Synthesis of some novel nitrogen-containing 5α-steroids based on tigogenin

A number of nitrogen-containing compounds were obtained using a condensation reaction catalyzed by acetic acid to investigate structure-chemical reactivity and structure-biological activity relationships in the search for potential biologically active steroids within ketones of the 5α-pregnane and 5α-androstane series. Novel steroidal hydrazones were synthesized from 5α-pregnan-3β-ol-20-one and 5α-pregna-9(11),16-dien-3α-ol-20-one, which, in turn, were obtained by a multistep transformation of 3β-acetoxy-5α-pregn-16-en-20-one. All of the starting steroid ketones were synthesized on the basis of a convenient domestic raw material – tigogenin, isolated from the Yucca gloriosa plant introduced in Georgia. Acetic acid catalyzed condensation reaction was carried out in ethanol using various reagents with pharmacophoric features – arylhydrazides, arylhydrazines, hydroxylamine, and semicarbazide. The structure of the newly obtained steroids was confirmed by1 H,13 C NMR, mass spectra and investigation of their biological activity is in process. The cytotoxic and antiviral activity of the previously synthesized steroid oximes, amines and hydrazones was assessed

Synthesis and biological activity of hydrazones of 5α-steroids.

Condensation reactions catalyzed by acetic acid of severalarylhydrazine (2,4-dinitrophenyl hydrazine) and hydrazides (hydrazides of bromobenzoic and salicylic acid, benzofuran-2- and indol-2-carboxylicacid) with 3β-acetoxy- and 3β-hydroxy-5α-pregn-16-en-20-one (1 and 2), epiandrosterone (6) and 5α-androst-2-en-17- one (9) were studied for the purpose of synthesizing potentially bioactive 5-steroidal hydrazones. The starting ketones (1,2,6,9) were synthesized on the bases of aglicon of steroidal saponine - tigogenin isolated from plant “Yucca gloriosa” introduced in Georgia. The structures of synthesized new hydrazones (3-5,7,8,10,11) were established by NMR 1H, 13C and mass-spectral data. The antiviral activity some of them (7,8,10,11) were studied

Synthesis of some 5α-androstano[17,16-d]pyrazoles from tigogenin

Condensation reaction of several arylhydrazines with 16α, 17α-epoxy-5α-pregnan-3β-ol-20-one synthesized from 5α-pregn-16-en-3β-ol-20-one–intermediate product of tigogenin transformation – were studied for the purpose of synthesizing potentially bioactive 5α-androstano [17,16-d] pyrazoles. Despite various conditions (different temperature, in protic and aprotic solvents) of the reaction, a complex mixture was obtained and then separated by column chromatography (eluent-hexane-ethylacetate). Two main products of intermolecular cyclization: 5α-androstano [17,16-d] pyrazole and its hydrogenated analogue – 5α-androstano [17,16-d]pyrazolines were isolated by substitution of electron-donating group (phenylhydrazine, p-methyl-, p-bromophenylhydrazine) at the hydrazine amine atom. In the presence of electron-withdrawing group (p-nitrophenylhydrazine) at the hydrazine amine atom cis-opening product of epoxygroup – 16α-acetoxy-5α-pregnan-3β, 17α-diol-20-one hydrazine – was obtained. The structures of synthesized compounds were established by NMR1H,13C and mass-spectral data. Structures of 3β-hydroxy-1/-phenyl-3/-methyl-5α-androstano [17,16-d] pyrazoles were confirmed by IR, NMR1H,13C, DEPT-135, HMBC and mass-spectral data. Synthesis of 5α-androstano [17,16-d] pyrazolines with 5α-androstano [17,16-d] pyrazoles by condensation reactions in the mentioned conditions was not described previously

Synthesis of New 5α-Steroidal Hydrazones from Tigogenin

In the present study potentially biologically active steroids, new hydrazones, semicarbazones, and 20O-methyloxime have been synthesized from ketones of the 5α-pregnene, 5α-pregnane, and 5αandrostane series. The condensation reaction of ketones – 5α-pregn-16-en-3β-ol-20-one, 5α-pregnan3β-ol-20-one and 5α-androstan-3β-ol-17-one – with various arylhydrazides, semicarbazide, and methoxyamine was carried out in ethanol with a catalytic amount of acetic acid. The starting ketones were made from tigogenin, an aglycone of steroidal saponins that is a domestic raw material for the synthesis of 5α-series steroids. Tigogenin was isolated from the Yucca gloriosa plant, which was introduced in Georgia.1H,13C NMR and mass spectra were used to confirm the structure of the newly obtained steroids. The cytotoxicity of these and previously synthesized hydrazones was investigated in vitro using the Rezazurin reduction test and Hoechst test aginst lung carcinoma (A549), colorectal adenocarcinoma (DLD-1) and normal skin fibroblasts (WS-1) cell lines in comparison to etoposide. The results show that, of all the compounds studied, only p-methyl-and pmethoxybenzoylhydrazone 5α-pregnan-3β-ol-20-one are of particular interest since, unlike the others, they demonstrate activity comparable to etoposide

Synthesis and cytotoxicity of epiandrosterone hydrazones

Two series of hydrazones were synthesized from 3β-hydroxy- and 3β-(1-adamantoate)-5α-androstan-17- one, respectively, to study the structure–activity relationship. Cytotoxicity studies showed that 5α-androstan3β-ol-17-one m-nitrobenzoylhydrazone exhibited pronounced specific activity in a Hoechst experiment against lung carcinoma (A-549) and colorectal adenocarcinoma cell lines (DLD-1)

Synthesis and biological activity of steroidal tigogenin hydrazones and pyrazolines

Steroidal hydrazones and pyrazolines were synthesized via condensation of a series of 5α-steroidal ketones with several hydrazines. Their cytotoxic activity against cancer cultures (A549 lung cancer, DLD-1 colorectal cancer, and WS1 normal skin fibroblasts) and antibacterial activity against E. coli and S. aureus strains were studied. The structures of the synthesized compounds were elucidated using PMR, 13C NMR, and mass spectra

Antimicrobial Activity of Some Steroidal Hydrazones

Twelve steroid based hydrazones were in silico evaluated using computer program PASS as antimicrobial agents. The experimental evaluation revealed that all compounds have low to moderate antibacterial activity against all bacteria tested, except for B. cereus with MIC at a range of 0.37–3.00 mg/mL and MBC at 0.75–6.00 mg/mL. The most potent appeared to be compound 11 with MIC/MBC of 0.75/1.5 mg/mL, respectively. The evaluation of antibacterial activity against three resistant strains MRSA, E. coli and P. aeruginosa demonstrated superior activity of compounds against MRSA compared with ampicillin, which did not show bacteriostatic or bactericidal activities. All compounds exhibited good antifungal activity with MIC of 0.37–1.50 mg/mL and MFC of 1.50–3.00 mg/mL, but with different sensitivity against fungi tested. According to docking studies, 14-alpha demethylase inhibition may be responsible for antifungal activity. Two compounds were evaluated for their antibiofilm activity. Finally, drug-likeness and docking prediction were performed

Antimicrobial Activity of Some Steroidal Hydrazones

Twelve steroid based hydrazones were in silico evaluated using computer program PASS as antimicrobial agents. The experimental evaluation revealed that all compounds have low to moderate antibacterial activity against all bacteria tested, except for B. cereus with MIC at a range of 0.37–3.00 mg/mL and MBC at 0.75–6.00 mg/mL. The most potent appeared to be compound 11 with MIC/MBC of 0.75/1.5 mg/mL, respectively. The evaluation of antibacterial activity against three resistant strains MRSA, E. coli and P. aeruginosa demonstrated superior activity of compounds against MRSA compared with ampicillin, which did not show bacteriostatic or bactericidal activities. All compounds exhibited good antifungal activity with MIC of 0.37–1.50 mg/mL and MFC of 1.50–3.00 mg/mL, but with different sensitivity against fungi tested. According to docking studies, 14-alpha demethylase inhibition may be responsible for antifungal activity. Two compounds were evaluated for their antibiofilm activity. Finally, drug-likeness and docking prediction were performed

Antimicrobial Activity of Nitrogen-Containing 5-α-Androstane Derivatives: In Silico and Experimental Studies

We evaluated the antimicrobial activity of thirty-one nitrogen-containing 5-α-androstane derivatives in silico using computer program PASS (Prediction of Activity Spectra for Substances) and freely available PASS-based web applications (such as Way2Drug). Antibacterial activity was predicted for 27 out of 31 molecules; antifungal activity was predicted for 25 out of 31 compounds. The results of experiments, which we conducted to study the antimicrobial activity, are in agreement with the predictions. All compounds were found to be active with MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration) values in the range of 0.0005–0.6 mg/mL. The activity of all studied 5-α-androstane derivatives exceeded or was equal to those of Streptomycin and, except for the 3β-hydroxy-17α-aza-d-homo-5α-androstane-17-one, all molecules were more active than Ampicillin. Activity against the resistant strains of E. coli, P. aeruginosa, and methicillin-resistant Staphylococcus aureus was also shown in experiments. Antifungal activity was determined with MIC and MFC (Minimum Fungicidal Concentration) values varying from 0.007 to 0.6 mg/mL. Most of the compounds were found to be more potent than the reference drugs Bifonazole and Ketoconazole. According to the results of docking studies, the putative targets for antibacterial and antifungal activity are UDP-N-acetylenolpyruvoylglucosamine reductase and 14-α-demethylase, respectively. In silico assessments of the acute rodent toxicity and cytotoxicity obtained using GUSAR (General Unrestricted Structure-Activity Relationships) and CLC-Pred (Cell Line Cytotoxicity Predictor) web-services were low for the majority of compounds under study, which contributes to the chances for those compounds to advance in the development

Novel antimicrobial agents' discovery among the steroid derivatives.

Fourteen steroid compounds were in silico evaluated using computer program PASS as antimicrobial agents. The experimental studies evaluation revealed that all compounds have good antibacterial activity with MIC at range of 0.003-0.96 mg/mL and MBC 0.06-1.92 mg/mL. Almost all compounds except of compound 4 (3β-acetoxy-1/-p-chlorophenyl-3/-methyl-5α-androstano[17,16-d]pyrazoline) were more potent than Ampicillin, and they were equipotent or more potent than Streptomycine. All compounds exhibited good antifungal activity with MIC at 0.003-0.96 mg/mL and MFC at 0.006-1.92 mg/mL but with different sensitivity against fungi tested. According to docking studies 14-alpha demethylase inhibition may be responsible for antifungal activity. Prediction of toxicity by PROTOX and GUSAR revealed that compounds have low toxicity and can be considered as potential lead compounds for the further studies