CN109851560B - Biphenyl diazole derivative and preparation method and application thereof - Google Patents
Biphenyl diazole derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN109851560B CN109851560B CN201910018160.1A CN201910018160A CN109851560B CN 109851560 B CN109851560 B CN 109851560B CN 201910018160 A CN201910018160 A CN 201910018160A CN 109851560 B CN109851560 B CN 109851560B
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- China
- Prior art keywords
- imidazol
- biphenyl
- propan
- carboxamide
- diazole
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- ACGSIYWQEKAUJY-UHFFFAOYSA-N 1,1'-biphenyl;1h-pyrazole Chemical class C=1C=NNC=1.C1=CC=CC=C1C1=CC=CC=C1 ACGSIYWQEKAUJY-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 14
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 11
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 27
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- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 10
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 10
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Abstract
The invention belongs to the field of pharmaceutical chemistry synthesis, and particularly relates to a biphenyl diazole derivative and a preparation method thereof, and further relates to application of the diazole derivative in preparation of medicines for treating various diseases caused by fungal or bacterial infection. In-vitro antibacterial activity tests show that the biphenyl diazole derivatives have strong antifungal and antibacterial activities, and compared with the existing antibacterial drugs, the biphenyl diazole derivatives have the advantages of novel structure, high efficiency, broad spectrum and the like, so that the biphenyl diazole derivatives have good application prospects.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a biphenyl diazole derivative and a preparation method thereof, and application of the diazole derivative in preparation of drugs for treating various diseases caused by fungal or bacterial infection.
Background
Fungal infection is a common disease and can be divided into superficial fungal infection and deep fungal infection according to the difference of infected parts. Wherein, the incidence of superficial fungal infection is high, which can cause infection of skin, nail, mucosa and the like, but generally can not cause serious consequences; the pathogenic bacteria of superficial fungal infection are Trichophyton and Epidermophyton. The deep fungal infection is also called as systemic fungal infection, and in recent years, with the use of a large amount of immunosuppressants and broad-spectrum antibiotics, the increasing number of radiotherapy and chemotherapy of cancer patients and AIDS patients, the normal immune function of a human body is seriously damaged, so that the incidence rate of the deep fungal infection is higher and higher; candida, cryptococcus and aspergillus fumigatus are the three major pathogenic bacteria that cause deep fungal infections; in addition, it has been reported that Zygomycetes, Fusarium and hyphomycetes can also cause deep fungal infections. Clinically, the medicines for treating superficial fungal infection are relatively more, while the medicines for treating deep fungal infection are relatively limited, and only amphotericin B and azole (fluconazole, itraconazole and the like) antibacterial medicines are available. Moreover, because the similarity between the fungal cells and the human cells is high, the antifungal drugs lack the selectivity on human cells, so that strong toxic and side effects are caused, and the clinical treatment requirements are difficult to meet. For example: amphotericin B has strong antifungal activity, but can be only injected intravenously, and has high nephrotoxicity, thus severely limiting the clinical application of amphotericin B; ketoconazole is used as a first oral broad-spectrum antifungal medicine, and stops production and sale in China in 2015 due to stronger hepatorenal toxicity and gastrointestinal reaction; itraconazole which is widely applied can inhibit cytochrome P4503A4, and can generate serious interaction when being taken with other medicines; the antibacterial spectrum of the 5-fluorocytosine is narrow, and drug resistance is easy to generate; similarly, the terbinafine antibacterial spectrum is also narrow and only used for superficial fungal infections. In addition, the problem of resistance to fungi has become more and more serious due to the widespread use of antifungal drugs. Therefore, the search for safe, highly effective, low-toxicity, broad-spectrum antifungal drugs has become a hot point of research.
Bacterial infection is another common disease in clinic, pathogenic bacteria usually invade blood circulation to grow and reproduce to generate acute systemic infection caused by toxin and other metabolites, clinically, the bacterial infection is characterized by shivering, hyperpyrexia, rash, arthralgia and hepatosplenomegaly, and part of the bacterial infection can have infective shock and migratory focus. Clinically, some patients also have dysphoria, cold limbs, cyanosis, thready pulse, rapid respiration, and blood pressure decrease. Especially, the elderly, children, patients with chronic diseases or immunologic hypofunction, and patients with complications before treatment, can develop septicemia or sepsis. Bacteria are the causative agents of many diseases, including tuberculosis, gonorrhea, anthrax, syphilis, plague, trachoma, etc. are all caused by bacteria. For example, several gram-positive species cause human disease, the most common organisms include staphylococcus, streptococcus, enterococcus, clostridium, bacillus, corynebacterium and listeria; examples of clinically refractory drug-resistant bacteria include methicillin-resistant staphylococcus aureus (MRSA), penicillin-resistant streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). Although the use of antibiotics effectively controls many serious bacterial infectious diseases in humans, the widespread use of antibiotics has also led to the increase of drug-resistant strains, reducing the antibacterial efficiency of existing antibiotics. However, the treatment of bacterial infections has become more difficult and expensive as bacteria have developed resistance to existing antibiotics, the transmission of highly toxic strains, and no more effective new antibacterial agents are available. It is presently believed that the most promising therapeutic strategy would be to render the pathogenic bacteria non-lethal and only attenuate the pathogenic toxicity of the pathogenic bacteria, without threatening the survival of the pathogenic bacteria themselves and without causing resistance problems. Recent studies have found that pathogenicity of pathogenic bacteria is regulated by a density-dependent quorum sensing system (QS) which mediates the expression of pathogenic genes to achieve its pathogenicity. When the density of the pathogenic bacteria reaches a certain degree, the pathogenic bacteria synthesize and release certain signal molecules, and can start the expression of related genes and regulate and control various biological behaviors of the pathogenic bacteria, such as bioluminescence, toxin generation, biofilm formation, antibiotic generation and the like.
Although many clinically available antibacterial drugs can have both antifungal and antibacterial effects, the clinical limitation problem of a single antibacterial effect exists, for example, azole drugs have irreplaceable clinical effects, but the drugs expose more and more defects, such as narrow antibacterial spectrum, drug resistance, toxic and side effects, single dosage form, drug interaction and the like, and the development of novel broad-spectrum, efficient, low-toxicity and diversified-administration antibacterial drugs is an important subject of research in the field. It is urgently needed to find a novel antibacterial drug which can not only treat common fungal infection in a targeted manner, but also well inhibit bacterial infection, can weaken the toxicity of pathogenic bacteria on the premise of not inhibiting the growth of pathogenic bacteria, is used for treating fungal or bacterial infectious diseases and avoids the increase of drug-resistant strains.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a biphenyl diazole derivative and a preparation method and application thereof; in-vitro antibacterial activity tests show that the biphenyl diazole derivatives have stronger antibacterial activity and have greater research value in treating fungal infection or bacterial infection diseases.
In order to achieve the above object, the present invention provides biphenyl diazole derivatives represented by the general formula I as follows.
X in the general formula is C or N, preferably C.
Y in the general formula is carbonyl or methylene.
R in the general formula1Is hydrogen radical, halogen, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, or substituted by halogen (C)1-C6) Alkyl or (C)1-C6) An alkoxy group; preferably hydrogen, halogen, (C)1-C6) Alkyl or (C)1-C6) An alkoxy group.
The halogen is fluorine, chlorine, bromine or iodine; the alkyl group is a linear or branched alkyl group.
R in the general formula2Is hydrogen radical, halogen, amino, cyano, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, or substituted by halogen (C)1-C6) Alkyl or (C)1-C6) An alkoxy group; preferably hydrogen, halogen, (C)1-C6) Alkyl or (C)1-C6) An alkoxy group.
The halogen is fluorine, chlorine, bromine or iodine; the alkyl group is a linear or branched alkyl group.
The derivatives of general formula I according to the invention are preferably the following compounds, but these compounds are not meant to limit the invention in any way:
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] - (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-fluoro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-chloro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-methyl- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-fluoro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-methyl- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-trifluoromethyl- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-cyano- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 ', 4 ' -difluoro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2-fluoro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -3-chloro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-1,2, 4-triazol-1 yl) propan-2-yl ] - (1, 1' -biphenyl) -4-carboxamide.
N- [ (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine.
N- [4 '-fluoro- (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine.
N- [4 '-chloro- (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine.
In order to achieve another object of the present invention, the preparation method of the derivatives of formula I of the present invention is specifically as follows.
In the first case: when Y is carbonyl:
step 1, synthesizing an intermediate biphenyl acid.
P-bromobenzoic acid and various substituted phenylboronic acids are used as raw materials in Pd (PPh)3)4Under the action of the reaction, Suzuki coupling reaction is carried out to obtain various substituted biphenyl acids. The synthetic route is as follows.
The reagent and the condition are (a) Pd (PPh)3)4,K2CO3,reflux,5h。
And 2, synthesizing a target compound.
Histidinol 4 is used as a starting material, and is subjected to condensation reagents EDCI and HOBt with intermediate biphenyl acid 3 to obtain an amide intermediate 5, and the intermediate 5 is subjected to substitution reaction with imidazole under the action of CDI to obtain a target compound 6. The specific synthetic route is shown in the specification.
The reagent and the condition (a) EDCI, HOBt, DIEA, r.t.,7 h; (b) CDI, imidazole, CH3CN,reflux,7h。
When X is N, the synthetic route is as follows.
Taking the intermediate 5 as a raw material, firstly carrying out chlorination under the action of thionyl chloride to obtain an intermediate 7, and then carrying out substitution reaction with triazole to obtain the triazole compound.
Reagents and conditions (a) SOCl2,DMF,r.t.,2h;(b)1H-1,2,4-triazole,Triethylamine,DMF,r.t.10h.
In the second case: when Y is-CH2-time.
Using p-bromobenzaldehyde and various substituted phenylboronic acids as raw materials in Pd (PPh)3)4Under the action of the reaction, Suzuki coupling reaction is carried out to obtain various substituted biphenyl aldehydes. The synthetic route is as follows.
The reagent and the condition are (a) Pd (PPh)3)4,K2CO3,reflux,5h。
And 2, synthesizing a target compound.
Histidinol 4 is used as a starting material, and is subjected to reductive amination with an intermediate biphenyl aldehyde 10 to obtain an intermediate 11, and the intermediate 11 is subjected to substitution reaction with imidazole under the action of CDI to obtain a target compound 12. The specific synthetic route is shown in the specification.
Reagents and conditions (a) Na2SO4,NaBH(OAc)3;(b)CDI,imidazole,CH3CN,reflux,7h。
The invention has remarkable effect.
The in vitro antifungal activity experiment of the designed diazole compound shows that the diazole compound has better antifungal activity, so that the invention can be used for preparing various antifungal medicines, such as medicines for resisting candida, candida albicans, trichophyton rubrum, saccharomycete rubrum, cryptococcus neoformans, trichosporon schenckii, trichophyton caespitosum, trichophyton gypseum, rhizopus, aspergillus fumigatus and the like. In addition, in vitro antibacterial activity research experiments show that the compound has strong antibacterial activity, and bacterial infectious diseases to be targeted by the compound are staphylococcus, streptococcus, enterococcus, clostridium, bacillus, corynebacterium and listeria caused by gram-positive bacteria; can be used for treating bacterial infectious diseases such as pimple, osteomyelitis, brain abscess, urinary tract infection, meningitis, osteomyelitis, bronchitis, rhinitis, tetanus, diarrhea, pseudomembranous colitis, toxic megacolon; systemic infections (e.g., bacteremia, sepsis); specific infections caused by gram-negative bacteria, such as intra-abdominal infections and pulmonary infections (e.g., pulmonary infections in patients with cystic fibrosis).
The compound has better antifungal and antibacterial activity, and has the advantages of novel structure, high efficiency, broad spectrum and the like compared with the existing antibacterial drugs, so the compound has good application prospect.
Detailed Description
The present invention will be described in detail with reference to the following embodiments.
Example 1N- [1- (1H-imidazol-1-yl) -3- (1H-imidazol-4-yl) propan-2-yl ] - (1, 1' -biphenyl) -4-carboxamide.
Step 11, preparation of 1' -Biphenylformic acid (intermediate 3).
Under the protection of argon, 2.75g (13.8mmol) of 4-bromobenzoic acid, 2g (16.4mmol) of phenylboronic acid and K2CO32.71g (27.3mmol), 0.2g of palladium tetrakistriphenylphosphine were added to 40mL dioxane solvent/water (10:1), the temperature was raised to 75 ℃ and the reaction was monitored by TLC for completion after 5 h. The reaction solution was cooled, filtered, the pH was adjusted to 2-3, a large amount of white solid was produced, and filtered to give 2.30g of white solid in 84.9% yield. MS [ M + H ]]+(m/z):199.2。
Step 2 preparation of intermediate 5.
Dissolving intermediate 3(2g,10.1mmol), EDC & HCl 2.13g (11.1mmol) and HOBt 1.50g (11.1mmol) in 40mL DMF, stirring at room temperature for 1h, adding histidinol hydrochloride 1.82g (11.1mmol) and DIEA2.61g (26.2mmol), stirring at room temperature for 8h, TLC monitoring reaction completion, adding 30mL water, extracting with ethyl acetate, washing organic layer with saturated saline, Na2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 2.88g of a brown oil in 88.8% yield. ESI-MS [ M + H ]]+(m/z):322.4。
Step 3 preparation of N- [1- (1H-imidazol-1-yl) -3- (1H-imidazol-4-yl) propan-2-yl ] - (1, 1' -biphenyl) -4-carboxamide.
Intermediate 5(1.00g,3.11mmol), CDI 0.76g (4.67mmol) and imidazole 0.42g (6.22mmol) were dissolved in 30mL acetonitrile and reacted at 70 ℃ for 5h with TLC monitoring of reaction completion. Concentrating the reaction solution under pressure, dissolving the residue in ethyl acetate, washing with water, washing with saturated saline, and washing with Na2SO4Dry overnight. The drying agent was filtered off, and concentrated under reduced pressure to give a reddish brown oil, which was subjected to column chromatography to give an off-white solid (0.75 g, yield 64.9%).
LC-MS m/z[M+H]+372.2.1H-NMR(400MHz,DMSO-d6)δ13.23(s,1H),9.01(d,J=7.9Hz,1H),8.70(s,1H),7.92(d,J=8.3Hz,2H),7.82(d,J=8.3Hz,2H),7.76(s,1H),7.70(d,J=7.3Hz,2H),7.65(s,1H),7.52(t,J=7.5Hz,2H),7.42(t,J=7.3Hz,1H),7.25(s,1H),6.86(s,1H),4.95(m,J=18.7Hz,1H),4.77-4.37(m,2H),2.94-2.64(m,2H).
Examples 2-11 were prepared according to the procedure of example 1, using substituted biphenyl acids as starting materials, respectively, via coupling, condensation, substitution reactions, and the like.
EXAMPLE 2N- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-fluoro- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+390.2.1H-NMR(600MHz,DMSO-d6)δ13.24(s,1H),9.04(d,J=8.0Hz,1H),8.76(s,1H),7.90(d,J=8.4Hz,2H),7.80(s,1H),7.68–7.65(m,2H),7.63(s,1H),7.60(td,J=7.9,1.5Hz,1H),7.51–7.43(m,1H),7.36–7.33(m,2H),7.23(s,1H),6.87(s,1H),4.88(ddd,J=9.9,8.1,4.7Hz,1H),4.57(dd,J=14.1,4.7Hz,1H),4.42(dd,J=14.1,10.0Hz,1H),2.96-2.63(m,2H).
EXAMPLE 3N- [1- (1H-Imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-chloro- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+406.2.1H-NMR(400MHz,DMSO-d6)δ13.15(s,1H),9.01(d,J=7.9Hz,1H),8.74(s,1H),7.85(d,J=8.3Hz,2H),7.76(s,1H),7.64(s,1H),7.62–7.58(m,1H),7.55(d,J=8.4Hz,2H),7.49–7.41(m,3H),7.23(s,1H),6.86(s,1H),5.02–4.90(m,1H),4.79–4.74(m,1H),4.41(dd,J=14.0,9.9Hz,1H),2.95-2.64(m,2H).
EXAMPLE 4N- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-methyl- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+386.1.1H-NMR(400MHz,DMSO-d6)δ13.13(s,1H),8.99(d,J=7.9Hz,1H),8.70(s,1H),7.81(d,J=8.4Hz,2H),7.74(s,1H),7.72(d,J=1.0Hz,1H),7.64(s,1H),7.43(d,J=8.4Hz,2H),7.34–7.25(m,3H),7.23(s,1H),6.87(s,1H),4.99–4.93(m,1H),4.82–4.73(m,1H),4.39(dd,J=14.1,9.8Hz,1H),2.94-2.64(m,2H),2.24(s,3H),.
EXAMPLE 5N- [1- (1H-Imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-fluoro- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+390.2.1H-NMR(400MHz,DMSO-d6)δ13.15(s,1H),9.02(s,1H),8.76(s,1H),7.91(d,J=8.4Hz,2H),7.76(s,1H),7.69–7.68(m,2H),7.66(d,J=7.7Hz,1H),7.57(s,1H),7.50-7.35(m,3H),7.13(s,1H),6.86(s,1H),4.99–4.95(m,1H),4.55–4.37(m,2H),2.94-2.64(m,2H).
EXAMPLE 6N- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-methyl- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+386.2.1H-NMR(400MHz,DMSO-d6)δ(ppm):13.05(s,1H),8.96(d,J=7.9Hz,1H),8.76(s,1H),7.98(d,J=8.4Hz,2H),7.89(d,J=8.4Hz,2H),7.81(s,1H),7.76(m,2H),7.67-7.63(m,3H),7.22(s,1H),6.86(s,1H),4.99–4.94(m,1H),4.54–4.37(m,2H),2.94-2.64(m,2H),2.52(s,3H),.
EXAMPLE 7N- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-trifluoromethyl- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+340.2.1H-NMR(400MHz,DMSO-d6)δ13.23(s,1H),9.03(d,J=7.9Hz,1H),8.75(s,1H),8.00–7.82(m,8H),7.76(s,1H),7.64(s,1H),7.22(s,1H),6.85(s,1H),4.99–4.93(m,1H),4.52(dd,J=14.0,5.0Hz,1H),4.40(dd,J=14.0,9.8Hz,1H),2.94-2.64(m,2H).
EXAMPLE 8N- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-cyano- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+397.2.1H-NMR(400MHz,DMSO-d6)δ13.23(s,1H),9.02(d,J=7.9Hz,1H),8.73(s,1H),8.22(s,1H),8.08(d,J=8.4Hz,1H),7.75(s,1H),7.93–7.87(m,5H),7.72(t,J=7.8Hz,1H),7.67(s,1H),7.24(s,1H),6.85(s,1H),5.00-4.91(m,1H),4.82–4.74(m,1H),4.43(dd,J=14.0,9.8Hz,1H),2.94-2.62(m,2H).
EXAMPLE 9N- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 ', 4 ' -difluoro- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+408.2.1H-NMR(400MHz,DMSO-d6)δ13.24(s,1H),9.02(d,J=7.9Hz,1H),8.75(s,1H),7.89(d,J=8.3Hz,2H),7.76–7.54(m,5H),7.48–7.35(m,1H),7.28–7.18(m,2H),6.85(s,1H),4.99–4.92(m,1H),4.80–4.74(m,1H),4.39(dd,J=14.0,9.9Hz,1H),2.94-2.64(m,2H).
EXAMPLE 10N- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2-fluoro- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+390.1.1H-NMR(400MHz,DMSO-d6)δ13.23(s,1H),9.02(d,J=7.9Hz,1H),8.77(s,1H),7.74(s,1H),7.71-7.65(m,3H),7.63(s,1H),7.60(d,J=8.4Hz,2H),7.51(t,J=7.4Hz,2H),7.43(d,J=7.2Hz,1H),7.22(s,1H),6.86(s,1H),4.95(dt,J=12.5,6.2Hz,1H),4.84–4.71(m,1H),4.44(dd,J=14.0,9.8Hz,1H),2.93-2.61(m,2H).
EXAMPLE 11N- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -3-chloro- (1, 1' -biphenyl) -4-carboxamide
LC-MS m/z[M+H]+406.2.1H-NMR(600MHz,DMSO-d6)δ13.08(s,1H),9.01(d,J=7.9Hz,1H),8.77(s,1H),7.79(d,J=1.7Hz,1H),7.76–7.69(m,4H),7.63(s,1H),7.50(t,J=7.4Hz,2H),7.44(d,J=7.4Hz,1H),7.35(d,J=7.9Hz,1H),7.24(s,1H),6.90(s,1H),5.05–4.93(m,1H),4.78–4.69(m,1H),4.35(dd,J=14.1,9.7Hz,1H),2.86-2.59(m,2H).
EXAMPLE 12N- [1- (1H-imidazol-1-yl) -3- (1H-1,2, 4-triazol-1-yl) propan-2-yl ] - (1, 1' -biphenyl) -4-carboxamide
Intermediate 51.0g (3.11mmol) was dissolved in dry DMF and thionyl chloride 1.11g (9.33mmol) was slowly added dropwise at 0 ℃. Reacting at room temperature for 2H, adding 0.64g (9.33mmol) of 1H-1,2, 4-triazole and 0.94g (9.99mmol) of triethylamine, continuing to react at room temperature for 8H, detecting by TLC to finish the reaction, adding 40mL of water, extracting with ethyl acetate, washing the organic layer with saturated saline solution, and adding Na2SO4Dry overnight. The drying agent was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.52g of a white solid with a yield of 44.8%.
LC-MS m/z[M+H]+373.2.1H-NMR(600MHz,DMSO-d6)δ13.13(s,1H),8.98(d,J=7.8Hz,1H),8.76(s,1H),8.52(s,1H),7.99(s,1H),7.88(d,J=8.5Hz,2H),7.79(d,J=8.5Hz,2H),7.76–7.70(m,3H),7.54–7.47(m,2H),7.45–7.41(m,1H),4.99–4.92(m,1H),4.87–4.81(m,1H),4.65(dd,J=14.0,8.9Hz,1H),2.94-2.64(m,2H).
Example 13N- [ (1, 1' -Biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine
Step 11, 1' -Biphenylcarboxaldehyde (intermediate 10) preparation
Under the protection of argon, 2.55g (13.8mmol) of 4-bromobenzaldehyde, 2g (16.4mmol) of phenylboronic acid and K2CO32.71g (27.3mmol), 0.2g of palladium tetrakistriphenylphosphine were added to 40mL dioxane solvent/water (10:1), the temperature was raised to 75 ℃ and the reaction was monitored by TLC for completion after 5 h. The reaction solution was cooled, filtered, the pH was adjusted to 2-3, a large amount of white solid was produced, and filtered to give 2.24g of white solid in 89.1% yield. MS [ M + H ]]+(m/z):183.2。
Step 2 preparation of intermediate 11.
Dissolving intermediate 10(2g,11.0mmol) and histidinol hydrochloride 1.80g (11.0mmol) in anhydrous ethanol, adding anhydrous sodium sulfate (2.61g, 21.9mmol), stirring at room temperature for 2 hours, adding sodium triacetoxyborohydride (2.79g, 13.2mmol) into the reaction system, continuing to react at room temperature for 8 hours, monitoring the reaction completion by TLC, adding saturated ammonium chloride to stop the reaction, extracting with ethyl acetate, washing the organic layer with saturated saline solution, and Na2SO4Dry overnight. The drying agent was filtered off and concentrated under reduced pressure to give 2.76g of a brown oil in 81.8% yield. ESI-MS [ M + H ]]+(m/z):308.4。
Step 3 preparation of N- [ (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine.
Intermediate 11(1.00g,3.25mmol), CDI 0.79g (4.88mmol) and imidazole 0.44g (6.51mmol) were dissolved in 30mL acetonitrile and reacted at 70 ℃ for 5h with TLC monitoring of reaction completion. Concentrating the reaction solution under pressure, dissolving the residue in ethyl acetate, washing with water, washing with saturated saline, and washing with Na2SO4Dry overnight. Filtering to remove the drying agent, concentrating under reduced pressure to obtain reddish brown oily substance, and performing column chromatography to obtain off-white solid 0.73g, yield 62.8%. LC-MS M/z [ M + H ]]+358.4.1H-NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.01(d,J=7.9Hz,1H),8.70(s,1H),7.76(s,1H),7.65(s,1H),7.64(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.46(d,J=7.3Hz,2H),7.41(t,J=7.5Hz,2H),7.35(t,J=7.3Hz,1H),7.25(s,1H),6.86(s,1H),4.77-4.37(m,2H),4.15(m,1H),3.82-3.80(m,2H),2.94-2.64(m,2H).
Examples 14 and 15 were prepared according to the procedure for example 13, using substituted biphenylaldehydes as starting materials, respectively, via coupling, reductive amination, substitution reactions, and the like.
EXAMPLE 14N- [4 '-fluoro- (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine
LC-MS m/z[M+H]+376.4.1H-NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.01(d,J=7.9Hz,1H),8.70(s,1H),7.76(s,1H),7.65(s,1H),7.61(d,J=8.3Hz,2H),7.47(d,J=7.3Hz,2H),7.41(d,J=7.3Hz,2H),7.25(s,1H),7.13(t,J=8.5Hz,2H),6.86(s,1H),4.47-4.21(m,2H),4.18(m,1H),3.84-3.81(m,2H),2.90-2.74(m,2H).
EXAMPLE 15N- [4 '-chloro- (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine
LC-MS m/z[M+H]+392.9.1H-NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.01(d,J=7.9Hz,1H),8.70(s,1H),8.01(d,J=8.3Hz,2H),7.76(s,1H),7.65(s,1H),7.63(t,J=8.5Hz,2H),7.45(d,J=7.3Hz,2H),7.39(d,J=7.3Hz,2H),7.25(s,1H),6.86(s,1H),4.73-4.31(m,2H),4.11(m,1H),3.80-3.74(m,2H),2.95-2.62(m,2H).
Firstly, in vitro antifungal activity test.
The experimental method is as follows: positive control drugs, namely fluconazole and itraconazole; the test strains are respectively as follows: candida tropicalis, Candida albicans, Trichophyton rubrum, Cryptococcus neoformans, Trichophyton gypseum, Rhizopus and Aspergillus fumigatus.
1. A drug sensitivity test method for spore-forming filamentous fungi (refer to a 2003 edition drug sensitivity test scheme for spore-forming filamentous fungi published by the National Committee for Clinical Laboratory Standardization (NCCLS), and PDA culture medium is used as culture medium for culture and dilution).
(1) Preparing antifungal drug diluent, namely performing drug sensitivity detection by using a disposable sterile 96-well plate; for each test fungus, Potato Dextrose Agar (PDA) medium wells without antifungal drug were used as growth control wells; the diluent used was first aspirated, and a stock solution of drug was added to the first tube, followed by 2-fold dilution.
(2) Preparation of the fungus inoculation liquid: most fungi must be activated with Potato Dextrose Agar (PDA) medium at 35 ℃ for 7 days, and 1ml of 0.85% saline containing 0.01ml of Tween 20 is added to the colonies incubated for 7 days to prepare a suspension. Adjusting the concentration of the bacterial suspension by using a spectrophotometer; the A value (optical density value) of the aspergillus is adjusted to 0.10; adjusting the A value (optical density value) of the rhizopus to 0.15; after 50-fold dilution, a 2-fold final concentration of the inoculum suspension was obtained.
(3) Culturing: the 96-well plate is kept stand and incubated for 24-72 hours in an aerobic environment at 35 ℃, and the result is observed.
2. Yeast-like fungus susceptibility test method (refer to yeast susceptibility test protocol published by national Committee for standardization of clinical laboratory (NCCLS), culture medium for culture and dilution is SDA culture medium).
(1) Dilutions of antifungal agents were prepared by performing the test in sterile tubes of 13 × 100mm, and control tubes containing only the Sapaul Dextrose Agar (SDA) medium liquid medium and the test strain without antifungal agent.
(2) Preparing a strain inoculation liquid: all tested strains should be transferred at least 2 times on Sapaul glucose agar (SDA) broth to ensure their purity and growth power, and the culture temperature should be 35 ℃ throughout. 5 colonies of Candida cultivated over 24 hours with a diameter of more than 1mm should be selected and used at a ratio of 0.85%Making into suspension with saline, and adjusting the concentration to 1 × 106-5×106Cells/ml. at inoculation, they were diluted 2000-fold with Sapaul glucose agar (SDA) medium to a final bacteria concentration of 1.0 × 103-2.0×103cells/mL.
(3) Inoculation of liquid medium: 0.1mL of the gradient dilution of the antifungal drug is dispensed into numbered test tubes, and only 0.1mL of the dilution without the drug is added into a growth control tube; after the inoculum is adjusted, 0.9mL of inoculum is added to the corresponding tube and shaken up to dilute each gradient 10-fold and the medium 1.11-fold.
(4) Culturing: the test tube was incubated at 35 ℃ for 24 to 72 hours in an aerobic environment, and the results were observed. The results are shown in Table 1.
Table 1 results of antifungal activity test of the compounds in the examples of the present invention.
The derivatives 1 to 15 defined in the examples of the present invention all showed different degrees of in vitro inhibitory activity against the tested fungi, wherein the in vitro inhibitory activity of some compounds against some of the tested fungi was better than or equal to that of the positive control drugs (itraconazole, fluconazole).
Second, in vitro antibacterial Activity test
Test strains: staphylococcus aureus, escherichia coli, streptococcus pneumoniae.
(1) The antibacterial activity of the compounds of the present invention against staphylococcus aureus, escherichia coli, streptococcus pneumoniae was tested by broth microdilution.
Sterilized 96-well plates were opened under sterile conditions, and 200. mu.L of M-H broth containing the drug was added to well 1 to a final concentration of 32. mu.g/mL. The remaining 11 wells were filled with 100. mu.L of blank medium. Accurately sucking 100 mu L from the 1 st hole by using a pipette gun, adding the pipette gun into the second hole, blowing and uniformly mixing, sucking 100 mu L from the 2 nd hole to the 3 rd hole, and repeating the steps until reaching the 10 th hole, sucking 100 mu L after uniform mixing, and discarding. The drug concentration per well at this time was 64, 32, 16, 8, 4, 2, 1, 0.5. mu.g/mL. The last 2 wells contained no drug, one as bacterial growth control and one as negative control.
In the 96-well plate, 0.5. mu.L of 108CFU/mL of bacterial suspension was added to the first 11 wells to obtain a final inoculum size of about 105CFU/mL. The bacterium adding speed is as fast as possible, so that the phenomenon that the result judgment is influenced due to the fact that the bacterium growth time of each hole is inconsistent because of too long time is avoided. Each strain was tested in 3 replicates simultaneously. The whole process is finished beside the sterilized alcohol lamp of the superclean bench. Carefully handling to prevent contamination. And (3) putting the inoculated 96-well plate into a constant-temperature incubator at 37 ℃ for culturing for 16-20h, and observing and recording the result.
After the completion of the culture, the 96-well plate was taken out from the incubator, and the growth of bacteria in the well was observed. Before the results are determined, the results are meaningful only when the bacteria in the growth control wells grow normally and the negative control wells do not grow. The concentration of the drug in the wells with no bacterial growth was visually observed as the MIC of the drug against the bacteria. If the hole jumping phenomenon occurs, repeated tests are needed for verification. The results of the bacteriostatic activity test are shown in table 2.
Table 2 results of the test of the activity of the compounds of the present invention against conventional bacteria (MIC, μ g/mL).
And thirdly, performing subacute toxicity experiments on mice.
The compound of any of examples 1-15 of the present invention was suspended in an aqueous base containing 0.5% methylcellulose at a concentration of 10mL/kg and used in subacute toxicity experiments in which ICR mice (male, four weeks old, body weight about 25 g) were gavaged with a suspension of 10mg/kg to 50mg/kg of compound via a 1mL syringe equipped with a probe once a day for two weeks; until the minimum oral dose was 10mg/kg, the indicators such as the survival and the weight change of the internal organs, liver enzymes and liver were observed for two weeks, and no toxic symptoms were detected. It can be seen that the compounds defined in the present invention have very low toxic side effects.
Claims (6)
1. The biphenyl diazole derivative is characterized in that the diazole derivative is shown as a general formula I
X in the general formula is C or N;
y in the general formula is carbonyl or methylene;
r in the general formula1Is hydrogen, halogen, cyano, (C)1-C6) Alkyl, or substituted by halogen (C)1-C6) An alkyl group;
r in the general formula2Is hydrogen or halogen.
2. The biphenyl diazole derivative according to claim 1, wherein X in said formula is preferably C.
3. Biphenyldiazole derivatives, characterized in that said derivatives are selected from:
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] - (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-fluoro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-chloro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 '-methyl- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-fluoro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-methyl- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-trifluoromethyl- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -4 '-cyano- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2 ', 4 ' -difluoro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -2-fluoro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-yl ] -3-chloro- (1, 1' -biphenyl) -4-carboxamide;
n- [1- (1H-imidazol-1-yl) -3- (1H-1,2, 4-triazol-1-yl) propan-2-yl ] - (1, 1' -biphenyl) -4-carboxamide;
n- [ (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine;
n- [4 '-fluoro- (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine;
n- [4 '-chloro- (1, 1' -biphenyl) -4-methyl ] -1- (1H-imidazol-1 yl) -3- (1H-imidazol-4 yl) propan-2-amine.
4. Use of the biphenyldiazole derivative according to any one of claims 1-3, for the preparation of antifungal or antibacterial agents.
5. The use of claim 4, wherein the fungus comprises Candida, Candida albicans, Trichophyton rubrum, Cryptococcus neoformans, Trichophyton gypseum, Rhizopus or Aspergillus fumigatus.
6. The use according to claim 4, wherein the bacteria are gram-positive bacteria.
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