RO134192A0 - Process for obtaining a new class of anthracene-imidazole compounds with anti-tuberculosis effect - Google Patents
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PROCEDEU PENTRU OBȚINEREA UNEI NOI CLASE DE COMPUȘI ANTRACENIMIDAZOLOCI CU ACTIVITATE ANTITUBERCULOASAPROCESS FOR OBTAINING A NEW CLASS OF ANTHRACENIMIDAZOLE COMPOUNDS WITH ANTITUBERCULOSIS ACTIVITY
Invenția se refera la un procedeu de obținere a unei noi clase de compuși antracenimidazolici cu activitate antituberculoasa, avind ca domeniul de aplicare chimia organica si chimia farmaceutica.The invention relates to a process for obtaining a new class of anthracenimidazole compounds with antituberculous activity, having as field of application organic chemistry and pharmaceutical chemistry.
Tuberculoza este o boala infectocontagioasa produsa de bacilul Mycobacterium tuberculosis, si care are o larga raspindire pe glob. Conform Organizației Mondiale a Sanatatii in anul 2017 au fost înregistrate 6,4 milioane de cazuri noi de tuberculoza iar numărul mortilor a fost de circa 1,3 milioane [1], Tratamentul tuberculozei a devenit in zilele noastre extrem de complex si de complicat, necesitind o terapie de durata si costisitoare. Apariția tuberculozei rezistente la medicamente, a tuberculozei rezistente la mai multe medicamente si recent, a tuberculozei total rezistente la medicamente, a complicat foarte mult situația cu privire la tratamentul tuberculozei. Mai mult, asocierea tuberculozei cu HIV / SIDA (dar si cu alte boli contagioase) reprezintă o alta problema dificila, care inrautateste si mai mult situația pacientilor bolnavi, astfel incit tuberculoza a devenit in prezent cauza principala a decesului in rindul pacientilor infectati cu HIV [1], In ultimii 50 de ani, deși cercetările pentru obținerea de noi medicamente antitubercoloase au fost si ramin extrem de intense, au fost introduse in terapia curenta doar 2 (doua) noi medicamente, Bedaquiline si Delamanid, chiar si acestea putând fi utilizate doar pentru tratamentul tuberculozei rezistente la medicamente [1-3]. Din aceste motive exista o cerere presanta de noi compuși biologic activi pentru tratamentul tuberculozei din partea societății, cu precădere din partea medicilor si a pacientilor, dar si a companiilor farmaceutice.Tuberculosis is an infectious disease caused by the bacillus Mycobacterium tuberculosis, which is widespread in the world. According to the World Health Organization, in 2017 there were 6.4 million new cases of tuberculosis and the death toll was about 1.3 million [1]. The treatment of tuberculosis has become extremely complex and complicated today, requiring a long and expensive therapy. The emergence of drug-resistant tuberculosis, multi-drug-resistant tuberculosis and, more recently, drug-resistant tuberculosis, has greatly complicated the situation regarding the treatment of tuberculosis. Moreover, the association of tuberculosis with HIV / AIDS (but also with other contagious diseases) is another difficult problem, which further worsens the situation of sick patients, so that tuberculosis has now become the leading cause of death among HIV-infected patients [ 1], In the last 50 years, although research to obtain new antituberculosis drugs has been and remains extremely intense, only 2 (two) new drugs, Bedaquiline and Delamanid, have been introduced into current therapy, even though they can only be used. for the treatment of drug-resistant tuberculosis [1-3]. For these reasons there is a pressing demand for new biologically active compounds for the treatment of tuberculosis from society, especially from doctors and patients, but also from pharmaceutical companies.
Exista mai multe clase de compuși care se utilizează in tratamentul curent al tuberculozei, una dintre acestea fiind cea a heterociclurilor cu azot de cinci si sase atomi, cele mai cunoscute din clasa fiind tuberculostaticele de prima linie Hidrazida Acidului Izonicotinic (sau Izoniazida, HIN), Pirazinamida si Etionamida. Principalul dezavantaj al medicametelor sus menționate (ca si a celorlalte utilizate in tratamentul tuberculozei), consta in aceea ca, acestea au început sa nu mai dea rezultate in foarte multe cazuri, datorita extraordinarei versatilitati si adaptabilitati la medicamente a bacilului Koch, Mycobacterium tuberculosis. Acest fapt a condus, asa după cum am mai subliniat, la instaurarea tuberculozei rezistente la medicamente, a tuberculozei rezistente la mai multe medicamente si recent aThere are several classes of compounds used in the current treatment of tuberculosis, one of which is that of nitrogen heterocycles with five and six atoms, the best known in the class being first-line tuberculostatics Izonicotinic Acid Hydrazide (or Isoniazid, HIN), Pyrazinamide and Ethionamide. The main disadvantage of the above-mentioned drugs (as well as others used in the treatment of tuberculosis) is that they have begun to fail in many cases, due to the extraordinary versatility and drug adaptability of the Koch bacillus, Mycobacterium tuberculosis. This has led, as I have already pointed out, to the establishment of drug-resistant tuberculosis, drug-resistant tuberculosis and, more recently,
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13/03/2019 tuberculozei total rezistente la medicamente, complicând foarte mult situația cu privire la tratamentul tuberculozei. In plus procedeele de obținere a acestor medicamente sunt cel mai adesea costisitoare, necesita multe etape de lucru, un timp îndelungat de obținere, cu randamente nu intodeauna mulțumitoare.13/03/2019 totally drug-resistant tuberculosis, greatly complicating the situation regarding the treatment of tuberculosis. In addition, the procedures for obtaining these drugs are most often expensive, require many steps of work, a long time to obtain, with yields not always satisfactory.
Datorita dezavantajelor sus menționate, grupul nostru de cercetare a întreprins in ultimul deceniu cercetării intense in vederea obținerii de noi copusi din categoria heterociclurilor cu azot de cinci si sase atomi, si care, sa fie biologic activi împotriva Mycobacterium tuberculosis, inclusiv asupra formelor rezistente la medicamente [4-9],Due to the above-mentioned disadvantages, our research group has undertaken intensive research over the last decade to obtain new kits from the category of five- and six-atom nitrogen heterocycles, which are biologically active against Mycobacterium tuberculosis, including drug-resistant forms. [4-9]
Scopul acestei invenții complexe este acela de a elabora un nou procedeu de sinteza si de a obține o noua clasa de compuși biologic activi antituberculosi cu schelet antracen imidazolic.The aim of this complex invention is to develop a new synthetic process and to obtain a new class of biologically active antituberculous compounds with imidazole anthracene skeleton.
Problemele pe care o rezolva prezenta invenție constau in:The problems solved by the present invention are:
elaborarea unui nou procedeu de sinteza pentru obținerea de compuși imidazol/benzimidazol-antracenici;elaboration of a new synthesis process for obtaining imidazole / benzimidazole-anthracene compounds;
obținerea unei noi clase de compuși din clasa a heterociclurilor cu azot de cinci atomi, si anume compuși imidazol/benzimidazol-antracenici, cu activitate biologica împotriva Mycobacterium tuberculosis.obtaining a new class of compounds from the class of heterocycles with nitrogen of five atoms, namely imidazole / benzimidazole-anthracene compounds, with biological activity against Mycobacterium tuberculosis.
Procedeul pentru obținerea noii clase de compuși imidazol/benzimidazol-antracenici prezintă marele avantaj ca necesita doar 2 (doua) etape de lucru (Schema 1):The process for obtaining the new class of imidazole / benzimidazole-anthracene compounds has the great advantage that it requires only 2 (two) work steps (Scheme 1):
1. O prima etapa consta in reacția de N-alchilare a azotului NI din imidazol 1 respectiv benzimidazol 2, cu 9-clorometil-antracen, cind se obțin intermediarii 1-(antracenil-9metilen)-lH-imidazol 4 si respectiv l-(antracenil-9-metilen)-lH-benzimidazol 5;1. A first step consists in the N-alkylation reaction of NI nitrogen from imidazole 1 and benzimidazole 2, respectively, with 9-chloromethyl-anthracene, when the intermediates 1- (anthracenyl-9-methylene) -1H-imidazole 4 and 1- (respectively) are obtained. anthracenyl-9-methylene) -1H-benzimidazole 5;
2. A doua etapa consta in reacția de cuatemizare cu nj-bromo-acetofenone Z-substituite a azotului N3 imidazolic/benzimidazolic din intermediarii 4 si 5, când se obține noua clasa de compuși imidazol/benzimidazol-antracenici, si anume bromura de l-(antracenil-9-metilen)-3(2-(4-Z-fenil)-2-oxoetil)-lH-imidazol-3-ium 6a-e si respectiv bromura de l-(antracenil-9metilen)-3-(2-(4-Z-fenil)-2-oxoetil)-lH-benzimidazol-3-ium 7a-e.2. The second stage consists in the Z-substituted nj-bromo-acetophenone Z-substituted N3 nitrogen imidazole / benzimidazole reaction of intermediates 4 and 5, when the new class of imidazole / benzimidazole-anthracene compounds is obtained, namely l-bromide (anthracenyl-9-methylene) -3 (2- (4-Z-phenyl) -2-oxoethyl) -1H-imidazol-3-yl 6a-e and 1- (anthracenyl-9-methylene) -3- bromide, respectively 2- (4-Z-phenyl) -2-oxoethyl) -1H-benzimidazole-3-yl 7α-e.
fele credite, la ONOFREIsuch credits, to ONOFREI
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Noii compuși obținuți sunt substanțe solide stabile, frumos cristalizate, solubile in apa si solventi organici (alcool, acetona, cloroform, acetat de etil, dimetil sulfoxid). Structura noilor compuși revendicati a fost confirmată prin metodele moderne ale analizei structurale organice: analiza elementala, spectroscopie de infrarosu, rezonanta magnetica nucleara monoși bidimensională (1H, 13C RMN și 2D).The new compounds obtained are stable solids, beautifully crystallized, soluble in water and organic solvents (alcohol, acetone, chloroform, ethyl acetate, dimethyl sulfoxide). The structure of the claimed new compounds was confirmed by modern methods of organic structural analysis: elemental analysis, infrared spectroscopy, one-dimensional two-dimensional nuclear magnetic resonance (1H, 13C NMR and 2D).
Activitatea biologica antituberculoasa in vitro a fost determinata împotriva Mycobacterium tuberculosis H37Rv in condiții aerobe, determinindu-se in acest sens următorii parametri:The in vitro antituberculosis biological activity was determined against Mycobacterium tuberculosis H37Rv under aerobic conditions, determining in this respect the following parameters:
- concentrația minima inhibitorie (MIC, μΜ), definita ca cea mai mica concentrație a compusului la care creșterea Mycobacterium tuberculosis a fost complet inhibată;- the minimum inhibitory concentration (MIC, μΜ), defined as the lowest concentration of the compound at which the growth of Mycobacterium tuberculosis was completely inhibited;
- concentrația inhibitorie a compusului care determina o inhibare a creșterii bacilului la 50% si respectiv la 90% (IC50 si IC90, μΜ).- inhibitory concentration of the compound which causes an inhibition of bacillus growth at 50% and 90%, respectively (IC50 and IC90, μΜ).
Activitatea compușilor noștri s-a dovedit a fi foarte buna, cu un MIC cuprins intre 10-40 μΜ, un IC50 cuprins intre 5-20 μΜ si un IC90 cuprins intre 15-45 μΜ.The activity of our compounds proved to be very good, with a MIC between 10-40 μΜ, an IC50 between 5-20 μΜ and an IC90 between 15-45 μΜ.
Avantajele inventei constau in:The advantages of the invention consist in:
elaborarea unui nou procedeu de lucru eficient si direct pentru obținerea compușilor imidazol/benzimidazol-antracenici, procedeul avind doar 2(doua) etape de lucru, are un timp de lucru redus, prezintă eficienta energetica si randamente bune;elaboration of a new efficient and direct working process for obtaining imidazole / benzimidazole-anthracene compounds, the process having only 2 (two) working stages, has a reduced working time, presents energy efficiency and good yields;
materiile prime utilizate (imidazol, benzimidazol, cu τυ-bromo-acetofenone Zsubstituite) sunt ușor accesibile ca preț;the raw materials used (imidazole, benzimidazole, with substituted τυ-bromo-acetophenone) are easily accessible in price;
accesibilitatea economica a clasei de compuși imidazol/benzimidazol-antracenici revendicate sub aspect eficienta/pret, datorita avantajelor sus menționate;economic affordability of the class of imidazole / benzimidazole-anthracene compounds claimed in terms of efficiency / price, due to the above-mentioned advantages;
obținerea unei noi clase de compuși imidazol/benzimidazol-antracenici si anume: bromura de l-(antracenil-9-metilen)-3-(2-(4-Z-fenil)-2-oxoetil)-lH-imidazol-3-ium 6a-e si respectiv bromura de l-(antracenil-9-metilen)-3-(2-(4-Z-fenil)-2-oxoetil)-lHbenzimidazol-3-ium 7a-e;obtaining a new class of imidazole / benzimidazole-anthracene compounds, namely: 1- (anthracenyl-9-methylene) -3- (2- (4-Z-phenyl) -2-oxoethyl) -1H-imidazole-3- bromide ium 6a-e and 1- (anthracenyl-9-methylene) -3- (2- (4-Z-phenyl) -2-oxoethyl) -1H-benzimidazole-3-ium 7a-e bromide, respectively;
activitate biologica foarte buna a compușilor împotriva Mycobacterittmfukerculosis.very good biological activity of compounds against Mycobacterittmfukerculosis.
exredite,exredite,
ClhioFREIClhioFREI
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Subliniem ca, procedeul de lucru pentru obținerea noi clase de compuși imidazol/benzimidazol-antracenici, noi produși ai clasei tip 6a-e si 7a-e, cit si rezultatele testărilor antituberculoase ale acestor compuși, nu au fost descrise anterior in literatura de specialitate.We emphasize that the working process for obtaining new classes of imidazole / benzimidazole-anthracene compounds, new products of class type 6a-e and 7a-e, as well as the results of antituberculosis tests of these compounds, have not been previously described in the literature.
Exemplu de realizare a invențieiEmbodiment of the invention
1. Obținerea intermediarilor l-(antracenil-9-metilen)-lH-imidazol 4 si l-(antracenil-9metileri)-lH-benzimidazol 51. Obtaining the intermediates 1- (anthracenyl-9-methylene) -1H-imidazole 4 and 1- (anthracenyl-9-methyl) -1H-benzimidazole 5
Sinteza intermediarilor 4 si 5 a fost realizata prin adaptarea unor metode de literatura prezentate anterior [12,13], Intr-un balon cu fund rotund de 250 ml si prevăzut cu 3 gaturi, se introduc 6 mmoli derivat imidazolic (0.402 g imidazol, respectiv 0.708 g benzimidazol) si se dizolva în 15 ml THF anhidru. Apoi se adaugă treptat, pe baie de gheata, 0.84 g (21 mmoli) NaH 60% (in ulei de mineral) suspendata in prealabil in 15 mL THF anhidru (NaH se spalata anterior cu «-hexan). După ce întreaga cantitate de NaH a fost adaugata, se adaugă lent cu ajutorul unei seringi, in mediu inert de azot, 6.6 mmoli (1.496 g) 9-clorometilantracen solubilizat in prealabil in 25 ml THF. După adaugarea completa a 9-clorometilantracenului, se continua agitarea timp de o ora sub azot, si se continua reacția la reflux, pe baie de ulei, timp de 12 h in cazul benzimidazolului si respectiv 20 h in cazul imidazolului. După terminarea reacției, se filtrează gravitațional, se spala pe filtru cu THF, si se concentrează la sec la rotavapor. Purificarea s-a realizat utilizind cromatografia rapida pe coloana, folosit ca amestec de eluenți CH2C12:CH3OH=(99:l/98:2).The synthesis of intermediates 4 and 5 was performed by adapting some of the previously presented literature methods [12,13]. In a 250 ml round bottom flask and provided with 3 necks, 6 mmol of imidazole derivative (0.402 g of imidazole, respectively) are introduced. 0.708 g benzimidazole) and dissolve in 15 ml of anhydrous THF. Then gradually add 0.84 g (21 mmol) of 60% NaH (in mineral oil) suspended in 15 mL of anhydrous THF (NaH previously washed with "-hexane") on an ice bath. After the entire amount of NaH has been added, 6.6 mmol (1,496 g) of 9-chloromethylanthracene previously solubilized in 25 ml of THF is slowly added using a syringe to an inert nitrogen medium. After complete addition of 9-chloromethylanthracene, stirring was continued for one hour under nitrogen, and the reaction was continued at reflux on an oil bath for 12 hours for benzimidazole and 20 hours for imidazole, respectively. After completion of the reaction, it is filtered by gravity, washed on the filter with THF, and concentrated to dryness on a rotary evaporator. Purification was performed using flash column chromatography, used as a mixture of eluents CH2Cl2: CH3OH = (99: 1/98: 2).
l-(antracenil-9-metilen)-lH-imidazol, 4. Precipitat alb-gălbui (η= 47%), pt 159-160 °C. *HRMN (500 MHz, CDC13): 6.08 (2H, s, CH2(6)), 6.85 (1H, s, H4), 6.99 (1H, s, H5), 7.48 (1H, s, H2), 7.51 (2H, t, Hio, Hh, J= 7.5 Hz), 7.57 (2H, t, H9, H15, J= 8.5 Hz), 8.08 (2H, d, Hi 1, H13, J= 8.5 Hz), 8.20 (2H, d, H8, Hi6, J= 9.0 Hz), 8.57 (1H, s, H12). 13C-RMN (125 MHz, CDCI3): 43.3 CH2(6), 119.0 C4, 123.0 C8,C]6, 124.7 C7, 125.4 Cio,Ci4, 127.5 C9,Ci5, 129.2 C5, 129.6 C11,C13, 129.7 C12, 130.9 C7a,Ci6a, 131.5 Cna,Ci2a, 136.8 C2. IR (KBr, Xcm’1): 3023, 2928, 1604, 1585, 1430. Anal. Calcd. pentru C18H14N2: C, 83.69; H, 5.46; N, 10.84; Găsit: C, 83.80; H, 5.36; N, 10.54.1- (anthracenyl-9-methylene) -1H-imidazole, 4. Yellowish-white precipitate (η = 47%), mp 159-160 ° C. * HRMN (500 MHz, CDCl 3 ): 6.08 (2H, s, CH 2 (6 )), 6.85 (1H, s, H 4 ), 6.99 (1H, s, H 5 ), 7.48 (1H, s, H) 2 ), 7.51 (2H, t, Hio, H h , J = 7.5 Hz), 7.57 (2H, t, H 9 , H15, J = 8.5 Hz), 8.08 (2H, d, Hi 1, H13, J = 8.5 Hz), 8.20 (2H, d, H 8 , Hi 6 , J = 9.0 Hz), 8.57 (1H, s, H12). 13 C-NMR (125 MHz, CDCl 3): 43.3 CH 2 ( 6), 119.0 C 4 , 123.0 C 8 , C ] 6 , 124.7 C 7 , 125.4 C 10, C 14, 127.5 C 9 , C 5 , 129.2 C 5 , 129.6 C11, C13, 129.7 C12, 130.9 C 7a , Ci 6 a, 131.5 Cn a , Ci2a, 136.8 C 2 . IR (KBr, Xcm 1 ): 3023, 2928, 1604, 1585, 1430. Anal. Calcd. for C 18 H 14 N 2: C, 83.69; H, 5.46; N, 10.84; Found: C, 83.80; H, 5.36; N, 10.54.
l-(antracenil-9-metilen)-lH-benzimidazol, 5. Precipitat galben (η= 41%), pt 177-180 °C. *HRMN (400 MHz, CDCI3): 6.18 (2H, s, CH2{8)), 7.26 (1H, s, H2), 7.37 (1H, H6, J= 7.2 Hz), 7.42 (1H, t, H5, J= 7.6 Hz), 7.52 (4H, dd, Hn, Ηι7, H12, Hi6, J= 6.8 fJ-^^X£^X.71 (1H, /X-/ I \ -prof.1- (anthracenyl-9-methylene) -1H-benzimidazole, 5. Yellow precipitate (η = 41%), mp 177-180 ° C. * HRMN (400 MHz, CDCl 3): 6.18 (2H, s, CH 2 {8) ), 7.26 (1H, s, H 2 ), 7.37 (1H, H 6 , J = 7.2 Hz), 7.42 (1H, t , H 5 , J = 7.6 Hz), 7.52 (4H, dd, Hn, 7ι 7 , H12, Hi 6 , J = 6.8 fJ - ^^ X £ ^ X.71 (1H, / X- / I \ -prof .
\ L>> \\ L >> \
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13/03/2019 d, H4, J= 8.0 Hz), 7.83 (1H, d, H7, J= 8.0 Hz), 8.10 (4H, dd, Hio, His, H,3, H15, J= 6.4 Hz, J= 3.2 Hz), 8.62 (1H, s, H|4). ,3C-RMN (100 MHz, CDCb): 41.5 CH2(8), 109.6 C4, 120.6 C7, 122.6 C6, 123.1 Cio,Ci8, 123.2 C5, 123.7 C9, 125.5 Ci2,Ci6, 127.7 Cn,Ci7, 129.6 Ci3,Ci5, 129.8 Ci4, 131.2 C9a,Ci8a, 131.5 Ci3a,Ci4a, 134.3 C3a, 142.3 C2, 144.0 C7a. IR (KBr, v(cm-'): 3045, 2930, 1580, 1550, 1442. Anal. Calcd. pentru C22Hi6N2: C, 85.69; H, 5.23; N, 9.08; Găsit: C, 85.79; H, 5.13; N, 9.28.13/03/2019 d, H 4 , J = 8.0 Hz), 7.83 (1H, d, H 7 , J = 8.0 Hz), 8.10 (4H, dd, Hio, His, H, 3 , H15, J = 6.4 Hz, J = 3.2 Hz), 8.62 (1H, s, H | 4 ). .3 C-NMR (100 MHz, CDCl 3): 41.5 CH 2 (8) , 109.6 C 4 , 120.6 C 7 , 122.6 C 6 , 123.1 C 10, Ci 8 , 123.2 C 5 , 123.7 C 9 , 125.5 Ci 2 , Ci 6 , 127.7 Cn, Ci 7 , 129.6 Ci 3 , Ci 5 , 129.8 Ci 4 , 131.2 C 9a , Ci 8a , 131.5 Ci 3a , Ci 4a , 134.3 C 3a , 142.3 C 2 , 144.0 C 7a . IR (KBr, v (cm-1): 3045, 2930, 1580, 1550, 1442. Calcd. Anal. For C 22 H 6 N 2 : C, 85.69; H, 5.23; N, 9.08; Found: C, 85.79 ; H, 5.13; N, 9.28.
2, Obținerea noii clase de compuși imidazol/benzimidazol-antracenici, si anume bromura de l-(antracenil-9-metilen)-3-(2-(4-Z-fenil)-2-oxoetil)-lH-imidazol-3-ium 6a-e si respectiv bromura de l-(antracenil-9-metilen)-3-(2-(4-Z-fenil)-2-oxoetil)-lH-benzimidazol-3-ium 7a-e,2, Obtaining the new class of imidazole / benzimidazole-anthracene compounds, namely 1- (anthracenyl-9-methylene) -3- (2- (4-Z-phenyl) -2-oxoethyl) -1H-imidazole-3 bromide -ium 6a-e and 1- (anthracenyl-9-methylene) -3- (2- (4-Z-phenyl) -2-oxoethyl) -1H-benzimidazole-3-ium 7a-e bromide, respectively
Intr-un balon cu fund rotund de 100 mL, se solubilizează 0.38 mmoli (0.1 g derivat de 1(antracenil-9-metilen)-lH-imidazol 4, respectiv 0.117g l-(antracenil-9-metilen)-lHbenzimidazol 5) in 12 mL acetona, apoi se adauga treptat 0.38 mmoli de ro-bromoacei o feno ne Z-substituite (e.g. 0.095 g de uj-bromo-/?ara-nitroacetofenona, etc) solubilizata in prealabil in 12 mL acetona. Reacția are loc sub agitare la temperatura camerei timp de 48 h. După terminarea reacției, se filtrează gravitațional, se spala pe filtru cu acetona si, se filtrează la vid. Produsii obținuți sunt puri si nu necesita alta prelucrare.In a 100 mL round-bottomed flask, 0.38 mmol (0.1 g of 1 (anthracenyl-9-methylene) -1H-imidazole 4 and 0.117 g of 1 (anthracenyl-9-methylene) -1H-benzimidazole 5) are solubilized. in 12 mL acetone, then gradually add 0.38 mmol of ro-bromoacene to a non-Z-substituted phenol (eg 0.095 g of uj-bromo - /? ara-nitroacetophenone, etc.) previously solubilized in 12 mL acetone. The reaction is stirred at room temperature for 48 hours. After completion of the reaction, it is filtered by gravity, washed on the acetone filter and filtered in vacuo. The products obtained are pure and do not require further processing.
Bromura de l-(antracenil-9-metilen)-3-(2-(4-nitrofenil)-2-oxoetil)-lH-imidazol-3-ium, 6d. Precipitat galben (η= 59%), pt 232-235 °C. 'H-RMN (500 MHz, DMSO-i/6): 5.99 (2H, s, CH2(i )), 6.63 (2H, s, CH2(6)), 7.62 (2H, t, Hio, Hi4, J= 7.5 Hz), 7.73-7.70 (3H, m, H9, Hi5, H5), 7.90 (1H, s, H4), 8.16 (2H, d, 2χΗ4·, J= 8.5 Hz), 8.23 (2H, d, Hn, Hi3, J= 8.5 Hz), 8.37 (2H, d, 2xH5’, J= 8.0 Hz), 8.54 (2H, t, H8, Hi6, J= 9.0 Hz), 8.79 (1H, s, H2), 8.86 (1H, s, Hi2). 13C-RMN (125 MHz, DMSO-î/6): 45.0 CH2(6), 55.8 CH2(r), 122.4 C4, 123.3 C8,Ci6, 123.5 C7, 124.0 2x0’, 124.1 C5, 125.6 Cio,Ci4, 127.8 C9,Ci5, 129.3 0,0, 129.4 2x0, 130.1 Ci2, 130.6 C7a,Ci6a, 131.0 Oa,Ci2a, 136.7 C2, 138.2 C3-, 150.4 O’, 190.5 O. IR (KBr, ν^ιη1): 3022, 2926, 1712, 1602, 1531, 1444, 1344. Anal. Calcd. pentru C26H20BrN3O3: C, 62.16; H, 4.01; N, 8.36; Găsit: C, 62.01; H, 4.11; N, 8.06.1- (Anthracenyl-9-methylene) -3- (2- (4-nitrophenyl) -2-oxoethyl) -1H-imidazole-3-yl bromide, 6d. Yellow precipitate (η = 59%), mp 232-235 ° C. 1 H-NMR (500 MHz, DMSO-6): 5.99 (2H, s, CH 2 ( i)), 6.63 (2H, s, CH 2 (6) ), 7.62 (2H, t, Hio, Hi 4 , J = 7.5 Hz), 7.73-7.70 (3H, m, H 9 , Hi 5 , H 5 ), 7.90 (1H, s, H 4 ), 8.16 (2H, d, 2χΗ 4 ·, J = 8.5 Hz ), 8.23 (2H, d, Hn, Hi 3 , J = 8.5 Hz), 8.37 (2H, d, 2xH 5 ', J = 8.0 Hz), 8.54 (2H, t, H 8 , Hi 6 , J = 9.0 Hz), 8.79 (1H, s, H 2 ), 8.86 (1H, s, Hi 2 ). 13 C-NMR (125 MHz, DMSO-6): 45.0 CH 2 (6), 55.8 CH 2 (r), 122.4 C 4, 123.3 C 8, C 16, 123.5 C 7, 124.0 2x0 ', 124.1 C 5, 125.6 C 10, C 14, 127.8 C9, Ci5, 129.3 0.0, 129.4 2x0, 130.1 Ci2, 130.6 C7a, Ci6a, 131.0 Oa, Ci2a, 136.7 C2, 138.2 C3-, 150.4 O ', 190.5 O. IR (KBr, ν ^ ιη 1 ): 3022, 2926, 1712, 1602, 1531, 1444, 1344. Anal. Calcd. for C 26 H 20 BrN 3 O 3 : C, 62.16; H, 4.01; N, 8.36; Found: C, 62.01; H, 4.11; N, 8.06.
Bromura de 1 -(antracenil-9-metilen)-3-(2-(4-nitrofenil)-2-oxoetil)-lH-benzoimidazol-3-ium, 7d. Precipitat galben (η= 72%), pt 219-220 °C. 'H-RMN (500 MHz, DMSO-î/6): 6.23 (2H, s, CH2(d), 6.86 (2H, s, CH2(8)), 7.63 (2H, t, Hi2, Hi6, J= 8.0 Hz), 7.68 (2H, t, Hn, Hi7, J= 8.0 Hz), 7.79 (1H, t, H6, J= 8.0 Hz), 7.86 (1H, t, H5, J= 8.0 Hz), 8.13 (1H, d, H7, J= 8.5 Hz), 8.17 (2H, d, 2xH4’, J= 9.0 Hz), 8.26 (2H, d, Hi3, His, J= 8.0 Hz), 8.37 (2H, d, 2x0, J= 8.5 Hz), 8.44 (2H, d, Hio, Hi8, J= 8.5 Hz), 8.50 (1H, d, H4, J= 8.5 Hz), 8.79/^^/¾^ (1H, s,1- (Anthracenyl-9-methylene) -3- (2- (4-nitrophenyl) -2-oxoethyl) -1H-benzoimidazole-3-yl bromide, 7d. Yellow precipitate (η = 72%), mp 219-220 ° C. 1 H-NMR (500 MHz, DMSO-6): 6.23 (2H, s, CH 2 (d), 6.86 (2H, s, CH 2 ( 8)), 7.63 (2H, t, Hi 2 , Hi 6 , J = 8.0 Hz), 7.68 (2H, t, Hn, Hi 7 , J = 8.0 Hz), 7.79 (1H, t, H 6 , J = 8.0 Hz), 7.86 (1H, t, H 5 , J = 8.0 Hz), 8.13 (1H, d, H 7 , J = 8.5 Hz), 8.17 (2H, d, 2xH 4 ', J = 9.0 Hz), 8.26 (2H, d, Hi 3 , His, J = 8.0 Hz), 8.37 (2H, d, 2x0, J = 8.5 Hz), 8.44 (2H, d, Hio, Hi 8 , J = 8.5 Hz), 8.50 (1H, d, H 4 , J = 8.5 Hz), 8.79 / ^^ / ¾ ^ (1H, s,
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H14). 13C-RMN (125 MHz, DMSO-t/6): 43.5 CH2(8), 53.6 CH2(i·), 114.1 C7, 114.4 C4, 121.8 C9, 123.3 Cio,Ci8, 123.9 2xC5·, 125.7 Ci2,Ci6, 126.8 C5, 127.1 C6, 128.0 Cn,C17, 129.4 C13,C15, 129.6 2xC4’, 130.5 Ci4, 131.0 Ci3a,Ci4a, 131.1 C9a,Ci8a, 131.3 C7a, 132.3 C3a, 138.2 C3·, 142.1 C2, 150.4 C6·, 190.4 C2’. IR (KBr, v(cm-'): 3051, 2897, 1712, 1602, 1527, 1446, 1342. Anal. Calcd. pentru C30H22BrN3O3: C, 65.23; H, 4.01; N, 7.61; Găsit: C, 65.03; H, 4.10; N, 7.81.H14). 13 C-NMR (125 MHz, DMSO-t / 6): 43.5 CH 2 (8 ), 53.6 CH 2 ( i ·), 114.1 C 7 , 114.4 C 4 , 121.8 C 9 , 123.3 C 10, C 18, 123.9 2xC 5 ·, 125.7 Ci 2 , Ci 6 , 126.8 C 5 , 127.1 C 6 , 128.0 Cn, C 17 , 129.4 C13, C15, 129.6 2xC 4 ', 130.5 Ci 4 , 131.0 Ci 3a , Ci 4a , 131.1 C 9a , Ci 8a , 131.3 C 7a , 132.3 C 3a , 138.2 C 3 ·, 142.1 C 2 , 150.4 C 6 ·, 190.4 C 2 '. IR (KBr, v (cm-1): 3051, 2897, 1712, 1602, 1527, 1446, 1342. Anal. Calcd for C 30 H 22 BrN 3 O 3 : C, 65.23; H, 4.01; N, 7.61; Found : C, 65.03; H, 4.10; N, 7.81.
3. Testarea in vitro a activitatii antituberculoase3. In vitro testing of antituberculosis activity
Testarea activitatii antituberculoase a fost efectuata prin realizarea unui screening primar standard in vitro împotriva Mycobacterium tuberculosis H37Rv (ATCC 27294). Metoda se bazeaza pe masurarea creșterii in mediu lichid a unei tulpini fluorescente de Mycobacterium tuberculosis H37Rv, iar citirea rezultatelor se face cu ajutorul unui cititor de placi BioTek™ Synergy 4, determinindu-se fie densitatea optica (OD), fie fluorescenta [10, 11], Se utilizează doua citiri pentru a minimiza problemele cauzate de autofluorescenta. Pe baza unui aparat matematic fundamentat, a fost stabilita o relație de dependenta liniara intre OD si fluorescenta cititia de aparat, care justifica utilizarea fluorescentei ca măsură a creșterii bacteriene. MIC pentru fiecare compus a fost determinat prin masurarea creșterii bacteriene după 5 zile in prezenta compusului testat. Compușii testati au fost preparati in 10 dilutii seriale, doua serii succesive, in mediu 7H9-Tw-OADC si DMSO, pe placi cu 96 de godeuri, cu o concentrație finala de DMSO de 2%. Cea mai mare concentrație utilizata pentru compus a fost 200 μΜ, cind compușii au fost solubilizati in DMSO la concentrația 10 miliM. Fiecare placa a inclus si martori/control de testare, rifampicina. Plăcile au fost inoculate cu Mycobacterium tuberculosis H37Rv si apoi incubate timp de 5 zile, iar creșterea a fost măsurată prin ODs9o si fluorescența (Ex 560 / Em 590) folosind un cititor de placi BioTek ™ Synergy 4. Pentru a calcula MIC, curba de răspuns obtinuta prin reprezentarea grafica a celor 10 dilutii seriale, a fost reprezentata grafic ca % procent de creștere, si fitata la modelul Gompertz folosind programul GraphPad Prism 5. MIC a fost definita ca cea mai mica concentrație a compusului la care creșterea Mycobacterium tuberculosis a fost complet inhibată, si a fost calculata din punctul de inflexiune al curbei fitate la asimptota cea mai mica unde creșterea este zero (Figura IA).Testing for antituberculosis activity was performed by performing a standard primary in vitro screening against Mycobacterium tuberculosis H37Rv (ATCC 27294). The method is based on measuring the growth in liquid medium of a fluorescent strain of Mycobacterium tuberculosis H37Rv, and the reading of the results is done using a BioTek ™ Synergy 4 plate reader, determining either the optical density (OD) or the fluorescence [10, 11 ], Two readings are used to minimize problems caused by autofluorescence. Based on a grounded mathematical apparatus, a linear dependence relationship was established between OD and fluorescence apparatus reading, which justifies the use of fluorescence as a measure of bacterial growth. The MIC for each compound was determined by measuring bacterial growth after 5 days in the presence of the test compound. The tested compounds were prepared in 10 serial dilutions, two successive series, on average 7H9-Tw-OADC and DMSO, on 96-well plates, with a final DMSO concentration of 2%. The highest concentration used for the compound was 200 μΜ, when the compounds were solubilized in DMSO at a concentration of 10 ml. Each plate also included control / test control, rifampicin. The plates were inoculated with Mycobacterium tuberculosis H37Rv and then incubated for 5 days, and growth was measured by ODs 9 o and fluorescence (Ex 560 / Em 590) using a BioTek ™ Synergy 4 plate reader. To calculate the MIC, the curve response obtained by plotting the 10 serial dilutions, was plotted as% percent increase, and fitted to the Gompertz model using the GraphPad Prism 5 program. MIC was defined as the lowest concentration of the compound at which the growth of Mycobacterium tuberculosis was completely inhibited, and was calculated from the inflection point of the fitted curve at the smallest asymptote where the increase is zero (Figure IA).
Pentru a calcula concentrațiile inhibitorii IC50 si IC9o ale compusului, curba de răspuns obtinuta prin reprezentarea grafica a celor 10 dilutii seriale a fost fitata folosind algoritmulTo calculate the inhibitory concentrations IC50 and IC 9 o of the compound, the response curve obtained by plotting the 10 serial dilutions was fitted using the algorithm
a ^019 00163a ^ 019 00163
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Levenberg-Marquardt, si s-au determinat concentrațiile care au condus la 50% si respectiv 90% inhibarea a creșterii Mycobacterium tuberculosis (Figura 1B).Levenberg-Marquardt, and concentrations were determined that led to 50% and 90% inhibition of Mycobacterium tuberculosis growth, respectively (Figure 1B).
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