Synthesis and kinetics studies of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazide derivatives as potent antidiabetic agents

A novel series of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazides were synthesized and studied for their α‐glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α‐glucosidase inhibition activity with IC₅₀ values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e , having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC₅₀ = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver–Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d , and 4e , on the α‐glucosidase activity, was found to be in the competitive mode.     

Novel pyridine‐2,4,6‐tricarbohydrazide thiourea compounds as small key organic molecules for the potential treatment of type‐2 diabetes mellitus: In vitro studies against yeast α‐ and β‐glucosidase and in silico molecular modeling

A range of novel pyridine‐2,4,6‐tricarbohydrazide thiourea compounds ( 4a–i ) were synthesized in good to excellent yields (63–92%). The enzyme inhibitory potentials of these compounds were investigated against α‐ and β‐glucosidases because these enzymes play a crucial role in treating type‐2 diabetes mellitus (T2DM). As compared to the reference compound acarbose (IC₅₀ 38.22 ± 0.12 μM), compounds 4i (IC₅₀ 25.49 ± 0.67 μM), 4f (IC₅₀ 28.91 ± 0.43 μM), 4h (IC₅₀ 30.66 ± 0.52 μM), and 4e (IC₅₀ 35.01 ± 0.45 μM) delivered better inhibition against α‐glucosidase and were quite inactive/completely inactive against β‐glucosidase. The structure–activity relationship of these compounds was developed and elaborated with the help of molecular docking studies.     

Synthesis and biological evaluation of novel N‐aryl‐ω‐(benzoazol‐2‐yl)‐sulfanylalkanamides as dual inhibitors of α‐glucosidase and protein tyrosine phosphatase 1B

α‐Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α‐glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N‐aryl‐ω‐(benzoazol‐2‐yl)‐sulfanylalkanamides were synthesized and assayed for their α‐glucosidase and PTP1B inhibitory activities, respectively. Compound 3l , exhibiting the most effective α‐glucosidase inhibitory activity (IC₅₀ = 10.96 μm ( 3l ), IC₅₀ = 51.32 μm (Acarbose), IC₅₀ = 18.22 μm (Ursolic acid)) and potent PTP1B inhibitory activity (IC₅₀ = 13.46 μm ( 3l ), IC₅₀ = 14.50 μm (Ursolic acid)), was identified as a novel dual inhibitor of α‐glucosidase and PTP1B. Furthermore, 3l is a highly selective PTP1B inhibitor because no inhibition was showed by 3l at 100 μm against PTP‐MEG2, TCPTP, SHP2, or SHP1. Subsequent kinetic analysis revealed 3l inhibited α‐glucosidase in a reversible and mixed manner. Molecular docking study indicated that hydrogen bonds, van der Waals, charge interactions and Pi‐cation interactions all contributed to affinity between 3l and α‐glucosidase/PTP1B.     

Synthesis,in vitro evaluation and molecular docking studies of novel coumarin‐isatin derivatives as α‐glucosidase inhibitors

This study synthesized a series of novel coumarin‐isatin derivatives and evaluated them for α‐glucosidase inhibitory activity. The majority of the screened compounds exhibited excellent inhibition activities with IC₅₀ values of 2.56 ± 0.08–268.79 ± 3.04 μm , when compared to acarbose. Among the newly derivatives, compound 5p was found to be the most active compound in the library of coumarin‐isatin derivatives. Furthermore, enzyme kinetic studies showed that compound 5p is a non‐competitive inhibitor with a K_i of 2.14 μm . Molecular docking analysis revealed the existence of hydrophobic and hydrogen interactions between compound 5p and the active site of α‐glucosidase. Our results indicate that coumarin‐isatin derivatives as a new class of α‐glucosidase inhibitors.     

A novel five‐step synthetic route to 1,3,4‐oxadiazole derivatives with potent α‐glucosidase inhibitory potential and their in silico studies

A series of new N‐aryl/aralkyl derivatives of 2‐methyl‐2‐{5‐(4‐chlorophenyl)‐1,3,4‐oxadiazole‐2ylthiol}acetamide were synthesized by successive conversions of 4‐chlorobenzoic acid ( a ) into ethyl 4‐chlorobenzoate ( 1 ), 4‐chlorobenzoylhydrazide ( 2 ) and 5‐(4‐chlorophenyl)‐1,3,4‐oxadiazole‐2‐thiol ( 3 ), respectively. The required array of compounds ( 6a–n ) was obtained by the reaction of 1,3,4‐oxadiazole ( 3 ) with various electrophiles ( 5a–n ) in the presence of DMF (N,N‐dimethylformamide) and sodium hydroxide at room temperature. The structural determination of these compounds was done by infrared, ¹H‐NMR (nuclear magnetic resonance), ¹³C‐NMR, electron ionization mass spectrometry, and high‐resolution electron ionization mass spectrometry analyses. All compounds were evaluated for their α‐glucosidase inhibitory potential. Compounds 6a, 6c–e, 6g , and 6i were found to be promising inhibitors of α‐glucosidase with IC₅₀ values of 81.72 ± 1.18, 52.73 ± 1.16, 62.62 ± 1.15, 56.34 ± 1.17, 86.35 ± 1.17, 52.63 ± 1.16 µM, respectively. Molecular modeling and ADME (absorption, distribution, metabolism, excretion) predictions supported the findings. The current synthesized library of compounds was achieved by utilizing very common raw materials in such a way that the synthesized compounds may prove to be promising drug leads.     

Evaluation of polyhydroxybenzophenones as α-glucosidase inhibitors

This experiment was designed to synthesize 18 kinds of polyhydroxybenzophenones by using Friedel‐Crafts reaction, and to measure the inhibitory activity on α‐glucosidase with p‐nitrophenyl‐β‐D‐galactopyranoside (PNPG) as a substrate. Here, acarbose (IC₅₀ = 1674.75 µmol L^?1) was used as the reference inhibitor. The results demonstrated that most of the target compounds had remarkable inhibitory activities on α‐glucosidase. Among all these compounds, 2,4,4′,6‐butahydroxydiphenylketone ( 11 ) was found to be the most potent α‐glucosidase inhibitor with an IC₅₀ value of 10.62 µmol L^?1. In addition, we found these compounds were competitive inhibitors through the kinetic analysis. The results suggested that such compounds might be utilized for the development of new candidates for diabetes treatment.     

Biological evaluation of selected 3,4‐dihydro‐2(1H)‐quinoxalinones and 3,4‐dihydro‐1,4‐benzoxazin‐2‐ones: Molecular docking study

In order to investigate new potential therapeutically active agents, we investigated the biological properties of two small libraries of quinoxalinones and 1,4‐benzoxazin‐2‐ones. The results obtained showed that compounds 5 , 9–11 have good cytotoxic activity against HeLa cells where the lowest IC₅₀ value (10.46 ± 0.82 μM/mL) was measured for compound 10 . Additionally, the most active compounds ( 5 , 9 – 11 ) showed much better selectivity for MRC‐5 cells (up to 17.4) compared to cisplatin. In vitro evaluation of the inhibition of the enzyme α‐glucosidase showed that compounds 10 and 11 exert significant inhibition of the enzyme at 52.54 ± 0.09 and 40.09 ± 0.49 μM, respectively. Competitive experiments with ethidium bromide (EB) indicated that all tested compounds have affinity to displace EB from the EB‐DNA complex through intercalation, suggesting good competition with EB (K_sv = (3.1 ± 0.2), (5.1 ± 0.1), (5.6 ± 0.2), and (6.3 ± 0.2) × 10³ M^?1). A molecular docking study was also performed to better understand the binding modes and to conclude the structure–activity relationships of the synthesized compounds.

     

Synthesis,In vitro and Docking Studies of New Flavone Ethers as α‐Glucosidase Inhibitors

We report herein the synthesis, α‐glucosidase inhibition and docking studies for a series of 3–15 new flavones. A simple nucleophilic substitution reaction takes place between 3′hydroxyflavone ( 2 ) with halides to afford the new flavones. Chalcone ( 1 ), 3′hydroxyflavone ( 2 ) and the newly synthesized flavones ( 3–15 ) were being evaluated for their ability to inhibit activity of α ‐glucosidase. Compounds 2 , 3 , 5 , 7 – 10 and 13 showed good inhibitory activity with IC₅₀ values ranging between 1.26 and 36.44 μ m as compared to acarbose (IC₅₀ = 38.25 ± 0.12 μ m ). Compounds 5 (5.45 ± 0.08 μ m ), 7 (1.26 ± 0.01 μ m ) and 8 (8.66 ± 0.08 μ m ) showed excellent inhibitory activity, and this may be due to trifluoromethyl substitution that is common for these compounds. Compound 7 , a 2,5‐trifluoromethyl‐substituted compound, recorded the highest inhibition activity, and it is thirty times better than the standard drug. Docking studies for compound 7 suggest that both trifluoromethyl substituents are well positioned in a binding pocket surrounded by Phe300, Phe177, Phe157, Ala278, Asp68, Tyr71 and Asp214. The ability of compound 7 to interact with Tyr71 and Phe177 is extremely significant as they are found to be important for substrates recognition by α ‐glucosidase.     

Design,synthesis, and biological evaluation of novel 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives as cytotoxic agents and COX‐2/LOX inhibitors

A new series of 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4H)‐imidazolone derivatives 4a–l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, ¹H NMR, DEPT‐Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)‐1, COX‐2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX‐2 rather than COX‐1, and the IC₅₀ values (0.25–1.7 µM) were lower than that of indomethacin (IC₅₀ = 9.47 µM) and somewhat higher than that of celecoxib (IC₅₀ = 0.071 µM). The selectivity index for COX‐2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC₅₀ values of 0.02–74.03 µM, while the IC₅₀ of the reference zileuton was 0.83 µM. The most active compound 4c (4‐chlorobenzoxazole derivative) was found to have dual COX‐2/LOX activity. All the synthesized compounds were docked inside the active site of the COX‐2 and LOX enzymes. They linked to COX‐2 through the N atom of the azole scaffold, while C?O of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.

     

Design,synthesis, molecular docking,and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors

Novel series of benzoxazole s 4 _a‐f ‐16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 _e was found to be the most potent against HepG2, HCT‐116, and MCF‐7 with IC₅₀ = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5 _c , 5 _f , 6 _b , 5 _d , and 6 _c showed the highest anticancer activities against HepG2 cells with IC₅₀ of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT‐116 cells with IC₅₀ of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF‐7 cells with IC₅₀ of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC₅₀ of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5 _c‐f and 6 _b,c were further evaluated for their vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibition. Compounds 5 _e and 5 _c potently inhibited VEGFR‐2 at lower IC₅₀ values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC₅₀ = 0.1 ± 0.02 µM). Compound 5 _f potently inhibited VEGFR‐2 at low IC₅₀ value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR‐2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.     

Some Hydrazones of 2‐Aroylamino‐3‐methylbutanohydrazide: Synthesis,Molecular Modeling Studies,and Identification as Stereoselective Inhibitors of HIV‐1

In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 _S , 11 _S , and 12 _S showed anti‐HIV‐1 activity with a 50% inhibitory concentration (IC₅₀) = 123.8 µM (selectivity index, SI > 3), IC₅₀ = 12.1 µM (SI > 29), IC₅₀ = 17.4 µM (SI > 19), respectively. Enantiomers 8 _R , 11 _R , and 12 _R were inactive against the HIV‐1 strain III_B. Hydrazones 8 _S , 11 _S , and 12 _S which were active against HIV‐1 wild type showed no inhibition against a double mutant NNRTI‐resistant strain (K103N;Y181C). Molecular docking calculations of R‐ and S‐enantiomers of 8 , 11 , and 12 were performed using the hydrazone‐bound novel site of HIV‐1 RT.     

Inhibition of nitrergic relaxations by the M3‐selective antagonist 4‐DAMP

The inhibitory effect of the selective M₃ musarinic acetylcholine receptor antagonist, 4‐diphenylacetoxy‐N‐methylpiperidine methobromide (4‐DAMP, 0.1–10 μM) on nicotine (100 μM)‐induced nitrergic relaxation was investigated in comparison to d‐tubocurarine (0.1–10 μM) and hexamethonium (0.1–10 μM) by using phenylephrine (1 μM)‐precontracted rat anococcygeus muscles in vitro. Nicotine produced a 60.1± 2.4% (n = 40) inhibition of phenylephrine precontractions. But this relaxant response was at a significantly lower magnitude of 20.2± 4.6% (n = 18, P < 0.01 vs. control) in the presence of the nitric oxide synthase (NOS) blocker N^G‐nitro‐L ‐arginine methyl ester (L ‐NAME, 30 μM), and it was 26.5± 5.5% (n = 8, P < 0.01 vs. control) in the presence of the soluble guanylate cyclase inhibitor methylene blue (30 μM). However, aminoguanidine (100 μM), a relatively selective blocker of the inducible nitric oxide synthase (iNOS), had no significant effect. Similarly, other iNOS inhibitors such as dexamethasone (5 mg/kg) or L ‐canavanine (100 mg/kg) did not modify contractile nor relaxant responses when they were given in vivo, concomitantly with Escherichia coli endotoxin (1 mg/kg, ip) 4 h before the isolation of the tissues. 4‐DAMP, hexamethonium, and d‐tubocurarine inhibited nicotine‐induced relaxation in a concentration‐dependent manner with the following order of potency: 4‐DAMP > hexamethonium > d‐tubocurarine with IC₅₀ values being 0.47± 0.04 μM, 0.75± 0.06 μM, and 1.02± 0.05 μM, respectively. Therefore, it was concluded that the selective M₃ muscarinic acetylcholine receptor antagonist 4‐DAMP also possesses potent antagonistic action on nicotinic receptors of peripheral nitrergic neurons that innervate the rat anococcygeus muscle. Drug Dev. Res. 46:148–154, 1999. © 1999 Wiley‐Liss, Inc.     

Synthesis,biological evaluation,and docking studies of some 5‐chloro‐2(3H)‐benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC₅₀ = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC₅₀ = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC₅₀ = 1.04 ± 0.04 mM) than Trolox (IC₅₀ = 1.50 ± 0.05 mM).

     

Benzoxazole/benzothiazole‐derived VEGFR‐2 inhibitors: Design,synthesis, molecular docking,and anticancer evaluations

A novel series of benzoxazole/benzothiazole derivatives 4a–c – 11a–e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT‐116, and MCF‐7 cells, with IC₅₀ values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f , and 9c showed the highest anticancer activities against HepG2 cells with IC₅₀ values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT‐116 cells with IC₅₀ values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF‐7 cells with IC₅₀ values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC₅₀ values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a–c, 9b,c,e,f,h , and 11c,e were further evaluated for their VEGFR‐2 inhibition. Compounds 4c and 4b potently inhibited VEGFR‐2 at IC₅₀ values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.     

Synthesis of thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines as a class of antimalarial agents

Novel thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines were synthesized by a facile one‐pot multicomponent approach by the reaction of 2‐amino‐4‐methyl‐5‐acetylthiazole, thiosemicarbazide or thiocarbohydrazide and phenacyl bromides or 3‐(2‐bromoacetyl)‐2H‐chromen‐2‐ones in acetic acid with good to excellent yields. These new compounds were screened in vitro for their antimalarial activity; among them, four compounds, 4h, 4i, 4k, 4l , showed moderate activity with half‐maximal inhibitory concentration (IC₅₀) values of 3.2, 2.7, 2.7, and 2.8 and 3.2, 3.2, 3.1, and 3.5 μM against chloroquine‐sensitive and ‐resistant strains of Plasmodium falciparum, respectively. Compound 4l inhibited the ring stage growth of P. falciparum 3D7 at an IC₉₀ concentration of 12.5 µM in a stage‐specific assay method, where the culture is incubated with specific stages of P. falciparum for 12 hr, and no activity was found against the trophozoite and schizont stages, confirming that 4l may have potent action against the ring stage of P. falciparum.     

Synthesis and Antitumor Activity of Novel Nitrogen Mustard‐Linked Chalcones

A series of nitrogen mustard‐linked chalcones were synthesized and evaluated for their antitumor activity in vitro against the K562 and HepG2 cell lines. The aldol condensation of [N,N‐bis(chloroethyl)‐3‐amino]‐acetophenone ( 2 ) with aromatic aldehydes afforded the nitrogen mustard‐linked chalcones. Among the analogs tested, compounds 5e and 5k exhibited significant anti‐proliferation activities against K562 cells with IC₅₀ values of 2.55 and 0.61 µM, respectively, which revealed higher cell toxicity than the standard drugs cisplatin (IC₅₀ > 200 µM) and adriamycin (IC₅₀ = 14.88 µM). The methoxyl and N,N‐dimethyl groups on the B‐ring of the chalcone frame enhanced the inhibitory activities against both the K562 and HepG2 cell lines. The structure–activity relationship study indicated that the inhibitory activities significantly varied with the position(s) and species of the substituted group(s).     

Design,synthesis, and antitumor evaluation of quinoline‐imidazole derivatives

A series of compounds bearing quinoline‐imidazole ( 8a–e , 9a–e , 10a–e , 11a–e , and 12a–e ) not reported previously were designed and synthesized. The target compounds were evaluated for antitumor activity against A549, PC‐3, HepG2, and MCF‐7 cells by the MTT method, with NVP‐BEZ235 being the positive control. Most compounds showed moderate activity and compound 12a showed the best activity against HepG2, A549, and PC‐3 cells, with half‐maximal inhibitory concentration (IC₅₀) values of 2.42 ± 1.02 µM, 6.29 ± 0.99 µM, and 5.11 ± 1.00 µM, respectively, which was equal to NVP‐BEZ235 (0.54 ± 0.13 µM, 0.36 ± 0.06 µM, 0.20 ± 0.01 µM). Besides, the IC₅₀ value of 12a against the cell line WI‐38 (human fetal lung fibroblasts) was 32.8 ± 1.23 µM, indicating that the target compounds were selective for cancer cells. So, 11a and 12a were evaluated against PI3Kα and mTOR to find out if the compounds acted through the PI3K‐Akt‐mTOR signal transduction pathway. The inhibition ratios to PI3Kα and mTOR were slightly lower than that of NVP‐BEZ235, suggesting there may be some other mechanisms of action. The structure–activity relationships and docking study of 11a and 12a revealed that the latter was superior. Moreover, the target compounds showed better in vitro anticancer activity when the C‐6 of the quinoline ring was replaced by a bromine atom.

     

Synthesis and calcium channel modulation effects of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates possessing ortho‐, meta‐, and para‐CH2S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents

A group of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates ( 13–15 ) possessing ortho‐, meta‐, and para‐CH₂S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents were synthesized using a modified Hantzsch reaction. Calcium channel (CC) modulating activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) in vitro assays. This class of –CH₂S(O)nMe and –S(O)nMe (n = 0–2) compounds ( 13–15a–f ) exhibited weaker CC antagonist activity on GPILSM (IC₅₀ = > 1.1 × 10^–5 to 4.1 × 10^–6 M range) than the reference drug nifedipine (IC₅₀ = 1.4 × 10^–8 M). The oxidation state of the sulfur atom was a determinant of smooth muscle CC antagonist activity where the relative activity profile was generally thio ( 13 , ‐CH₂SMe, ‐SMe) and sulfonyl ( 15 , ‐CH₂SO₂Me, ‐SO₂Me) > sulfinyl ( 14 , ‐CH₂SOMe, ‐SOMe). The point of attachment of the phenyl substituent was a determinant of activity for the –CH₂SMe ( 13a–c ), ‐CH₂SOMe ( 14a–c ) and SOMe ( 14d–f ) isomers where the relative potency order was meta and para > ortho. Compounds in this group ( 13–15 ), unlike Bay K 8644 (EC₅₀ = 2.3 × 10^–7 M on GPILSM), did not exhibit an agonist effect on GPILSM. The meta‐CH₂SMe ( 13b ), ortho‐CH₂SMe ( 13c ), meta‐SMe ( 13e ), and ortho‐CH₂SO₂Me ( 15c ) C‐4 phenyl derivatives exhibited respectable in vitro cardiac positive inotropic activities (EC₅₀ = 1.00 × 10^–6 to 7.57 × 10^–6 M range) relative to the reference drug Bay K 8644 (EC₅₀ = 7.70 × 10^–7 M) in the GPLA assay. In contrast to Bay K 8644, which acts as an undesirable calcium channel agonist on smooth muscle (GPILSM), compounds 13b (IC₅₀ = 4.11 × 10^–6 M), 13c (IC₅₀ = 2.29 × 10^–5 M), 13e (IC₅₀ = > 1.20 × 10^–5 M) and 15c (IC₅₀ = 6.22 × 10^–6 M) exhibited a desirable simultaneous calcium channel antagonist effect on smooth muscle at a similar ( 13b , 15c ), or lower ( 13c , 13e ), concentration relative to its cardiac agonist EC₅₀ value. Model compounds such as 13b , 13c , 13e , and 15c , that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulators that offer a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:177–186, 2000. © 2001 Wiley‐Liss, Inc.     

Efficient Total Synthesis and Biological Activities of 6‐Deoxyisojacareubin

6‐Deoxyisojacareubin was directly synthesized in a six‐step route with an overall yield of about 20%. In this route, the excellent site selectivity of this Claisen rearrangement‐cyclization reaction cascade was achieved by inserting a bulky p‐tosyl group into the free 1‐OH, and in the last step, some efficient demethylation methods were explored. Furthermore, all synthesized intermediates including 6‐deoxyisojacareubin were evaluated for their inhibitory activity against the QGY‐7703 cell line. Of these, compound 1 and 6‐deoxyisojacareubin showed moderate activities with IC₅₀ values of 39.61 and 9.65 µM, respectively, when compared to the positive control 5‐fluorouracil with an IC₅₀ value of 11.24 µM. Further investigation using non‐radioactive detection of protein kinase C (PKC) suggested that these two compounds possessed potency in the inhibition of PKC.     

Facile synthesis and in-vitro antimalarial activity of novel α-hydroxy hydrazonates

A series of previously unreported α‐hydroxy hydrazonates were synthesized and tested for their antimalarial properties. Structure optimization of the antiplasmodially active α‐hydroxy hydrazonate III furnished derivatives with strong in‐vitro antimalarial activity against 3D7 strains of Plasmodium falciparum with IC₅₀ values lower than 2.0 µM.