimetiltiazol-2-il) -2,5-difenil tetrazolio bromuro (MTT) ? stato eseguito per valutare l'attivit? metabolica delle cellule trattate e quindi la citotossicit? dei composti Nutlin-3a, RM37 e RM53 sulle cellule. Dopo l'aggiunta di 20 ?l di MTT (5 mg / mL) a ciascun pozzetto, le cellule sono state incubate per 4 ore a 37?C. Le cellule sono state quindi lisate con DMSO e l'assorbanza ? stata misurata a 560 nm utilizzando lo strumento Glomax Multy Detection System (Promega).
Nella Figura 2 sono riportati i dosaggi MTT a 24, 48 e 72 ore dopo la somministrazione dei composti alle concentrazioni indicate. I risultati sono espressi come % di vitalit? cellulare; cellule non trattate sono state utilizzate come controllo.
Esempio 3 - Effetti sull?espressione di citochine, chemochine e fattori di crescita in infezione da Chlamydia Trachomatis
Durante le infezioni si ha una potente attivazione dell'infiammazione. Pertanto, sono state dosate le concentrazioni di 48 tra citochine, chemochine e fattori di crescita, sui surnatanti cellulari (Hela cell) relativi alla reinfezione da Clamidia usando lisati cellulari infetti trattati con e senza Nutlina, RM37 o RM53 per 24 ore. Questo ? stato fatto per determinare se il trattamento farmacologico pu? influire in senso positivo anche sui processi infiammatori e su quali citochine.
La quantificazione delle concentrazioni di chemochine, citochine e fattori di crescita ? stata eseguita su supernatanti di cellule 24 ore dopo la reinfezione alle condizioni indicate, e su cellule non infette, utilizzando dosaggi Luminex Multiplex quantitativi (Bio ? Plex, BIO ? RAD), secondo leistruzioni del produttore, per la misurazione dei 48 analiti.50 ?l di ciascun supernatante e standard di reazione sono stati aggiunti a una piastra multipozzetto a 96 pozzetti contenente perline di analita e incubati per 30 minuti a temperatura ambiente. Il reporter anticorpo-biotina ? stato aggiunto dopo il lavaggio e incubato per 10 minuti con streptavidina-ficoeritrina. La determinazione dei livelli delle citochine ? stata eseguita usando il kit per l?analisi quantitativa di Bio ? Plex (Luminex). Il software Bio?Plex Manager ha ottimizzato le curve standard e riportato i dati come intensit? di fluorescenza mediana (MFI) e concentrazione (pg/ml). I risultati sono riportati nella Figura 3 che mostra l?espressione di mediatori immunitari nei supernatanti delle cellule HeLa. Sono riportati i mediatori che hanno mostrato variazioni di espressione. I risultati sono espressi come pg/ml.
Fra gli effetti pi? interessanti osservati dopo la reinfezione sulle cellule Hela sono la riduzione marcata di IL-8 da parte di RM37, molto superiore rispetto a Nutlina, e di IL9 dove l?effetto ? simile fra Nutlina e RM37, un effetto di modulazione (inibizione) su interferone 10 (Hu IP-10) da parte sia di Nutlina che di RM37 ed un effetto marcato di inibizione della chemochina RANTES pi? potente per RM37 rispetto a Nutlina.
Legenda della Fig. 3: NI = Non infetto. I = Infetto, 24 ore dopo la reinfezione con lisati di cellule infette (MOI 0,5) non trattate. NUTLIN 20?M; RM3720?M; RM5320?M = Infetto, 24 ore dopo la reinfezione con lisati di cellule infette (MOI 0,5) trattati con i composti indicati alle concentrazioni indicate per 24 ore.
Esempio 4 - Conferma dell?assenza di effetto antibiotico per i composti dell?invenzione di formula (I)
Considerando la struttura di RM37, che ? un estere di una cefalosporina, ? stato anche dimostrato che la molecola risulta stabile alle condizioni dei test biologici e non ha alcun effetto antibiotico. Al contrario l?analogo RM53, che ? l?acido libero corrispondente di RM37, ha attivit? antibiotica, con la funzione carbossilica acida presente sul nucleo cefalosporinico di questi derivati betalattamici protetta i composti dell?invenzione sono potenti inibitori di MDM2/p53 privi per? di attivit? antibiotica. Il dato ? stato confermato su una coltura di Stafilococco A., i dati sono riportati nella Tabella 1.
Tabella 1
*OD (densit? ottica) a 600 nm, 24 ore dopo post crescita di Staphylococcus aureus (0,5 McFarland) per trattamento con differenti composti ;*Terreno di coltura senza batteri
Claims (14)
- RIVENDICAZIONI 1. Un composto di formula (I):
- in cui m ? 0 o un intero variabile da 1 a 2; X ? scelto nel gruppo comprendente -CH(R3)- dove R3 ? H o (C1-C6)-alchile; -O; -S(=O)n- dove n ? 0 o un intero variabile da 1 a 2; -C=(N-R4)- dove R4 ? ?OH, ?O-(CH2)p-CO-NR5R6 ciascuno di R5 e R6 ? indipendentemente H o (C1-C6)alchile e p ? un intero variabile da 1 a 4 oppure ?O-(CH2)p-COO(C1-C6)-alchile; -C(=O)-; o -NH-SO2-; R1 ? scelto nel gruppo comprendente idrogeno; alogeno; -NO2; (C1-C6)-alchile, opzionalmente sostituito da alogeno; oppure ?O-(CH2)p-CO-NR5R6 come sopra definito; R2 ? H o (C1-C6)-alchile, preferibilmente H; Q ? un sostituente avente una struttura betalattamica di formula I?, I?? o I???,
- dove q ? 0 o un intero variabile da 1 a 2; Q? ? scelto nel gruppo comprendente -O(C1-C6)alchile; -O(CH2)r-fenile, dove r ? un intero variabile da 1 a 4, preferibilmente 1 e il fenile ? opzionalmente sostituito da alogeno, (C1-C6)alchile, -OR2, dove R2 ? come definito sopra; -OCO(C1-C6)alchile; -N(R2)2, dove ciascuno di R2 ? indipendentemente come sopra definito; NHCO(C1-C6)alchile; NHCOO(C1-C6)alchile; NHCOO-(CH2)s-fenile, dove s ? 0 o un intero variabile da 1 a 2 e fenile ? opzionalmente sostituito da alogeno, (C1-C6)alchile, -OR2, dove R2 ? come sopra definito; -NH-O-R2,dove R2 ? come sopra definito; N(R2)-O-R2 dove ciascuno di R2 ? indipendentemente come sopra definito; e NH-OCO(C1-C6)alchile; Z ? H, -(C1-C6) alchile, -(CH2)s-O-CO-(C1-C6) alchile, dove t ? un intero variabile da 1 a 4; W ? scelto nel gruppo comprendente H; -(C1-C6)alchile opzionalmente sostituito da alogeno; -(CH2)t-O-CO-(C1-C6)alchile dove t ? un intero da 1 a 4, preferibilmente 1; alogeno; -NO2;?O-(CH2)p-CO-NR5R6 come sopra definito; oppure ?CH2-CO-NH-CHR7-CONH-R2 dove R2 ? come sopra definito e R7 ? ?(CH2)w-NH-CO-Q? dove w ? un intero da 1 a 4 e Q? ? come sopra definito; o un suo sale farmaceuticamente accettabile, per l?uso nella prevenzione e/o nel trattamento di malattie infettive. 2. Un composto di formula (I), o un suo sale farmaceuticamente accettabile, per l?uso secondo la rivendicazione 1 in cui: m and X sono come definiti nella rivendicazione 1; R1 ? scelto nel gruppo comprendente idrogeno, alogeno, -NO2, metile opzionalmente sostituito da alogeno; oppure ?O-CH2-CO-N(CH3)2; R2 ? H; Q ? un sostituente avente una struttura betalattamica di formula I?, I?? o I??? come definiti nella rivendicazione 1, in cui Q? ? scelto nel gruppo comprendente -O(C1C6)alchile, preferibilmente ?O-etile e ?O-tert-butile; oppure -O(CH2)r-fenile, dove r ? un intero variabile da 1 a 4, preferibilmente 1, e il fenile ? opzionalmente sostituito da alogeno, preferibilmente fluoro, o -O-(C1-C6)alchile, preferibilmente ?O-CH3; Z ? H; W ? ?CH2-CO-NH-CHR7-CONH-R2 dove R2 ? (C1-C6)-alchile e R7 ? ?(CH2)w-NH-CO-Q? dove w ? come definito nella rivendicazione 1 e Q? ? -O(C1-C6)alchile; -O(CH2)r-fenile, dove r ? come sopra definito, e il fenile ? opzionalmente sostituito da alogeno, preferibilmente fluoro, o -O(C1-C6)alchile, preferibilmente ?OCH3. 3. Un composto di formula (I), o un suo sale farmaceuticamente accettabile, per l?uso secondo la rivendicazione 1 scelto nel gruppo costituito da:
- 4. Un composto di formula (I), o un suo sale farmaceuticamente accettabile, per l?uso secondo la rivendicazione 1 avente formula:
- 5. Un composto di formula (I) per l?uso secondo le rivendicazioni 1-3, in cui la malattia infettiva ? una infezione da batteri, virus, funghi e protozoi.
- 6. Un composto di formula (I) per l?uso secondo la rivendicazione 5, in cui l?infezione da batteri ? scelta tra infezioni da batteri gram-positivi quali cocci del tipo Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Enterococci, e bacilli del tipo Clostridia, Bacillus anthracis, Corynebacterium diphtheria, Erysipelothrix rhusiopathiae, Listeria monocytogenes; infezioni da batteri gram-negativi quali Brucella, Campylobacter jejuni, Bartonella henselae, Neisseria meningitidis, Vibrio cholera, Escherichia coli, Haemophilus influenza, Spirochetes, Moraxella, Klebsiella, Enterobacter, Serratia, Legionella, Bordetella pertussis, Yersinia pestis, Pseudomonas aeruginosa, Salmonella, Proteus, Shigella, Francisella tularensis, Veillonella, Prevotella; le infezioni causate da altri tipi di batteri come Clamydia Trachomatis, Rickettsia, Borellia, Mycoplasma, Legionella, Helicobacter, Mycobacteria e Nocardia.
- 7. Un composto di formula (I) per l?uso secondo la rivendicazione 5, in cui l?infezione da virus ? scelta tra infezioni da virus appartenenti alle famiglie: Adenoviridae come Human mastadenovirus; Anelloviridae come Torque teno viruses; Astroviridae come Mamastroviruses; Caliciviridae come Norovirus, NoV (Norwalk virus) e Sapovirus (Sapporo virus); Coronaviridae come MERS-CoV, SARS-CoV, SARS-CoV-2 (COVID19) e varianti (Pandemiche); Filoviridae come Ebolavirus; Flaviviridae come Tick-borne encephalitis virus; Herpesviridae come HSV1 ed HSV2; Orthomyxoviridae come Influenza A virus (pandemica); Papillomaviridae come Human Papilloma virus (HPV); Paramyxoviridae come Hendra henipavirus ed Nipah henipavirus; Parvoviridae; Picornaviridae come Enterovirus A (Coxsackievirus), Enterovirus B (Echovirus) ed Enterovirus C (Poliovirus), o anche Hepatovirus come Hepatovirus A ed Hepatovirus E, o anche Kobuvirus o Parechovirus; Poxviridae; Polyomaviridae come Human polyomavirus; Reoviridae come Orthoreovirus e Rotavirus A; Retroviridae come HIV; Rhabdoviridae come Rabbia.
- 8. Un composto di formula (I) per l?uso secondo la rivendicazione 5, in cui l?infezione da funghi ? scelta tra Candidiasi da Candida albicans; Dermatofitosi da onychomycosis (tinea); Aspergillosi da Aspergillus; Mucormicosis da Rhizopus, Rhizomucor, e Mucor; Histoplasmosi da Histoplasma capsulatum; Blastomicosi da Blastomyces dermatitidis; Coccidioidomicosi da Coccidioides immitis; Paracoccidioidomicosi da Paracoccidioidiosi brasiliensis; Cryptococcosi da Cryptococcus neoformans o C. gattii.
- 9. Un composto di formula (I) per l?uso secondo la rivendicazione 5, in cui l?infezione da protozoi ? scelta tra Amebiasi da Entamoeba histolytica; Cheratite Amebica da Acanthamoeba; Meningo encefalite amebica primaria da Naegleria fowleri; Tripanosomiasi da T. brucei gambiense and T. brucei rhodesiense o da Trypanosoma cruzi; Malattia di Changas da American Trypanosomiasis; Leishmaniosi da Leishmania; Criptosporiadi da Cryptosporidium; Giardiasi da Giardia; Malaria da Plasmodio; Toxoplasmosi da Toxoplasma gondii; Babesiosi da Babesia; Ciclosporiasi da Cystoisospora (Isospora) belli; Encefalite granulomatosa Amebica da Acanthamoeba species o da Balamuthia mandrillaris.
- 10. Un composto di formula (I) per l?uso secondo la rivendicazione 6, in cui l?infezione ? da Clamydia Trachomatis.
- 11. Un composto di formula (I) per l?uso secondo la rivendicazione 7, in cui la malattia infettiva ? da SARS-CoV-2.
- 12. Un composto di formula (I) per l?uso secondo le rivendicazioni 1-4 in associazione con antibiotici betalattamici quali penicilline, cefalosporine, carbapenemi, monobattami, inibitori di betalattamasi, tetracicline, macrolidi, aminoglicosidi, gramicidina, polimixine, bacitracina, vancomicina, actinomicina, lincosamidi, ansamicine, streptogramine, antracicline, cloramfenicolo ed analoghi, acido fusidico, fosfomicina, mupirocina, cicloserina; o in associazione con adiuvanti chemioterapici; chinoloni ed analoghi interferoni; immunostimolanti; inibitori di COX2.
- 13. Formulazione farmaceutica comprendente come principio attivo un composto di formula (I) come definito nelle rivendicazioni 1-4 e un eccipiente e/o veicolo farmaceuticamente accettabile per l'uso nella prevenzione e/o nel trattamento di malattie infettive.
- 14. Uso di un composto di formula (I) come definito nelle rivendicazioni 1-4 nella marcatura di cellule e tessuti infettati da patogeni in diagnostica medica in-vitro.
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