Design,synthesis and biological evaluation of 6-(benzyloxy)-4-methylquinolin-2(1H)-one derivatives as PDE3 inhibitors

Selective PDE3 (phosphodiesterase 3) inhibitors improve cardiac contractility and may be used in congestive heart failure. However, their proarrhythmic potential is the most important side effect. In this work ten new synthetic compounds (3-[(4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy]methylbenzamide analogs: 4a–j) were designed, synthesized and tested for the inhibitory activity against human PDE3A and PDE3B. The strategy of the design was based on the structure of vesnarinone (a selective PDE3 inhibitor) and its docking analysis results. The synthetic compounds showed better PDE3 inhibitory activity in comparison with vesnarinone. Using docking analysis, a common binding model of each compound toward PDE3 was suggested. In the next step the potential cardiotonic activity of the best PDE3A inhibitors (4b, IC₅₀ = 0.43 ± 0.04 μM) was evaluated by using the spontaneously beating atria model. In the experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of the synthetic compound were assessed. That was carried out in comparison with vesnarinone. The best pharmacological profile was obtained for the compound 4b, which displayed selectivity for increasing the force of contraction (46 ± 3% change over the control) rather than the frequency rate (16 ± 4% change over the control) at 100 μM.     

1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors

Herein we report an assessment of 24 1,2,3,4-tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC₅₀ values below 200 μM. The most potent was 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one ( 2 ) (IC₅₀=134.35±11.38 μM) exhibiting slightly better IC₅₀ value compared to three other active compounds, 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-phenylethan-1-one ( 15 ) (IC₅₀=147.51±14.87 μM), 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one ( 18 ) (IC₅₀=149.07±2.98 μM) and 2-[6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one ( 22 ) (IC₅₀=148.31±2.96 μM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC-5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.     

Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B: Synthesis,molecular modelling and in-silico ADME evaluation

A series of sulfonyl hydrazones derived from 3-formylchromone was synthesized and discovered to be effective, non-selective inhibitors of monoamine oxidases (MAO-A and MAO-B). The compounds are easily (synthetically) accessible in high yields, by simple condensation of 4-methylbenzenesulfonohydrazide with different (un)substituted 3-formylchromones. All compounds had IC₅₀ values in lower micro-molar range (IC₅₀ = 0.33–7.14 μM for MAO-A, and 1.12–3.56 μM for MAO-B). The most active MAO-B inhibitor was N′-[(E)-(6-fluoro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3e) with IC₅₀ value of 1.12 ± 0.02 μM, and N′-[(E)-(6-chloro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3f) was the most active MAO-A inhibitor with IC₅₀ value of 0.33 ± 0.01 μM. From enzyme kinetic studies, the mode of inhibition against MAO-B was found to be competitive, whereas against MAO-A, it was found to be non-competitive. Molecular docking studies indicated a new binding pocket for non-competitive MAO-A inhibitors. The activity of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.     

Inhibition of acetylcholinesterase by two arylderivatives: 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione and cis-N-p-Acetoxy-phenylisomaleimide

Two arylderivatives, 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione 3 and cis-N-p-Acetoxy-phenylisomaleimide 4, were synthesized from anthranilic acid and para-aminophenol, respectively. The inhibitory effects of these compounds on acetylcholinesterase (AChE) activity were evaluated in vitro as well as by docking simulations. Both compounds showed inhibition of AChE activity (K_i = 4.72 ± 2.3 μM for 3 and 3.6 ± 1.8 μM for 4) in in vitro studies. Moreover, they behaved as irreversible inhibitors and made π–π interaction with W84 and hydrogen bonded with S200 and Y337 according to experimental data and docking calculations. The docking calculations showed ΔG bind (kcal/mol) of ? 9.22 for 3 and ? 8.58 for 4. These two compounds that can be use as leads for a new family of anti-Alzheimer disease drugs.     

Syntheses of 1-[2-(Phosphonomethoxy)Alkyl]Thymine Monophosphates and an Evaluation of their Inhibitory Activity Toward Human Thymidine Phosphorylase

A series of new monophosphates of 1-[2-(phosphonomethoxy)alkyl]thymines, such as PMPTp_, 3-MeO-PMPTp, HPMPTp, and FPMPTp, were synthesized and tested for their ability to inhibit human thymidine phosphorylase. Kinetic measurements of enzyme activity were performed using thymidine and inorganic phosphate as the substrates. The data show that some monophosphates provide a considerable increase of the multisubstrate inhibitory effect. The highest inhibitory potency was found with (R)-FPMPTp 4c (K _i ^dT = 4.09 ± 0.47 μM, K _i(P_i) = 2.13 ± 0.29 μM) and (R) 3-MeO-PMPTp 4d (K _i ^dT = 5.78 ± 0.71 μM, K _i(P_i) = 2.71 ± 0.37 μM).     

Synthesis of pyrrolo[2,3-d]pyridazinones as potent,subtype selective PDE4 inhibitors

A series of pyrrolo[2,3-d]pyridazinones was synthesized and tested for their inhibitory activity on PDE4 subtypes A, B and D and selectivity toward Rolipram high affinity binding site (HARBS). New agents with interesting profile were reported; in particular compound 9e showed a good PDE4 subtype selectivity, being 8 times more potent (IC₅₀ = 0.32 μM) for PDE4B (anti-inflammatory) than for PDE4D (IC₅₀ = 2.5 μM), generally considered the subtype responsible for emesis. Moreover the ratio HARBS/PDE4B was particularly favourable for 9e (147), suggesting that the best arranged groups around the pyrrolopyridazinone core are an isopropyl at position-1, an ethoxycarbonyl at position-2, together with an ethyl group at position-6.

For compounds 8 and 15a the ability to inhibit TNFα production in PBMC was evaluated and the results are consistent with their PDE4 inhibitory activity.     

Structure–activity relationship studies of 3-dodecanoylindole-2-carboxylic acid inhibitors of cytosolic phospholipase A2α-mediated arachidonic acid release in intact platelets: variation of the keto moiety

Recently we found that 1-methyldodecanoylindole-2-carboxylic acid (1) and 1-[2-(4-carboxyphenoxy)ethyl]-3-dodecanoylindole-2-carboxylic acid (4) were inhibitors of the cytosolic phospholipase A₂α (cPLA₂α)-mediated arachidonic acid release in calcium ionophore A23187-stimulated human platelets with IC₅₀-values of 4.8 μM (1) and 0.86 μM (4). We have now replaced the 3-acyl residue of these compounds by alkylated sulfinyl-, sulfony-, sulfinamoyl-, sulfamoyl-, carbonylamino-, or carbonylaminomethyl-substituents. Structure–activity relationship studies revealed that the pronounced cellular activity of 4 strongly depends on the presence of the 3-acyl moiety. Surprisingly, when testing 4 and its derivatives in an assay with the isolated cPLA₂, none of these compounds showed an inhibitory potency at 10 μM indicating that they do not inhibit cPLA₂α in the cells by a direct interaction with the active site of the enzyme.     

Binding of DL-[3H]-alpha-Amino-3-Hydroxy-5-Methyl-Isoxazole-4-Propionic Acid (AMPA) to Rat Cortex Membranes Reveals Two Sites or Affinity States

Abstract

A method for measuring [³H]-AMPA binding in rat cortex membranes is described. Specific binding was saturable and accounted for 95% of total binding at 5 nM of [³H]-AMPA. Non linear curve fitting of [³H]-AMPA saturation isotherms suggested the presence of two binding sites: the high affinity site showed a pKd of 8.26 ± 0.07 (Kd = 5.49 nM) and a Bmax of 0.19 ± 0.03 pmol/mg protein, whereas the low affinity site indicated a pKd of 7.28 ± 0.05 (Kd = 52 nM) and a Bmax of 1.30 ± 0.23 pmol/mg protein. The pharmacological profile of [³H]-AMPA binding has been determined by studying a series of compounds in binding displacement experiments: Quisqualate was the most potent inhibitor of [³H]-AMPA binding (IC₅₀ = 9.7 nM), followed by AMPA (19 nM), CNQX, DNQX and L-Glutamate (272–373 nM). Kainate was a moderate displacer (6.2 μM); Ibotenic acid and glycine were very weak inhibitors (74 and 92 μM, respectively). CPP, GAMS and L-Aspartic acid showed IC₅₀-values of over 400 μM and MK-801, DL-AP5 and NMDA were almost inactive at the maximal concentration used in our experiments.     

Design,Synthesis, Characterization and Computational Studies of Mannich Bases Oxadiazole Derivatives as New Class of Jack Bean Urease Inhibitors

Mannich bases consisting of 1,3,4-oxadiazole-2-thione ( 3 a – 3 l ) bearing various substituents were synthesized and found potent jack bean urease inhibitors. The prepared compounds showed significantly good inhibitory activities with IC₅₀ values from 9.45±0.05 to 267.42±0.23 μM. The compound 3 k containing 4-chlorophenyl (−R) and 4-hydroxyphenyl (−R′) was most active with IC₅₀ 9.45±0.05 μM followed by 3 e (IC₅₀ 22.52±0.15 μM) in which −R was phenyl and −R′ was isopropyl group. However, when both −R and −R′ were either 4-chlorophenyl groups ( 3 l ) or only −R′ was 4-nitrophenyl ( 3 i ), both compounds were found inactive. The detailed binding affinities of the produced compounds with protein were explored through molecular docking and data-supported in-vitro enzyme inhibition profiles. Drug likeness was confirmed by in silico ADME investigations and molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps were got from DFT calculations. ESP maps exposed that there are two potential binding sites with the most positive and most negative parts.     

The increase in rat ventricular automaticity induced by salbutamol is mediated through β(1)- but not β(2)-adrenoceptors: role of phosphodiesterases

AimsWhile β₂-adrenoceptor (AR) agonists are useful bronchodilators, they also produce cardiac arrhythmias. These agents are not fully selective and also activate β₁-AR, but the involvement of β₁-AR and β₂-AR in the observed pro-arrhythmic effect has not been established. We studied the effect of β₁-AR and β₂-AR activation on ventricular automaticity and the role of phosphodiesterases (PDE) in regulating this effect.Main methodsExperiments were performed in the spontaneously beating isolated right ventricle of the rat heart. We also measured cAMP production in this tissue.Key findingsThe β₂-AR agonist salbutamol (1-100 μM) produced a concentration-dependent increase in ventricular automaticity that was not affected by 50 nM of the β₂-AR antagonist ICI 118551. This effect was enhanced by the non-selective PDE inhibitor theophylline (100 μM) and by the selective PDE4 inhibitors rolipram (1 μM) and Ro 201724 (2 μM), but not modified by the selective PDE3 inhibitors cilostamide (0.3 μM) or milrinone (0.2 μM). The effects of salbutamol alone and in the presence of either theophylline or rolipram were virtually abolished by 0.1 μM β₁-AR antagonist CGP20712A. Salbutamol (10 μM) increased the cAMP concentration, and this effect was abolished by CGP 20712A (0.1 μM) but enhanced by theophylline (100 μM) or rolipram (1 μM). Cilostamide (0.3 μM) failed to modify the effect of salbutamol on cAMP concentration.SignificanceThese results indicate that the increase of ventricular automaticity elicited by salbutamol was exclusively mediated through β₁-AR and enhanced by non-selective PDE inhibition with theophylline or selective PDE4 inhibition. However, PDE3 did not appear to regulate this effect.     

Novel Series of [ddN]-[TSAO-T] Heterodimers as Potential Bi-Functional Inhibitors of HIV-1 RT. Studies in the Linker and ddN Region

Abstract

Novel series of [ddN]-(CH₂)_n-[TSAO-T] heterodimers have been prepared and tested for their anti-HIV-1 and HIV-2 activity. The most active compound of this series was the [d4T]-(CH₂)₃-[TSAO-T] heterodimer (EC₅₀ = 0.018 ± 0.03 μM).     

Synthesis of Imidazole-2,3-dihydrothiazole Compounds as VEGFR-2 Inhibitors and Their Support with in Silico Studies

In this study, 12 novel 2-((1-(4-(1H-imidazol-1-yl)phenyl)ethylidene)hydrazineylidene)-3-ethyl-4-(substitutephenyl)-2,3-dihydrothiazole derivatives were obtained. Among these compounds, 2-((1-(4-(1H-imidazol-1-yl)phenyl)ethylidene)hydrazineylidene)-4-([1,1′-biphenyl]-4-yl)-3-ethyl-2,3-dihydrothiazole ( 4h ) was chosen as the most active derivative in the series. According to the MTT results, compounds 4h and 4k showed activity with IC₅₀=4.566±0.246 μM and IC₅₀=4.537±0.463 μM, respectively. Unlike other derivatives, compound 4h carries a phenyl ring in the 4th position of the phenyl ring. This bulky group allowed the compound to settle in the enzyme active site. Dynamic studies show that the stability of the compound does not change over 40 ns. RMSD, RMSF and Rg parameters all remained within acceptable limits. The uninterrupted aromatic hydrogen bonding of the enzyme active site with the important amino acids Cys919, Glu885 and Asp1046 proves the inhibitory potential of compound 4h on the VEGFR-2 enzyme. It is thought that more active compounds will be reached with the derivatives to be synthesized starting from compound 4h .     

Chemical Investigation of Marine-Derived Fungus Aspergillus flavipes for Potential Anti-Inflammatory Agents

The marine fungus, Aspergillus flavipes (MTCC 5220), was isolated from the pneumatophore of a mangrove plant Acanthus ilicifolius found in Goa, India. The crude extract of A. flavipes was found to show anti-inflammatory activity. It blocked interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production in lipopolysaccharide (LPS)-activated THP-1 cells with IC₅₀ of 2.69±0.5 μM and 6.64±0.4 μM, respectively. The chemical investigation led to the isolation of optically inactive 4β-[(1E)-propen-1-yl]cyclopentane-1β,2β-diol ( 1 ) along with a new optically active diastereoisomeric compound, 4β-[(1E)-propen-1-yl]cyclopentane-1β,2α-diol ( 2 ). In addition, the fungus also produced known compounds (+)-terrein ( 3 ), butyrolactone I ( 4 ) and butyrolactone II ( 5 ) in high yields. Among these, (+)-terrein ( 3 ) exhibited IL-6 and TNF-α inhibition activity with IC₅₀ of 8.5±0.68 μM and 15.76±0.18 μM, respectively, while butyrolactone I ( 4 ) exhibited IC₅₀ of 12.03±0.85 μM (IL-6) and 43.29±0.76 μM (TNF-α) inhibition activity with low toxicity to host cells in LPS stimulated THP-1 cells. This is the first report of the isolation and characterization of 4β-[(1E)-propen-1-yl]cyclopentane-1β,2α-diol ( 2 ). The structures of all the isolated compounds were elucidated on the basis of extensive detailed NMR spectroscopic data. Anti-inflammatory activity of the fungi A. flavipes is presented here for the first time, which was due to (+)-terrein and butyrolactone I, as the major constituents and they can be further explored in the therapeutic area.     

Design,synthesis and preliminary activity evaluation of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as aminopeptidase N/CD13 inhibitors

Aminopeptidase N (APN/CD13) over expressed on tumour cells, plays a critical role in tumour invasion, metastasis and tumour angiogenesis. In this article, we described the design, synthesis and preliminary activity studies of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as APN inhibitors. The in vitro enzymatic inhibitions on APN from porcine kidney showed that compound 7e had the most potent inhibitory activity against APN with the IC₅₀ value to 1.26?±?0.01 μM, which is better than that of bestatin (IC₅₀?=?2.55?±?0.11 μM). In addition, compound 7e also showed better inhibitory activity against APN on human ovary clear cell carcinoma cell ES-2 than bestatin with the IC₅₀ value to 30.19?±?1.02 μM versus 60.61?±?0.1 μM. Compound 7e could be used as the lead compound in the future for anti-cancer agent research.     

Synthesis and DNase I inhibitory properties of some 4-thiazolidinone derivatives

Twelve new thiazolidinones were synthesized and, together with 41 previously synthesized thiazolidinones, evaluated for inhibitory activity against deoxyribonuclease I (DNase I) in vitro. Ten compounds inhibited commercial bovine pancreatic DNase I with an IC₅₀ below 200 μM and showed to be more potent DNase I inhibitors than crystal violet (IC₅₀ = 365.90 ± 47.33 μM), used as a positive control. Moreover, three compounds were active against DNase I in rat liver homogenate, having an IC₅₀ below 200 μM. (3-Methyl-1,4-dioxothiazolidin-2-ylidene)-N-(2-phenylethyl)ethanamide ( 41 ) exhibited the most potent DNase I inhibition against both commercial and rat liver DNase I with IC₅₀ values of 115.96 ± 11.70 and 151.36 ± 15.85 μM, respectively. Site Finder and molecular docking defined the thiazolidinones interactions with the most important catalytic residues of DNase I, including the H-acceptor interaction with residues His 134 and His 252 and/or H-donor interaction with residues Glu 39 and Asp 168. The three most active compounds against both commercial and rat liver DNase I ( 31 , 38 , and 41 ) exhibited favorable physico-chemical, pharmacokinetic, and toxicological properties. These observations could be utilized to guide the rational design and optimization of novel thiazolidinone inhibitors. Thiazolidinones as novel DNase I inhibitors could have potential therapeutic applications due to the significant involvement of DNase I in the pathophysiology of many disease conditions.     

(3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors

In this study, we have synthesised (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and a series of its derivatives (5, 13–16) and tested the ability of these compounds to inhibit two metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I and hCA II. The synthesised compounds showed inhibitory effect on hCA I and hCA II isozymes. The results showed that synthesised compounds (5, 13–16) demonstrated the best inhibition activity against hCA I (IC₅₀: 3.22–54.28 μM) and hCA II (IC₅₀: 18.52–142.01 μM). The compound 14 showed the highest inhibiton effect against hCA I (IC₅₀: 3.22 μM; K_i: 1.19?±?1.4 μM). On the other hand, the compound 13 showed the highest inhibiton effect against hCA II (IC₅₀: 18.52 μM; K_i: 3.25?±?1.13 μM).     

Synthesis,and In Vitro and In Silico α-Glucosidase Inhibitory Studies of 5-Chloro-2-Aryl Benzo[d]thiazoles

Twenty-five derivatives of 5-chloro-2-aryl benzo[d]thiazole (1–25) were synthesized and evaluated for their α-glucosidase (S. cerevisiae EC 3.2.1.20) inhibitory activity in vitro. Among them eight compounds showed potent activity with IC₅₀ values between 22.1 ± 0.9 and 136.2 ± 5.7 μM, when compared with standard acarbose (IC₅₀ = 840 ± 1.73 μM). The most potent compounds 4, 9, and 10 showed IC₅₀ values in the range of 22.1 ± 0.9 to 25.6 ± 1.5 μM. Compounds 2, 5, 11, and 19 showed IC₅₀ values within the range of 40.2 ± 0.5 to 60.9 ± 2.0 μM. Compounds 1 and 3 were also found to be good inhibitors with IC₅₀ values 136.2 ± 5.7 and 104.8 ± 9.9 μM, respectively. Their activities were compared with α-glucosidase inhibitor drug acarbose (standard) (IC₅₀ = 840 ± 1.73 μM). The remaining compounds were inactive. Structure-activity relationships (SAR) have also been established. Kinetics studies indicated compounds 2, 3, 10, 19, and 25 to be non-competitive, while 1, 5, 9, and 11 as competitive inhibitors of α-glucosidase enzyme. All the active compounds (1–5, 9–11, and 19) were also found to be non-cytotoxic, in comparison to the standard drug i.e., doxorubicin (IC₅₀ = 0.80 ± 0.12 μM) in MTT assay. Furthermore, molecular interactions of active compounds with the enzyme binding sites were predicted through molecular modeling studies.     

Exploring antidiabetic potential of adamantyl-thiosemicarbazones via aldose reductase (ALR2) inhibition

The role of aldose reductase (ALR2) in diabetes mellitus is well-established. Our interest in finding ALR2 inhibitors led us to explore the inhibitory potential of new thiosemicarbazones. In this study, we have synthesized adamantyl-thiosemicarbazones and screened them as aldehyde reductase (ALR1) and aldose reductase (ALR2) inhibitors. The compounds bearing phenyl 3a, 2-methylphenyl 3g and 2,6-dimethylphenyl 3m have been identified as most potent ALR2 inhibitors with IC₅₀ values of 3.99 ± 0.38, 3.55 ± 0.26 and 1.37 ± 0.92 µM, respectively, compared with sorbinil (IC₅₀ = 3.14 ± 0.02 μM). The compounds 3a, 3g, and 3m also inhibit ALR1 with IC₅₀ value of 7.75 ± 0.28, 7.26 ± 0.39 and 7.04 ± 2.23 µM, respectively. Molecular docking was also performed for putative binding of potent inhibitors with target enzyme ALR2. The most potent 2,6-dimethylphenyl bearing thiosemicarbazone 3m (IC₅₀ = 1.37 ± 0.92 µM for ALR2) and other two compound 3a and 3g could potentially lead for the development of new therapeutic agents.     

Potential Inhibitors of Angiogenesis. Part II: 3-(Azolylmethylene)-2,3-dihydrobenzo[b]furan-2-ones

The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)-2,3-dihydrobenzo[b]furan-2-ones 8-10 and 3-(3,5-dimethylpyrrol-2-ylmethylene)-2,3-dihydrobenzo[b]furan-2-one 11, analogues of SU-5416, as potential inhibitors of angiogenesis, are reported. Compounds 8 and 11 were prepared by a Knoevenagel reaction starting from 2-hydroxyphenylacetic acid 2 and 4-formylimidazole 5 or 2-formyl-3,5-dimethylpyrrole 7, followed by acid-catalysed cyclodehydration. For compounds 9 and 10, an alternative method was used; it consisted in carrying out the Knoevenagel reaction with the 2,3-dihydrobenzo[b]furan-2-ones 3 and 4. The antiangiogenic activity of these compounds was evaluated in the three-dimensional in vitro rat aortic rings test at 1 μM. At this concentration, compound 11 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density index at 1 μM of 11 and SU-5416 were 30±10 and 22±4% of control, respectively.     

Synthesis and Biological Evaluation of 1,3,5-Trisubstituted 2-Pyrazolines as Novel Cyclooxygenase-2 Inhibitors with Antiproliferative Activity

A new series of 1,3,5-trisubstituted 2-pyrazolines for the inhibition of cyclooxygenase-2 (COX-2) were synthesized. The designed structures include a COX-2 pharmacophore SO₂CH₃ at the para-position of the phenyl ring located at C-5 of a pyrazoline scaffold. The synthesized compounds were tested for in vitro COX-1/COX-2 inhibition and cell toxicity against human colorectal adenocarcinoma cell lines HT-29. The lead compound (4-chlorophenyl){5-[4-(methanesulfonyl)phenyl]-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl}methanone ( 16 ) showed significant COX-2 inhibition (IC₅₀=0.05±0.01 μM), and antiproliferative activity (IC₅₀=5.46±4.71 μM). Molecular docking studies showed that new pyrazoline-based compounds interact via multiple hydrophobic and hydrogen-bond interactions with key binding site residues of the COX-2 enzyme.