8-Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis

There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8-hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure–activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8-hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of <5 μM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub-family of 2-styryl-substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC₅₀ of <100 μM). Further development of this series as antitubercular agents should address the cytotoxicity liability. However, the 8-hydroxyquinoline series represents a useful tool for chemical genomics to identify novel targets in M. tuberculosis.     

Enkephalin-degrading enzyme inhibitors Crucial role of the C-terminal residue on the inhibitory potencies of retro-hydroxamate dipeptides

The retro-inversion of the amide bond in kelatorphan and analogs, the first series of complete inhibitors of enkephalin metabolism, led to compounds highly efficient only against the neutral endopeptidase 24-11 (NEP). In order to increase the recognition of the aminopeptidase N (APN) and dipeptidylaminopeptidase (DAP), without loss of affinity for NEP, the malonyl group of these retro-inhibitors was replaced by diversely substituted succinyl moieties. All the molecules synthesized are highly efficient NEP inhibitors with K_i's in the 0.2–1 nM range, indicating that NEP possesses a relatively large and not very selective S₂’subsite. In contrast, inhibition of DAP activity is crucially dependent on the size and the position of the substituent in the succinyl moiety. Inhibitory potencies in the nanomolar range are obtained with compounds containing a benzyl group in the α-position related to thc rctro amide bond. Finally, a relatively modest inhibition of APN was observed with K_i's in the 0.5-1 μM range for compounds with benzyl or cyclohexyl group in P₂'position. However, these data demonstrate that efficient and complete inhibition of enkephalin degradation can be obtained with hydroxamate dipeptides containing a retro amide bond. The analgesic potency of the most active inhibitors was measured using the hot plate test in mice. Significant antinociceptive responses were obtained but these effects were rather weaker than those expected from the in vitro inhibitory potencies of these compounds on the three enkephalin-degrading enzymes.     

“Vinylogs” and “Acetylenylogs” of β-Adrenergic Agents

Vinylogous (Groups III and V ) and acetylenologous (Group IV ) analogs of the classical β-adrenergic agents — stimulants and blockers — were prepared in order to evaluate the effect of degree of saturation, position of unsaturation and rigidity of the chain linking the aromatic ring and the amino containing functional group on biological activity. Derivatives from Group III , which represent 4-aryl-3-butenyl-2-ol-amine analogs of Group II , retained β₁-adrenoceptor antagonist activity albeit substantially less potent (50–200-fold) than that possessed by their aryloxy counterparts. Consistent with the SAR for Group II compounds, substitution at position 2 of the aromatic ring yielded the most potent antagonists ( 5a, 5d, 5g ), with K_B's ranging from 73–93 nM while 3,4-dichloro substitution ( 5e ) markedly reduced antagonist potency (K_B = 2,400 nM). Agonist activity was also noted for 5b and 5d , suggesting that these compounds may be best classified as partial agonists. Representatives from Groups IV and V were inactive as antagonists at the β₁-adrenoceptor confirming the importance of the spatial relationship between the hydroxyl and the amino nitrogen.     

Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5

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New Arylpiperazines with Flexible versus Partly Constrained Linker as Serotonin 5‐HT1A/5‐HT7 Receptor Ligands

A series of new long‐chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5‐HT_1A and 5‐HT₇ receptor ligands. The compounds were prepared by a two‐step procedure using naphthalimide and 2H‐1,3‐benzoxazine‐2,4(3H)‐dione as imides, and 1‐(2‐methoxyphenyl)piperazine (o‐OMe‐PhP) and 1,2,3,4‐tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta‐ and hexamethylene chains as well as partly constrained m‐ and p‐xylyl moieties. In general, the new compounds were more active at the 5‐HT_1A than at the 5‐HT₇ receptor, and the o‐OMe‐PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o‐OMe‐PhP series, except for a small binding reduction for ligands containing the m‐xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure–activity relationship was visible only for the interaction of the compounds with the 5‐HT₇ receptor, which strongly favored flexible analogs.     

Design,synthesis, antileishmanial,and antifungal biological evaluation of novel 3,5-disubstituted isoxazole compounds based on 5-nitrofuran scaffolds

Nineteen 3,5-disubstituted-isoxazole analogs were synthesized based on nitrofuran scaffolds, by a [3 + 2] cycloaddition reaction between terminal acetylenes and 5-nitrofuran chloro-oxime. The compounds were obtained in moderate to very good yields (45–91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p–r were active on both the promastigote and amastigote forms, with emphasis on compound 14p , which showed strong activity against the amastigote form (IC₅₀ = 0.6 μM and selectivity index [SI] = 5.2). In the alkyl series, compound 14o stands out with an IC₅₀ = 8.5 μM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron-donor groups, such as trimethoxy isoxazole 14g (IC₅₀ = 1.2 μM and SI = 20.2); compound 14h , with IC₅₀ = 7.0 μM and SI = 6.1; and compound 14j containing the 4-SCH₃ group, with IC₅₀ = 5.7 μM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration [MIC] = 3.4 μM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 μM for C. glabrata, lower than that of the fluconazole used as the reference drug.     

Synthesis and Comparative Study of Anti‐Mycobacterium Activity of a Novel Series of Fluoronitrobenzothiazolopyrazoline Regioisomers

In an attempt to find a new and a safer drug for tuberculosis, we have synthesized a series of fluoronitrobenzothiazolopyrazolines for antitubercular activity. The series comprises three subclasses: fluorobenzothiazolopyrazolines ( 11a–f ), fluoronitrobenzothiazolopyrazoline, nitro group at 5^th position ( 12a–f ) and 4^th position ( 13a–f ). All compounds were screened for their in‐vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain by using Middlebrook 7H‐9 broth. An introduction of ? NO₂ group at 5^th position of benzothiazole ring ( 12a–f ) increased the antitubercular activity whereas introduction of ? NO₂ group at 4^th position ( 13a–f ) was found to decrease the activity remarkably. Two compounds from each series showing good antitubercular activity were tested for cytotoxicity on THP‐1 cell lines and they showed low cytotoxicity.     

Amino Acid Derivatives,Part 4: Synthesis and Anti‐HIV Activity of New Naphthalene Derivatives

A new series of 2‐(naphthalen‐2‐yloxy)‐N‐[(aryl‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐triazol‐3‐yl)methyl] acetamides 5a–f was synthesized from naphthalene‐derived glycine derivative 2 via the hydrazinoacetamide analogs 4a–f . Alternatively, treatment of 4a with H₂SO₄ afforded 2‐(naphthalen‐2‐yloxy)‐N‐((5‐(phenylamino)‐1,3,4‐thiadiazol‐2‐yl)methyl) acetamide 6a . Alkylation or sulphonylation of 5a afforded the S‐alkylated derivatives 7 and 8 , respectively. Interestingly, treatment of 3 with methoxide ion gave the triazine derivative 9 . The synthesized compounds have been screened for their inhibitory activity against HIV‐1 and HIV‐2 in MT‐4 cells. However, 7 was found to be the potent inhibitor in vitro for the replication of HIV‐1 (EC₅₀ = 0.20 μg/mL), suggesting a new lead in the development of an antiviral agent.     

Topical Delivery of 5-Fluorouracil and 6-Mercaptopurine by Their Alkylcarbonyloxymethyl Prodrugs from Water: Vehicle Effects on Design of Prodrugs

Purpose. To determine whether the fluxes through hairless mouse skin for three homologous series of prodrugs of 5-fluorouracil (5-FU, 1) and 6-mercaptopurine (6-MP, 2) from saturated aqueous suspensions show dependencies on aqueous (S _AQ) and isopropyl myristate (S _IPM) solubilities similar to those shown by the identical compounds delivered from IPM. Methods. Flux through hairless mouse skin from water (J _MAQ) and solubility data were measured for a homologous series of six 3-alkylcarbonyloxymethyl (ACOM) prodrugs of 5-FU (3-ACOM-5-FU), and five 6-ACOM-6-MP prodrugs, then combined with literature data for five bis-6,9-ACOM-6-MP prodrugs to give a data base. Multiple linear regression using SPSS 7.5 was performed on log S _IPM, log S _AQ, molecular weight and log J _MAQ data to determine the best fit coefficients to the transformed Potts-Guy equation: log J _MAQ = x + y log S _IPM + (1 - y) log S _AQ + z MW. Permeability coefficients (P _MAQ) were calculated from J _MAQ/S _AQ. Results. The best fit coefficients for the flux from AQ(J _MAQ)were x = -1.497, y = 0.660 and z = -0.00469 (r ² = 0.765) with an average error of prediction equal to 0.193 log units. The best fit coefficients for the flux from IPM (J _MIPM) were x = -0.557, y = 0.536 and z = -0.00261 (r ² = 0.941) with an average error of prediction equal to 0.109 log units. For all three series, log P _MAQ increased whereas log P _MIPM decreased with increasing alkyl chain lengths in the promoiety and with decreasing solubility parameter values. Conclusions. The transformed Potts-Guy equation can be used to predict J _MAQ but with less certainty than J _MIPM. S _IPM and S _AQ have consistently been shown to have a positive influence on J _MIPM, and now on J _MAQ, with a balance between the two solubilities being obviously important. The previous observation that log P _MAQ increased with lipophilicity is an artifact of normalizing J _MAQ by S _AQ.     

Structure–activity study of fluorine or chlorine-substituted cinnamic acid derivatives with tertiary amine side chain in acetylcholinesterase and butyrylcholinesterase inhibition

In this study, a series of new fluorine or chlorine-substituted cinnamic acid derivatives that contain tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results show that almost all the derivatives containing tertiary amine side chain (compounds 4a–9d ) exhibit moderate or potent activity in AChE inhibition. By contrast, their parent compounds (compounds 3a–3f ) in the absence of tertiary amine moitery exhibit poor inhibitory activity against AChE. For the compounds containing pyrroline or piperidine side chain, the bioactivity in AChE inhibition is much intense than those containing N,N-diethylamino side chain. The chlorine or fluorine substituted position produces a significant effect on the bioactivity and selectivity in AChE inhibition. Most of the compounds that contain para-substituted fluorine or chlorine exhibit potent activity against AChE and poor activity against BChE, while ortho-substituted analogs show the opposite effect. It is worth noticing that the compounds containing N,N-diethylamino side chain are exceptions to this pattern. Among the newly synthesized compounds, compounds 6d are the most potent in AChE inhibition (IC₅₀ = 1.11 ± 0.08 μmol/L) with high selectivity for AChE over BChE (selectivity ratio: 46.58). An enzyme kinetic study of compounds 6d suggests it produces a mixed-type inhibitory effect in AChE.     

Thiazolyl‐N‐substituted amides: A group of effective anti‐inflammatory agents with potential for local anesthetic properties. Synthesis,biological evaluation,and a QSAR approach

A series of thiazolyl‐N‐substituted amides were synthesized and tested for anti‐inflammatory activity. Their R_M values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and log D_7.4 was also performed. The effect of the synthesized compounds on inflammation, using the carrageenan‐induced mouse paw edema model was studied. In general, the studied compounds were found to be potent anti‐inflammatory agents (23.2–72.1%). Anti‐inflammatory activity was influenced by some structural characteristics of the synthesized compounds. An attempt was made to correlate their biological activity with some physicochemical parameters using a quantitative structure–activity relationship approach (QSAR). A parabolic dependence of activity from clog D_7.4 and a linear dependence from surface tension were found. The anti‐inflammatory activity of the thiazolyl‐amides were found to a great extent to be under pharmacokinetic control. Drug Dev. Res. 48:53–60, 1999. © 1999 Wiley‐Liss, Inc.     

Synthesis,In Vitro Antimicrobial and Antioxidant Activities of Some New 4,5‐Dihydro‐1H‐1,2,4‐triazol‐5‐one Derivatives

A series of compounds derived from 4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐one were synthesized and characterized by spectral data. The 12 new compounds were analyzed for their potential in vitro antioxidant activities by three different methods. Compound 4f showed the best activity for the iron binding. In addition, the compounds 4 were titrated potentiometrically with tetrabutylammonium hydroxide in non‐aqueous solvents. The RP‐HPLC capacity factors (k′) of the series were also determined on a C18 column, with methanol/water as the mobile phase. The correlation between log k′ with the percentage of methanol in the mobile phase was used for the determination of the log k_w values for these compounds. The antimicrobial activities of these compounds were also screened against bacteria and yeast.     

Design,synthesis, evaluation,and molecular modeling studies of indolyl oxoacetamides as potential pancreatic lipase inhibitors

A series of indolyl oxoacetamide analogs was synthesized, characterized, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (type II) and 4-nitrophenyl butyrate. Compound 8d exhibited a potent inhibition, with an IC₅₀ value of 4.53 µM, followed by 8c (IC₅₀ = 5.12 µM), compared with the standard drug, orlistat (IC₅₀ = 0.99 µM). Furthermore, analogs 8c and 8d exhibited a reversible competitive inhibition, similar to orlistat. Molecular docking studies of the compounds 7a–f and 8a – f were in agreement with the in vitro results, wherein 8d exhibited a potential MolDock score of −163.052 kcal/mol. A 10-ns molecular dynamics simulation of 8d complexed with pancreatic lipase confirmed the role of π–π stacking and π–cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation ≈ 2 Å). The present study led to the identification of novel indolyl oxoacetamides ( 8a – d ) as potential pancreatic lipase inhibitory leads that might further result in enhanced potency through lead optimization.     

Evaluation of New Indole and Bromoindole Derivatives as pp60c‐Src Tyrosine Kinase Inhibitors

A series of N‐benzyl‐indole‐3‐imine‐, amine derivatives and their 5‐bromo congeners were synthesized and their biological activity were evaluated against the pp60^c‐Src tyrosine kinase target. To afford the imine derivatives, aldehydes were reacted with substituted benzylamines and the corresponding amine derivatives were obtained by NaBH₄ reduction of these imines. Except insoluble N‐benzyl‐indole‐3‐imine derivatives, all the derivatives showed some activity against the kinase target. Screening of these compounds for their biological activity revealed that among N‐benzyl‐indole derivatives, those bearing 5‐bromo substitution have the enhanced potency, where the amine derivatives were more active than imines.     

Synthesis and pp60c‐Src Tyrosine Kinase Inhibitory Activities of Novel Indole‐3‐Imine and Amine Derivatives Substituted at N1 and C5

A series of novel 1,3,5‐trisubstituted indole derivatives, namely, N‐benzyl 5‐phenyl indole‐3‐imine, N‐benzyl‐5‐(p‐fluorophenyl)indole‐3‐imine and their corresponding amine congeners, were designed and synthesized as pp60^c‐Src tyrosine kinase inhibitors, and their inhibitory activities toward pp60^c‐Src tyrosine kinase were evaluated by in‐vitro kinase assay. Pre‐screening at two doses of compounds against kinase target revealed that, except for the N‐benzyl‐5‐phenyl indole imine derivatives 7a – 7d , all indole derivatives show the target inhibition at varying levels. Consequently, the compounds, 8c , 8f , 8g , and 8h , were selected for prescreening tests. The dose‐response curves for up to six concentrations (250 to 7.8 μM) of the active compounds were obtained by tyrosine kinase assay and the four‐parameter logistic analysis of these data resulted in the IC₅₀s of 4.69, 74.79, 75.06, and 84.23 μM for compounds 8c , 8f , 8g , and 8h , respectively. Therefore, compound 8c , 1‐(1‐benzyl‐5‐phenyl‐1H‐indole‐3‐yl)‐N‐(4‐fluorobenzyl)methanamine·HCl, was the promising inhibitor for pp60^c‐Src, followed by compounds 8g and 8h . Under the same conditions, compound 8f did not provide any reasonable inhibition pattern to be considered as active compound. Therefore, among all four active compounds, compound 8f was not found suitable for further analysis.     

Syntheses,calcium channel modulation effects,and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates

A group of racemic 4‐aryl(heteroary)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxy‐lates possessing a potential nitric oxide donor C‐5 O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester [alkyl=(CH₂)_n, n=1–4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C‐4 2‐trifluoromethylphenyl ( 16 ), 2‐pyridyl ( 17 ), or benzofurazan‐4‐yl ( 20 ) substituent generally exhibited more potent smooth‐muscle calcium channel antagonist activity (IC₅₀ values in the 0.55 to 38.6 μM range) than related analogs having a C‐4 3‐pyridyl ( 18 ), or 4‐pyridyl ( 19 ) substituent with IC₅₀ values > 29.91 μM, relative to the reference drug nifedipine (IC₅₀=0.0143 μM). The point of attachment of C‐4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2‐pyridyl > 3‐pyridyl and 4‐pyridyl. Subgroups of compounds 16a–d , 17a–d , and 20a–d having alkyl spacer groups of variable chain length [–CO₂(CH₂)_nO–, n=1–4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester “methyl” moiety of Bay K 8644 by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate group provided the Bay K 8644 group of analogs 16a‐d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O²‐ethyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)pyridine‐5‐carboxylate ( 16b , EC₅₀=0.096 μM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC₅₀=0.77 μM). A similar replacement of the ester “isopropyl” group in the C‐4 benzofurazan‐4‐yl group of compounds by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester substituent provided compounds 20 (n=1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202‐791 ( 3 , EC₅₀=9.40 μM). The O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester moiety present in 1,4‐dihydropyridine calcium channel modulating compounds 16–20 is not a suitable ?NO donor moiety because the percent nitric oxide released upon in vitro incubation with either l ‐cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res. 60:204–216, 2003. © 2003 Wiley‐Liss, Inc.     

Synthesis and structure activity study of N‐1 substituted (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins as potential anticonvulsant agents

A series of (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins with various N‐1 substituents were synthesized and tested for anticonvulsant activity to better understand the structure–activity relationship (SAR) of 2‐iminohydantoins. Compounds with N‐1 phenoxycarbonyl (2), ethoxycarbonyl (6), t‐butoxycarbonyl (7), propoxycarbonyl (12), and p‐methyl phenoxycarbonyl (14) groups provided the most substantial anticonvulsant activity against the maximal electroshock seizure (MES) test with ED₅₀ values in the range of 72–124 mg/kg. All of the above compounds except 7 also showed activity against the pentylenetetrazol (PTZ) test with ED₅₀ values in the range of 65–178 mg/kg. Compound 6 provided the highest protective index (PI) value against the PTZ test, while 7 provided the highest PI value against the MES test. All significantly active compounds against the MES test (1, 2, 6, 7, 12, and 14) possessed aliphatic hydrocarbon chains of relatively small carbon length or aryl/arylalkyl groups not greater than benzyl in the carbamate moiety. Longer or larger than a benzyl group (3, 5, 8, 9, 10, and 11) or a saturated six‐member ring (4) destroyed the activity. In addition, N‐1 methoxycarbonyl substituted compound (13) was also devoid of significant activity. These results suggest that steric size of the substituent at N‐1 oxycarbonyl sidechain in the 2‐iminohydantoin molecule plays an important role in providing anticonvulsant activity, and that an alkyl substituent with a proper size further enhances PTZ anticonvulsant activity while maintaining MES activity. Drug Dev. Res. 47:17–26, 1999. © 1999 Wiley‐Liss, Inc.     

An efficient synthesis and antioxidant properties of novel imino and amino derivatives of 4-hydroxy coumarins

Series of imino and amino derivatives of 4-hydroxy coumarins were synthesized via conventional and microwave promoted procedure and evaluated for antioxidant potential through different in vitro models such as (DPPH) free radical scavenging activity, linoleic acid emulsion model system, reducing power assay and phosphomolybdenum method. All prepared compounds possess good antioxidant activity and among them p-nitro-phenyl derivative 6c with IC₅₀ at 25.9 μM possesses radical scavenging activity which is comparable to standard BHT, while the best reducing power was observed in a case of benzyl amino compound 8c (RP₅₀ 255.6 μM). Also, observed data indicated that compounds may serve as inhibitors of lipid peroxidation process.     

3β-羟基-孕甾-5-烯-20-酮衍生物(A,B环)的合成及其构—效关系的研究

本文报道3β-羟基-孕甾-5-烯-20-酮(孕甾烯醇酮)C₃-位羟基的酯及A,B环重排成6β-羟基-3,5-环孕甾烷-20-酮有关衍生物的合成。抗炎实验发现除水杨酸酯和苯甲酸酯有与临床应用的抗炎松(孕甾烯醇酮乙酰水杨酸酯)相当的抗炎作用外,其余酯类(三氯乙酸酯、氯乙酸酯、呋喃-2′-羧酸酯、对甲苯磺酸酯、邻苯二甲酸单酯)及重排产物6β-羟基-3,5-环孕甾烷-20-酮都有较抗炎松略强的抗炎作用,其作用为临床应用的琥珀酸单酯的两倍多。为了定量地阐明孕甾烯醇酮衍生物的脂溶性对抗炎活性的影响,我们用疏水性碎片常数估算了孕留烯醇酮衍生物的脂水分配系数log P,发现除孕甾烯醇酮3-甲醚和3β-氯-孕甾-5-烯-20-酮以外,当log P0时,随着logP增高,抗炎活性logA明显地加大,两者之间呈抛物线关系。