The application of tandem aza-wittig reaction to synthesize artemisinin-guanidine hybrids and their anti-tumor activity

Three series of novel artemisinin–guanidine hybrids 4a–4f , 8a–8h and 9a–9h have been facilely synthesized via four‐component reaction (aza‐Wittig reaction) and evaluated for their anti‐tumor activities against A549, HT‐29 and MDA‐MB‐231 cell lines in vitro. All of the tested compounds showed enhanced anti‐tumor activities with IC₅₀ values ranging from 0.02 µM to 12.0 µM as compared to DHA (dihydroartemisinin). Among them, artemisinin derived dimers, compounds 9b (IC₅₀ = 0.05 µM), 9d (IC₅₀ = 0.06 µM) and 9f (IC₅₀ = 0.02 µM) were found to be most active against HT29 cells.     

Synthesis and cytotoxicity studies of novel 2-Hydrazonylpyrido[2,3-b]pyrazin-3(4H)-ones

In an attempt to develop potent antitumor agents, a series of novel 2‐hydrazonylpyrido[2,3‐b]pyrazin‐3(4H)‐one derivatives were designed and synthesized. All the prepared compounds were screened for their cytotoxic activities against A549, MDA‐MB‐231 and HT‐29 cell lines in vitro. Pharmacological data indicated that five of the target compounds showed cytotoxicity against A549 cell line below a concentration of 1 µM. Compound 15g was the most potent one with IC₅₀ values of 0.19, 2.11 and 2.15 µM against A549, MDA‐MB‐231 and HT29 cell lines, respectively.     

In-vitro antiproliferative activity of benzopyranone derivatives in comparison with standard chemotherapeutic drugs

The cytotoxic activities of five new benzopyranone derivatives containing basic amino side chain are described. Their cytotoxicities against ER(+) MCF‐7 and ER(–) MDA‐MB‐231 human breast cancer cell lines, and Ishikawa human endometrial cell line were determined after 72 h drug exposure employing CellTiter‐Glo assay at concentrations ranging from 0.01–1.0 × 10⁵ nM. The antiproliferative activities of these compounds were compared to tamoxifen (TAM), 4‐hydroxytamoxifen (4‐OHT, active metabolite of tamoxifen), and raloxifene (RAL). In‐vitro results indicated that compounds 9 , 10 , 12 , and 13 were more potent than TAM against the human breast cancer cell lines with IC₅₀ < 20 µM. The in‐silico structure–activity relationships of these compounds and their binding mode within the estrogen receptor (ER) binding site using AutoDock vina are discussed.     

Anti-tumor activity of new artemisinin-chalcone hybrids

In an attempt to develop potent and selective anti‐tumor agents, three new series of artemisinin–chalcone hybrids 10a – 10g , 11a – 11g and 12a–12h were designed, synthesized and screened for their anti‐tumor activity against five cell lines (HT‐29, A549, MDA‐MB‐231, HeLa and H460) in vitro. Among compounds 10a–g and 11a–11g , most of them displayed enhanced activity and good selectivity toward HT‐29 and HeLa cell lines with IC₅₀ values ranging from 0.12 to 0.85 µM as compared with DHA (dihydroartemisinin). Compounds 10a and 11a are most active toward HeLa cells with IC₅₀ values of 0.12 and 0.19 µM. The results revealed that the presence of chalcone moiety is beneficial to their activity and selectivity. In addition, compounds 12a ‐ 12h containing a ‘reversed chalcone’ moiety showed only slight improvement in activity than those of DHA.     

Synthesis and Biological Evaluation of Novel 6‐Hydrazinyl‐2,4‐bismorpholino pyrimidine and 1,3,5‐Triazine Derivatives as Potential Antitumor Agents

A series of 6‐hydrazinyl‐2,4‐bismorpholino pyrimidine and 1,3,5‐triazine derivatives ( 5a – 5l and 8a – 8o ) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for antiproliferative activity against three cancer cell lines (H460, HT‐29, and MDA‐MB‐231). Several potent compounds were further evaluated against two other cell lines (U87MG, H1975). Most of the prepared compounds, particularly compounds 5c and 5j with IC₅₀ values (0.07 and 0.05 µM, respectively) in the nM range, exhibited moderate to excellent antiproliferative activity and high selectivity against the H460 cancer cell line as compared with compound 1 . The most promising compound 5j , possessing a cyano group at the 3‐position of the benzene ring, showed strong antiproliferative activity against H460, HT‐29, and MDA‐MB‐231 cell lines with IC₅₀ values of 0.05, 6.31, and 6.50 µM, which were 4.6‐ to 190.4‐fold more active than compound 1 (9.52, 29.24, and 36.21 µM), respectively.     

Synthesis and biological activities of 2-amino-thiazole-5-carboxylic acid phenylamide derivatives

In an attempt to develop potent and selective anti‐tumor drugs, a series of novel 2‐amino‐thiazole‐5‐carboxylic acid phenylamide derivatives were designed based on the structure of dasatinib. All compounds were synthesized by a systematic combinatorial chemical approach. Biological evaluation revealed that N‐(2‐chloro‐6‐methylphenyl)‐2‐(2‐(4‐methylpiperazin‐1‐yl)acetamido)thiazole‐5‐carboxamide ( 6d ) exhibited high antiproliferative potency on human K563 leukemia cells comparable to dasatinib. Against mammary and colon carcinoma cells 6d was either inactive (MDA‐MB 231) or distinctly less active (MCF‐7 and HT‐29: IC₅₀ = 20.2 and 21.6 µM, respectively). Dasatinib showed at each cell line IC₅₀ < 1 µM. The results of this structure activity relationship study clearly documented that the pyrimidin‐4‐ylamino core of dasatinib is responsible for the anti‐tumor activity against non‐leukemia cell lines.     

Synthesis and Biological Evaluation of Distamycin Analogues – New Potential Anticancer Agents

Eight of analogues of distamycin, potential minor‐groove binders, were synthesized and tested for in‐vitro cytotoxicity towards human breast cancer cells MCF‐7 and MDA‐MB‐231. The method of synthesis is simple and convenient. All of the compounds 1 – 8 showed antiproliferative and cytotoxic effects against both cell lines in the range 3.47 to 12.53 μM for MDA‐MB‐231 and 4.35 to 12.66 μM for MCF‐7. All compounds demonstrated activity against DNA topoisomerases I and II at a concentration of 50 μM. The ethidium bromide assay showed that these compounds bind to plasmid pBR322, yet weaker than distamycin. Further investigations concerning the mechanism of cytotoxicity are now in progress, but the IC₅₀ values suggest that synthetic distamycin analogues with a free amino group, 3 – 4 and 7 – 8 , can serve as potential carriers of strong acting elements, e. g. alkylating groups.     

Synthesis and anticancer activity of Indolin-2-one derivatives bearing the 4-thiazolidinone moiety

A novel series of indolin‐2‐one derivatives containing the 4‐thiazolidinone moiety ( 5a—5p ) was synthesized and the cytotoxicity of these derivatives was evaluated in vitro against three human cancer cell lines (HT‐29, H460 and MDA‐MB‐231) by standard MTT assay. Some prepared compounds exhibited significant cytotoxicity against different human cancer cell lines. Several potent compounds were further evaluated against one normal cell line (WI‐38). In particular, the promising compound 5h showed remarkable cytotoxicity and selectivity against the HT‐29 and H460 cancer cell lines (IC₅₀ = 0.016 µmol/L, 0.0037 µmol/L, respectively).     

Exploration of imidazole and imidazopyridine dimers as anticancer agents: Design,synthesis, and structure–activity relationship study

Dimerization of proteins/receptors plays a critical role in various cellular processes, including cell proliferation and differentiation. Therefore, targeting such dimeric proteins/receptors by dimeric small molecules could be a potential therapeutic approach to treating various diseases, including inflammation‐associated diseases like cancer. A novel series of bis‐imidazoles ( 13–18 ) and bis‐imidazo[1,2‐a]pyridines ( 19–28 ) were designed and synthesized from Schiff base dimers ( 1–12 ) for their anticancer activities. All the synthesized compounds were screened for anticancer activities against three cancer cell lines, including cervical (HeLa), breast (MDA‐MB‐231), and renal cancer (ACHN). From structure–activity relationship studies, imidazo[1,2‐a]pyridines ( 19–28 ) showed remarkable cytotoxic activities, with compounds 19 and 24 showing the best inhibitory activities against all three cell lines. Especially, both 19 and 24 were very effective against the breast cancer cell line ( 19 , GI₅₀ = 0.43 µM; 24 , GI₅₀ = 0.3 µM), exceeding the activity of the control adriamycin (GI₅₀ = 0.51 µM). The in vivo anticancer activity results of compounds 19 and 24 were comparable with those of the animals treated with the standard drug tamoxifen. Therefore, the dimeric imidazo[1,2‐a]pyridine scaffold could serve as a potential lead for the development of novel anticancer agents.     

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.

     

Synthesis and Antiproliferative Activitiy of Novel Diaryl Ureas Possessing a 4H‐Pyrido[1,2‐a]pyrimidin‐4‐one Group

We herein disclose a series of novel diaryl urea derivatives possessing a 4H‐pyrido[1,2‐a]pyrimidin‐4‐one group as novel potent anticancer compounds. The structures were confirmed by IR, ¹H‐NMR, and MS. All the compounds were screened for their antiprofilerative activity agaist the human breast cancer cell line (MDA‐MB‐231). The pharmacological results indicated that most of the compounds showed moderate activity. The best of this series is compound 4c (IC₅₀ = 0.7 μmol/L), with a potency 3.6‐fold higher than Sorafenib (IC₅₀ = 2.5 μmol/L), which was approved in 2005.     

Design,synthesis, docking,and anticancer evaluations of phthalazines as VEGFR-2 inhibitors

Twenty new N-substituted-4-phenylphthalazin-1-amine derivatives were designed, synthesized, and evaluated for their anticancer activities against HepG2, HCT-116, and MCF-7 cells as VEGFR-2 inhibitors. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 7f was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, with 50% inhibition concentration, IC₅₀ = 3.97, 4.83, and 4.58 µM, respectively, which is more potent than both sorafenib (IC₅₀ = 9.18, 5.47, and 7.26 µM, respectively) and doxorubicin (IC₅₀ = 7.94, 8.07, and 6.75 µM, respectively). Fifteen of the synthesized derivatives were selected to evaluate their inhibitory activities against VEGFR-2. Compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC₅₀ value of 0.08 µM, which is more potent than sorafenib (IC₅₀ = 0.10 µM). Compound 8c inhibited VEGFR-2 at an IC₅₀ value of 0.10 µM, which is equipotent to sorafenib. Moreover, compound 7a showed very good activity with IC₅₀ values of 0.11 µM, which is nearly equipotent to sorafenib. In addition, compounds 7d , 7c , and 7g possessed very good VEGFR-2-inhibitory activity, with IC₅₀ values of 0.14, 0.17, and 0.23 µM, respectively.     

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.     

Design,Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors

A series of novel hybrids of indole–pyrimidine‐containing piperazine moiety were designed, synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. The results indicated that most of these compounds possessed significant cytotoxic potency against four cancer cell lines, HT‐29, A549, MDA‐MB‐231 and MCF‐7. Particularly, the most promising compound 34 showed more potent and broad‐spectrum cytotoxic activities with the IC₅₀ values ranged from 5.01 to 14.36 μm against A549, MDA‐MB‐231 and MCF‐7 cell lines. Meanwhile, 34 also displayed the most potent tubulin polymerization inhibitory activity with IC₅₀ value of 11.2 μm . Furthermore, molecular docking analysis demonstrated 34 interacts and binds efficiently with the tubulin protein at the colchicine‐binding site. It was worth noting that the compound did not affect the normal human embryonic kidney cells, HEK‐293. These results suggest that this novel class of indole–pyrimidine hybrids may have potential to be developed as new a class of tubulin polymerization inhibitors.     

Synthesis of new arylazopyrazoles as apoptosis inducers: Candidates to inhibit proliferation of MCF‐7 cells

New 4‐arylazo‐3,5‐diamino‐1H‐pyrazole derivatives substituted in the 4‐aryl ring with the acetyl moiety were designed and synthesized. The antiproliferative activity of the novel arylazopyrazoles was examined against the MCF‐7 cell line. Among all target compounds, 8b (IC₅₀ 3.0 µM) and 8f (IC₅₀ 4.0 µM) displayed higher cytotoxicity as compared with the reference standard imatinib (IC₅₀ 7.0 µM). Further studies to explore the mechanism of action were performed on the most active hit of our library, 8b , via anti‐CDK2 kinase activity. It demonstrated good inhibitory effects for CDK2 (IC₅₀ 0.24 µM) with 62.5% inhibition, compared with imatinib. The cell cycle analysis in the MCF‐7 cell line revealed apoptosis induction by 8b and cell cycle arrest at the S phase. Docking in the CDK2 active site and pharmacophore modeling confirmed the affinity of 8b to the CDK2 active site. Absorption, distribution, metabolism, and excretion studies revealed that our target compounds are orally bioavailable, with no permeation through the blood–brain barrier.     

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.     

Design, synthesis and cytotoxicity of novel chalcone analogs derived from 1-cyclohexylpyrrolidin-2-one and 2,3-dihydrobenzo[f]chromen-1-one

Two divergent series of novel chalcone analogs, one derived from 1‐cyclohexylpyrrolidin‐2‐one and the other derived from 1‐benzo[f]chromanone, were designed, synthesized and evaluated for cytotoxicity against two murine cancer cell lines. Two 1‐benzo[f]chromanone analogs, 4g and 4j yielded moderate toxicity against both melanoma B16 and lymphoma L1210 cell lines with IC₅₀ values between the range of 5 and 6 µM. With an IC₅₀ value of 3.4 µM, compound 4g was also active against human MDA‐MB‐435 melanoma cells. X‐ray structures of the β‐hydroxy ketone product ( 4a ) and the α,β‐unsaturated ketone ( 4h ) were collected, and confirm the syn‐configuration between the carbonyl moiety and the β‐vinylic proton in 4h . X‐ray structures of two 1‐cyclohexylpyrrolidin‐2‐one derivatives were also obtained, and both showed an E‐configuration for the double bond.     

5-(4-Methoxybenzylidene)thiazolidine-2,4-dione-derived VEGFR-2 inhibitors: Design,synthesis, molecular docking,and anticancer evaluations

A novel series of 5-(4-methoxybenzylidene)thiazolidine-2,4-dione derivatives, 5a–g and 7a–f , was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT116, and MCF-7 cells. HepG2 and HCT116 were the most sensitive cell lines to the influence of the new derivatives. In particular, compounds 7f , 7e , 7d , and 7c were found to be the most potent derivatives of all the tested compounds against the HepG2, HCT116, and MCF-7 cancer cell lines. Compound 7f (IC₅₀ = 6.19 ± 0.5, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively) exhibited a higher activity than sorafenib (IC₅₀ = 9.18 ± 0.6, 8.37 ± 0.7, and 5.10 ± 0.4 µM, respectively) against HepG2 and MCF-7, cells but a lower activity against HCT116 cancer cells, respectively. Also, this compound displayed a higher activity than doxorubicin (IC₅₀ = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively) against HepG2 and MCF-7 cells, but nearly the same activity against HCT116 cells, respectively. All derivatives, 5a–g and 7a–f , were evaluated for their inhibitory activities against vascular endothelial growth factor receptor-2 (VEGFR-2). Among them, compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC₅₀ value of 0.12 ± 0.02 µM, which is nearly the same as that of sorafenib (IC₅₀ = 0.10 ± 0.02 µM). Compounds 7e , 7d , 7c , and 7b exhibited the highest activity, with IC₅₀ values of 0.13 ± 0.02, 0.14 ± 0.02, 0.14 ± 0.02, and 0.18 ± 0.03 µM, respectively, which are more than the half of that of sorafenib. Furthermore, molecular docking was performed to investigate their binding mode and affinities toward the VEGFR-2 receptor. The data obtained from the docking studies highly correlated with those obtained from the biological screening.     

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.     

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.