Synthesis and antimicrobial properties of 17β-amino-4-aza-5α-androstane and derivatives

Solomons, William E.; Doorenbos, Norman J.

doi:10.1002/jps.2600630105

Cited by 25 publications

(9 citation statements)

References 14 publications

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“…The 17ß-[ -( 1 '-ethylpropyljamino] analogue 20 (0.14 g, 57% yield) was prepared from the 3,17-dione 5 (0.20 g, 0.66 mmol) by method B: mp 135-137 °C; IR (KBR, cm"1) 3320, 2906, 2844, 1624, 1448, 1382, 1352, 1294, 1220, 1094, 1024; NMR (CDC13) 0.64 (s, 3 H, 18-CH3), 0.69-0.72 (m, 1 ), 0.79 (dd, J = 6.8, 7.3 Hz, 3 H, 3'-CH3), 0.81 (dd, J = 3.6, 4.9 Hz, 3 H, 3'-CH3), 0.82 (s, 3 H, 19-CHs), 0.86-1.19 (m, 2 ), 1.21-1.39 (m, 12 ), 1.48-1.54 (m, 2 ), 1.71-1.83 (m, 3 ), 1.93 (dd, J = 3.3, 8.7 Hz, 2 H), 2.35 (dd, J = 5.1, 6.0 Hz, 1 H), 2.37 (dd, J = 4.6, 9.7 Hz, 2 H), 2.53 (t, J = 8.3 Hz, 1 , 17a-H), 2.86 (s, 3 H, 4-NCH3), 2.96 (dd, J = 3.5,12.5 Hz, 1 , 5a-H), 6.15 (br s, 1H, 17/3-NH); 13C NMR (CDCls) <5170.6, 65.6, 58.4, 52.7, 52.1, 50.4, 42.8, 37.6, 36.3, 34.3, 33.8, 30.3, 30.2, 29.8, 29.0, 26.5, 26.4, 25.2, 23.4, 20.7, 12.3, 11.6, 10.0, 9.9; EI-MS m/s (rel intensity) 374 (M+, 8), 359 (5), 345 (60), 331 (32), 315 (16), 305 (30), 288 (27), 138 (18), 126 (89), 112 (48), 98 (66), 84 (52), 70 (100); HRMS caled for C24H42O1N2 374.3296, found 374.3272. 17/8-(jV-Cyclopropylamino)-4-methyl-4-aza-5a-androstan-3-one (21). The 17/9-tiV-cyclopropylamino) analogue 21 (1.70 g, 99% yield) was prepared from 3,17-dione 5 (1.5 g, 4.95 mmol) by method A: mp 165-167 °C; IR (KBr, cm"1) 3292, 2924, 2842,1654,1436,1402,1381,1226,1094; NMR (CDC13) 0.27 (dd, J = 3.5, 7.2 Hz, 2 ), 0.36 (d, J = 6.6 Hz, 2 ), 0.67 (s, 3 H, 18-CH3), 0.85 (s, 3 H, 19-CHs), 0.94 (ddd, J = 2.1, 3.4, 5.2 Hz, 2 ), 1.10-1.50 (m, 8 ), 1.52-1.75 (m, 3 ), 1.78-2.08 (m, 5 ), 2.09-2.15 (m, 1 ), 2.40 (dd, J = 4.7, 10.2 Hz, 2 H), 2.62 (t, J = 8.6 Hz, 1 , 17a-H), 2.89 (s, 3 H, 4-NCH3), 2.99 (dd, J = 3.6, 12.3 Hz, 1 H, 5a-H), 5.87 (br s, 1 H, 17/3-NH); 13C NMR (CDCls) 170.7, 68.9, 65.7, 52.7, 52.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and in Vitro Activity of 17.beta.-(N-Alkyl/arylformamido and N-alkyl/arylalkyl/arylamido)-4-methyl-4-aza-3-oxo-5.alpha.-androstan-3-ones as Inhibitors of Human 5.alpha.-Reductases and Antagonists of the Androgen Receptor

Li¹,

Singh²,

Labrie³

1995

J. Med. Chem.

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A number of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza-5 alpha-steroids were prepared from 17 beta-hydroxy-4-azasteroids and evaluated as inhibitors of human 5 alpha-reductase and antagonists of the androgen receptor. Jones' oxidation of 17 beta-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc)3/NaBH3CN to give 17 beta-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH4. Formylation of amines 10-27 gave 17 beta-(N-alkylformamides) 28-41; however, acylation afforded 17 beta-[(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; IC50 = 4.15 nM), 17 beta-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5 alpha-reductase, IC50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type I enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC50s = 9.57 and 16.9 nM, respectively), showed also strong inhibitory activity (IC50s = 14.0 and 18.4 nM, respectively) for human type II 5 alpha-reductase, in comparison to N-(1',1'-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (MK-906; IC50 = 4.53 nM). Other compounds in this series showed moderate activities (IC50 > 100 nM) on the type II enzyme. 17 beta-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5 alpha-reductase with IC50s of 1.77, 2.42, 2.93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100 < IC50s < 1000 nM), except for compound 48 (IC50 = 3.75 nM). In another substitution pattern, N-aryl/alkylamides were studied; an electron-donating group increased the potency of compound 51, whereas an electron-withdrawing group decreased the potency of compounds 52 and 53 compared to parent compound 50. In addition to their 5 alpha-reductase activities, 17 beta-(N-alkylformamides) were also studied for their inhibitory activities on dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107).(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Methodsmentioning

confidence: 99%

Synthesis and in Vitro Activity of 17.beta.-(N-Alkyl/arylformamido and N-alkyl/arylalkyl/arylamido)-4-methyl-4-aza-3-oxo-5.alpha.-androstan-3-ones as Inhibitors of Human 5.alpha.-Reductases and Antagonists of the Androgen Receptor

Li¹,

Singh²,

Labrie³

1995

J. Med. Chem.

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“…The synthesized compounds were tested for their antimicrobial activity against gram positive and gram negative bacteria as well as some fungal-plants. The sensitivity of the selected microorganisms towards the compounds under investigation was determined in vitro culture dissolved in chloroform, Appling the filter paper and hole plate method [ 39 ]. The sterile filter paper disc was saturated with 10 μL of 0.5 mg ml −1 w/v solution of the compound under investigation in DMF.…”

Section: Methodsmentioning

confidence: 99%

Regioselectivity of 1,3-dipolar cycloadditions and antimicrobial activity of isoxazoline, pyrrolo[3,4-d]isoxazole-4,6-diones, pyrazolo[3,4-d]pyridazines and pyrazolo[1,5-a]pyrimidines

Zaki

Sayed

Elroby

2016

Chemistry Central Journal

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BackgroundIsoxazoles exhibit interesting biological activities, and the 1,3-dipolar cycloaddition(13DC) reactions play an important role in both mechanistic and synthetic organic chemistry. Pyrazoles and annulated pyrazoles exhibit some diverse biological activities. They are used as antipyretic, analgesic drugs, tranquilizing, and herbicidal agents. Pyrazoles are also used extensively as useful synthons in organic synthesis. Pyrazolo[3,4-d]pyridazines showed good antimicrobial, anti-inflammatory and analgesic activities. Several oximes are found to be hyperglycemic, anti-neoplastic, anti-inflammatory, anti-leishmanial and VEGFR-2 kinase inhibitors.ResultsThe present work describes an efficient synthesis protocol and molecular orbital calculations of isoxazoline and pyrrolo[3,4-d]isoxazole-4,6-dione derivatives from the reaction of hydroximoyl chloride with acrylonitrile, acrylamide, and N-arylmalemides. In addition, pyrazoles and pyrazolo[3,4-d]pyridazines are obtained via the reaction of 3-(dimethylamino)-1-(2,4-dimethyl-1,3-thiazol-5-yl)prop-2-ene-1-one with hydrazonoyl halides. Pyrazolo[1,5-a]pyrimidines were derived from condensation of either Sodium Salt of 3-Hydroxy-1-(2,4-dimethylthiazol-5-yl)prop-2-en-1-one (10) or 3-(dimethylamino)-1-(2,4-dimethyl)(1,3-thiazol-5-yl)prop-2-en-1-one (11) with aiminopyrozoles. A comparative study of the biological activity of the synthesized compounds with ampicillin and tetracycline is compiled in Table 3. Generally, all synthesized compounds showed an adequate inhibitory efficiency of growth of gram-positive and gram-negative bacteria. Structures of the newly synthesized compounds were elucidated by elemental analysis, spectral data and a computational study.ConclusionsIn summary, new and efficient synthetic routes of isoxazoline, pyrrolo[3,4-d]isoxazole-4,6-dione derivatives, pyrazoles, pyrazolo[3,4-d]pyridazines and pyrazolo[1,5-a]pyrimidines have been achieved and the biological activity has been investigated.Graphical abstractNew and efficient synthetic routes of isoxazoline, pyrrolo[3,4-d]isoxazole-4,6-dione derivatives, pyrazolo[3,4-d]pyridazines and pyrazolo [1,5-a] pyrimidines

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“…Studies of the biological activities of steroidal heterocycles revealed that the fusion of a heterocyclic ring to the 2,3-position of various steroids was effective in the production of a variety of compounds possessing anabolic [1,2], anti-inflammatory [3,4], antiprogestational [5], contraceptive [6] and anticancer [7,8] properties, also several steroid derivatives are well authenticated to have antimicrobial activity versus many species of bacteria and fungi [9,10]. In view of these observations and in continuation of studies involving the synthesis of novel modified steroids [11Ϫ13], we have synthesized some steroidal heterocyclic derivatives using 5α-cholestan-3-one (1) as starting material and the antimicrobial activities of the new synthesized compounds against a wide spectrum of gram positive, gram negative bacteria and fungi were studied.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antimicrobial Evaluation of Some Novel Cholestane Heterocyclic Derivatives

Elmegeed

Wardakhan

Younis

et al. 2004

Archiv der Pharmazie

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This study was performed to investigate the reactivity of 5alpha-cholestan-3-one (1) towards various chemical reagents to produce new steroidal heterocyclic derivatives. The aminothieno[2, 3:2, 3]cholestane derivative 2 was synthesized according to Gewald's conditions. The diazonium salt of compound 2 coupled with malononitrile to afford dicyanomethylenhydrazinothieno[2', 3':2, 3]cholestane derivative 5. The behavior of compound 5 towards nitrogen nucleophiles and several active methylene reagents was investigated. Additionally, a variety of steroidal heterocyclic derivatives like compounds 15a, b-22a, b were synthesized starting with 5alpha-cholestan-3-one (1). The structures of the compounds were established based on the analytical and spectral data. The in vitro antimicrobial activity of some newly synthesized compounds against bacteria and fungi was studied.

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Synthesis and antimicrobial properties of 17β-amino-4-aza-5α-androstane and derivatives

Cited by 25 publications

References 14 publications

Synthesis and in Vitro Activity of 17.beta.-(N-Alkyl/arylformamido and N-alkyl/arylalkyl/arylamido)-4-methyl-4-aza-3-oxo-5.alpha.-androstan-3-ones as Inhibitors of Human 5.alpha.-Reductases and Antagonists of the Androgen Receptor

Synthesis and in Vitro Activity of 17.beta.-(N-Alkyl/arylformamido and N-alkyl/arylalkyl/arylamido)-4-methyl-4-aza-3-oxo-5.alpha.-androstan-3-ones as Inhibitors of Human 5.alpha.-Reductases and Antagonists of the Androgen Receptor

Regioselectivity of 1,3-dipolar cycloadditions and antimicrobial activity of isoxazoline, pyrrolo[3,4-d]isoxazole-4,6-diones, pyrazolo[3,4-d]pyridazines and pyrazolo[1,5-a]pyrimidines

Synthesis and Antimicrobial Evaluation of Some Novel Cholestane Heterocyclic Derivatives

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