Position Of Phenyl Ring Research Articles

Design And Synthesis Of Novel Thiazole Linked Tetrahydropyridine Analogues As Anticancer Agents.

A library of new thiazole linked tetrahydropyridines (6a-q) synthesized and screened for their invitro anticancer activity against human breast adeno carcinoma cell viz. MCF-7 and MDA-MB-231. The two compounds 6d containing -F and -Cl functions in para and meta position of phenyl ring (9.94 ± 1.02µM, 9.78 ± 1.08µM) and 6e with -Cl and -NH2 functions on pyridine ring (9.72 ± 0.91 µM,9.54 ± 0.95µM) demonstrated outstanding activity against both the cell lines when compared to Doxorubicin. The benzofuran analogue 6o presented good activity with an IC50 value of 12.19 ± 1.03µM (MCF-7) and 12.22 ± 1.07µM (MDA-MB-231). The molecular docking study of potent molecule 6e against crystal structure of breast tumor kinase presented promising docking score and binding interactions. Predicted pharmacokinetics properties of compounds 6a-q and presented boiled diagram of compounds 6d and 6e implied favourable drug-likeness properties.

Design, Synthesis, Biological and Computational Analysis of Isatin-based bis-Thiourea Analogues as Anti-diabetic and Anti-nematode Agents

A new series of isatin derivatives were synthesized, characterized by 1HNMR, 13CNMR and HREI-MS, and screened for α-glucosidase and alpha amylase inhibition. All the analogues were found to be dual inhibitors and showed good inhibitory potentials with IC50 values ranging from 5.28 ± 0.10 to 38.66 ± 0.30 µM (against alpha-amylase), and 5.45 ± 0.10 to 39.25 ± 0.50 µM (against alpha-glucosidase), as compared to the standard drug acarbose (IC50 = 11.12 ± 0.15 and 11.29 ± 0.07 µM, respectively). The most potent inhibitor among the series was analogue 24 (IC50 = 5.28 ± 0.10 for alpha-amylase and IC50 = 5.46 ± 0.10 µM for alpha-glucosidase), which has a nitro group attached at the meta-position of the phenyl ring A and the para position of phenyl ring B. Structure-activity relationship has been established mainly based on the position, nature and number of the substituent(s) attached to the phenyl ring. To investigate the binding interaction of the potent analog with the active site of an enzyme, molecular docking studies were carried out. To study the drug-likeness properties, the ADME study was also carried out. The most active compounds engage most of the amino acids composing the active site and display maximum interactions. These interactions majorly include formation of strong hydrogen bonds, which might be due to the presence of highly electronegative heteroatoms on aromatic rings. All the analogues were also tested for in vivo anti-nematodal activity against C. elegans to assess their cytotoxicity in comparison to the reference Levamisole. The cytotoxicity profile demonstrated that analogues 2, 7, 20 and 22 displayed minimum cytotoxicity at every concentration.

Mono-/multi-fluorination of 1,8-naphthalimides for developing AIE/AIEE fluorophores with tuning emission wavelength

Aggregation-induced emission/aggregation-induced emission enhancement (AIE/AIEE) luminogens provides amount of highly emissive materials in density states for versatile applications. Most of the AIE/AIEEgens were designed with the multiply rotation unit, in which the additional rotation units not only extend the molecular structure but also suffer from low atom economy. Herein, a fluorination strategy was introduced to construct ten AIE/AIEEgens with 1∼3 fluorine (F) atoms at different position of phenyl ring at previous developed AIEgen, 4-phenyl-1,8-naphthalimide, which can output tuning emissive wavelength and high quantum yields in both aqueous solutions and solids. In these compounds, five AIEgens with ortho-F atom and five AIEEgens without ortho-F atom were obtained. All compounds show bright blue emissions centered at 430–485 nm in aqueous solutions and wide emissions covering visible region in solid states. We calculated the ratio of quantum yields between their aqueous solution and THF solution (Φwater/ΦTHF). The AIE luminogens show the higher ratios between 10.19 and 24.89 and the AIEEgens show the lower ratios between 1.89 and 6.40. This strategy based on changing the substituent positions of F atoms provides an efficient and convenient method for construction of novel AIE-active materials with variable photophysical properties in density states.

Benzylidene-isophorone hybrids with strong anticancer activity

Isophorone is a cyclic ketone that has gained significant attention in the field of organic chemistry due to its versatile reactivity and structural attributes. Derivatives of isophorone offer a broad spectrum of applications ranging from pharmaceuticals to polymer chemistry. With the aim of developing novel hybrid structures based on benzylidene by combining with isophorone scaffold, we report 3 derivatives of the benzylidene-isophorone hybrids and its potent anticancer activity. In order to optimize the anticancer activity of hybrids di-substitution of –Cl group in C2 and C6 position of phenyl ring (compound1), –OCH3 group in C2 and C5 position of phenyl ring (compound2), and –OCH3 group in C2 and C3 position of phenyl ring (compound3) of benzylidene (PhCH=) moiety were made. The structure of Compounds1,2 and 3 were elucidated using spectral and XRD methods. Compounds1,2 and 3 exhibit space group P c a 21, P-1, and P 1 21/n 1 respectively. Compounds1,2 and 3 were tested for the potent anticancer activity on MDA MB-231 cell line. All the three compounds exhibit good anticancer activity on the breast cancer cells. The parent hybrid with ortho, ortho directing –Cl (1) exhibits strong antiproliferation effect (IC50 = 0.028 µM) on MDA-MB 231 cell line. However, hybrid structures with ortho, meta directing –OCH3 (2) group showed moderate effect (IC50 = 0.061 µM) and hybrid with ortho, meta directing –OCH3 (3) substitution showed the least potent anticancer activity (IC50 = 0.074 µM). The benzylidene-isophorone hybrids exhibit anticancer effects in the following order: 1 > 2 > 3.

Combined computational and synthetic strategies for the development of potent pyrazolo-pyridine derivatives as anticancer agents

PI3K comprise a group of lipid kinases mainly made up of three classes and have a particular role in signal transduction. The aberration of class IA PI3K is most frequently shown in cancer. The computation techniques have been applied for the identification of potent compounds. This involved the generation of a library of novel compounds (2700) through R-group enumeration study. The screening process utilized a combination of pharmacophore-based virtual screening and various docking algorithms, leading to the discovery of ten novel compounds. The docking studies against PI3K kinase highlighted MSA6 and MSA7 as the most promising compounds, with docking scores of -9.03 and -9.0 kcal/mol, respectively. Results of docking studies of all derivatives confirmed satisfactory binding mode of the compounds within the active site of the target protein PI3K kinase. The screened pyrazolo-pyridine derivatives (MSA1-MSA10) were synthesized and evaluated as anti-cancer agents against NSCLC using A549 cell line. MSA6 showed the dose dependent enhancement in ROS production at concentration of 10 and 20 µM in A549 cells. MSA6 triggered caspase 3 cleavage in lung cancer cells in a dose-dependent manner. MSA6 treatment at 10 and 20 µM levels boosted NF-κβ expression in the cytoplasm while decreasing it in the nucleus, as demonstrated by flow cytometry with an anti-NF-κβ antibody. The modulation of PI3K activity have been observed at 10 µM and 20 µM concentration of MSA6. A549 cells treated with MSA6 with 20 µM showed significant reduction in wound healing in cancerous cell. A549 cells treated with 20 µM showed significantly reduction in number of colonies compared to control group. Compound MSA6 having a methyl group at the para position of phenyl ring at imine carbon and phenyl ring substitution at nitrogen of pyrazole ring exhibited remarkable growth inhibitory activity with IC50 value of 49.23 μM. Based on the above results, pyrazolo-pyridine derivatives can be used for the further development of novel PI3K kinase inhibitors as anticancer agents.

Phenalenyl-substituted stilbenes as the basis for spin switches: quantum-chemical modeling

Isomers of stilbenes containing phenalenyl substituents in the para - and meta -positions of phenyl rings were studied by means of density functional theory method. Exchange coupling in structures with the trans -form of stilbenes is absent. In the cis -isomer of a meta -substituted compound, the state with a closed electron shell is stabilized due to two-electron multicenter interactions, which is confirmed by CASSCF calculations. The predicted transition between the triplet and singlet states as a result of trans-cis isomerization opens up prospects for using the discovered effect in the development of organic spin switches.

Synthesis, in vitro evaluation and molecular docking studies of hybrid 4-quinolinyl bearing 1,3,4-thiadiazole-2-amine as a new inhibitor of α-amylase and α-glucosidase

Synthesized scaffolds (1–19) of 4-quinolinyl based 1,3,4-thiadiazole-2-amine were evaluated in vitro for their α-amylase and α-glucosidase inhibition. All the newly synthesized scaffolds (1–19) were found to illustrate variable degree of inhibitory profile against α-amylase and α-glucosidase enzymes ranging from 1.30 ± 0.05 to 45.60 ± 0.80 µM and 2.70 ± 0.10 µM to 47.60 ± 0.90 µM. Among the series, compounds 2 (IC50 = 2.20 ± 0.10 µM), (IC50 = 8.40 ± 0.20 µM), 3 (IC50 = 4.10 ± 0.10 µM), (IC50 = 5.60 ± 0.10 µM), 4 (IC50 = 1.30 ± 0.05 µM), (IC50 = 2.90 ± 0.10 µM) and 5 (IC50 = 1.90 ± 0.10 µM), (IC50 = 2.70 ± 0.10 µM) were found to be the most potent inhibitors of α-amylase and α-glucosidase enzymes. The elevated inhibitory profile of these scaffolds might be due to presence of flouro and chloro group at different positions of phenyl ring attached to 1,3,4-thiadiazole ring. Various types of spectroscopic techniques such as 1H-, 13C- NMR and HREI-MS spectroscopy were used to confirm the structure of all the newly developed scaffolds. To find SAR, molecular docking studies were performed to understand the binding mode of potent inhibitors with active site of enzymes and results supported the experimental data. Molecular dynamics study were performed to further investigate the orientation and binding interaction of the synthesized analogues with active site of α-amylase and α-glucosidase enzyme. ADMET prediction and in silico drug likeness analysis of the synthesized analogues demonstrated that these analogues have satisfactory ADMET profile and drug likeness.

Method of Molecular Parameters for Columnar Mesomorphism Prediction of Tristriazolotriazines

The possibility of using the method of molecular parameters, developed earlier for the prediction of columnar mesomorphism in discotic compounds, was analyzed as applied to star-shaped derivatives of tristriazolotriazine (TTT). Two series of TTT derivatives of different isomeric structures with tangential t-TTT (79 structures) and radial r-TTT (22 structures) positions of phenyl rings were used for analysis. The mesomorphism of these compounds was known from the literature data. Modeling and optimization of 101 structures were carried out and data on the prediction of columnar mesomorphism were obtained using the “CMP ChemCard” software product. The high reliability of the prediction was proved only for t-isomer derivatives of TTT (coincidence with the experiment – 80.4%). For r-isomers, the reliability of the prediction was 52.3%. Based on the prediction results, it is assumed that 29 mesogenic structures of t-TTT series, for which the supramolecular structure of the mesophase has not been previously identified, form mesophase of columnar type.

Synthesis, in-vitro α-glucosidase inhibition and molecular docking studies of 1,3,4-thiadiazole-5,6-diphenyl-1,2,4-triazine hybrids: Potential leads in the search of new antidiabetic drugs

A series of 1,3,4-thiadiazole-5,6-diphenyl-triazine hybrids 7a-l have been designed, synthesized and investigated for the α-glucosidase inhibitory activities. All the synthesized compounds 7a-l showed better inhibitory activities with IC50 values ranging between 14.36 ± 0.70 to 743.15 ± 0.86 µM in comparison with the standard drug acarbose (IC50 = 844.81 ± 0.53 µM) towards α-glucosidase. Compound 7 g with chloro substituent at the ortho position of phenyl ring at thiadiazole moiety was found to be the most active inhibitor in the series. In the kinetic analysis, the most potent compounds 7 g, 7j, 7d, 7 h and 7l exhibited mixed mode of inhibition with respect to the substrate. Furthermore, the blind molecular docking studies of all the hybrid compounds were also performed to discover the binding pose and binding interactions at the enzymatic site of α-glucosidase. The current study reveals the potential of 1,3,4-thiadiazole-5,6-diphenyl-triazine hybrids 7a-l as α-glucosidase inhibitors.

Substituted diamides of dipicolinic acid as extractants and ionophores for rare earth metals

The variety of newly synthesized diamides of dipicolinic acid (DPA) bearing methyl- and oxymethyl substituents in various positions of phenyl ring was investigated as potential ligands for liquid–liquid extraction of rare earth metal ions and as membrane active compounds in plasticized polymeric membranes of potentiometric sensors. It is found that scandium is extracted with 2,6-pyridinedicarboxylic acid diamides similarly to heavy lanthanides, while yttrium is extracted together with light group lanthanides. DPA shows high selectivity for the separation of cadmium/zinc, lead/nickel or copper/nickel pairs. The four out of six studied ligands demonstrate significant potentiometric sensitivity towards scandium, yttrium and lanthanides in 10−7–10−3 mol/L concentration range in nitric acid solutions. The trends in sensitivity values vary depending on a ligand structure and the highest values are observed for Sc3+ and heavy lanthanides. According to the evaluated selectivity Sm3+ is the most preferred ion, while La3+ is the most discriminated. The differences in sensor behavior in rare earth metal solutions assume that such devices can be applied in sensor arrays for potentiometric analysis of lanthanide mixtures.

Synthesis, in vitro evaluation, and molecular docking studies of benzofuran based hydrazone a new inhibitors of urease

This work has described the synthesis of novel class (1 – 25) of benzofuran based hydrazone. The hybrid scaffolds (1 – 25) of benzofuran based hydrazone were evaluated in vitro , for their urease inhibition. All the newly synthesized analogues (1 – 25) were found to illustrate moderate to good urease inhibitory profile ranging from 0.20 ± 0.01 to 36.20 ± 0.70 µM. Among the series, compounds 2 2 (IC 50 = 0.20 ± 0.01 µM), 5 (IC 50 = 0.90 ± 0.01 µM), 23 (IC 50 = 1.10 ± 0.01 µM) and 25 (IC 50 = 1.60 ± 0.01 µM) were found to be the many folds more potent than thiourea as standard inhibitor (IC 50 = 21.86 ± 0.40 µM). The elevated inhibitory profile of these analogues might be due to presence of dihydroxy and flouro groups at different position of phenyl ring B attached to hydrazone skeleton. These dihydroxy and fluoro groups bearing compounds have shown many folds better inhibitory profile through involvement of oxygen of dihydroxy groups in hydrogen bonding with active site of enzymes. Various types of spectroscopic techniques such as 1 H-, 13 C- NMR and HREI-MS spectroscopy were used to confirm the structure of all the newly developed compounds. To find SAR, molecular docking studies were performed to understand, the binding mode of potent inhibitors with active site of enzymes and results supported the experimental data.

Understanding the role of cyclometalating ligand regiochemistry on the photophysics of charged heteroleptic iridium(III) complexes

The ability to tune the emission energy of cyclometalated iridium(III) complexes through ligand modification is well understood. Changing the electronic profile of functional groups affords complexes that exhibit emission spanning the visible spectrum, but the regiochemistry of substitution, and its effect on photophysical properties beyond emission energy, remains less explored. In this paper we investigate the substitution pattern of an electron-donating (-OCH3) and electron-withdrawing (-CF3) functional group around the phenyl-ring of 2-phenylpyridine cyclometalating ligands. A family of heteroleptic [Ir(C∧N)2(phen)]PF6 complexes, containing C∧N as the cyclometalating and 1,10-phenanthroline (phen) as the ancillary ligand, were synthesized and characterized using a range of experimental and theoretical techniques. Optical spectroscopy revealed that iridium(III) complex photophysics were most significantly affected when substitution occurred at the 5 phenyl-ring position, para relative to the orthometalated carbon atom. Subtle differences were also observed when substitution occurred at either the 4 or the 6 phenyl-ring position, despite substitution at either site being meta relative to the organometallic bond.

Synthesis, analgesic, anti-inflammatory, COX/5-LOX inhibition, ulcerogenic evaluation, and docking study of benzimidazole bearing indole and benzophenone analogs

Inflammation therapy is particularly focused on the development of safer non-steroidal anti-inflammatory drugs (NSAIDs), administered to control inflammation. It is typically considered that dual-inhibition of COX/5-LOX, which improves efficacy and has fewer side effects, is an effective technique for combating inflammation. In this perspective, the series of titled compounds (10a-j) were designed, synthesized, and characterized following with the anti-inflammatory, analgesic, and ulcerogenic evaluation. The investigation of the potentiality of the titled compounds (10a-j) displayed a high degree of anti-inflammatory activity. The compounds displaying potential analgesic activity were identified and validated further for evaluation of analgesic, anti-inflammatory activity, and subsequent ulcerogenic evaluation. In addition, the COX-1, COX-2, and 5-LOX analyses were carried out in vitro. Among (10a-j) series, compound 10c with para substitution of fluoro group on the benzoyl ring and two chloro groups at ortho position in phenyl ring of benzophenone was observed to have good inhibitory potency. Furthermore, the in silico docking study was performed by using AutoDock tools docking software.

SYNTHESIS AND CHARACTERIZATION OF NOVEL 3-(AMINOMETHYL)-5- BENZYLIDENETHIAZOLIDINE-2,4-DIONE DERIVATIVES AS ANTICANCER AGENTS

Thiazolidine-2, 4-dione (TZD) is a vital nucleus in heterocyclic chemistry. Novel 3-(aminomethyl)-5- benzylidenethiazolidine-2,4-dione derivatives were synthesized and characterized by 1H NMR, IR and Mass spectroscopy. The compounds wer synthesized by knoevenagel condensation with cyclization reaction and evaluated for anticancer activity against human cancer cell lines of HeLa (Cervical cancer cells) and HCT-8 (Colon carcinoma) using sulforhodamine B (SRB) method. Compound 3i was the most potent derivative of the series against both cell lines HeLa and HCT-8 with IC50 value of 0.007 μM and 0.001 μM, consecutively. By comparing the activities of potent compounds (3a, 3b, 3f, 3g, 3i, 3n, 3q) with other derivatives, it was revealed that the presence of electronegative groups at C-2 and C-3 positions of phenyl ring confers the highest cytotoxic activity against Cervical cancer and Colon carcinoma cell lines. The physicochemical parameters of these compounds followed the Lipinski rule of five.

Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms.

A series of aryl-substituted 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a–4q) were designed and synthesized via reaction of 6-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. The structures of the novel compounds 4b, 4c, 4f, 4g, 4i, 4l, 4m, and 4o–4q were established according to IR, 1H-NMR, 13C-NMR/13C-NMR-DEPT, and MS. The benzochromene derivative 4c with a single chlorine at the meta position of the phenyl ring and, to a lesser extent, other benzochromenes with monohalogenated phenyl ring (4a, 4c–4f) exhibited the highest cytotoxicity against six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, 5,637, and Hep G2. The mechanisms of the cytotoxic activities of benzochromenes with monohalogenated phenyl ring (4a, 4c–4f) were further analyzed using triple-negative breast cancer cell line MDA-MB-231. Cell cycle analysis showed accumulation of the treated cells in S phase for 4a, 4d–4f, and S-G2/M phases for 4c. In vivo, 4a and 4c–4f inhibited growth, proliferation, and triggered apoptosis in preestablished breast cancer xenografts grown on the chick chorioallantoic membranes while exhibiting low systemic toxicity. Compounds 4a and 4c–4f increased levels of mitochondrial superoxide and decreased mitochondrial membrane potential resulting in initiation of apoptosis as demonstrated by caspase 3/7 activation. In addition, 4c induced general oxidative stress in cancer cells. The SAR study confirmed that halogens of moderate size at meta or para positions of the pendant phenyl ring enhance the cytotoxic activity of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles, and these compounds could serve as leads for the development of novel anticancer therapies.

Structure‐Property Correlation of C10‐(H)‐Arylated‐N‐(pyren‐1‐yl)‐picolinamide Regioisomers towards Cu2+ and Fe3+ Sensing

AbstractRecently developed C10‐(H)‐arylated‐N‐(pyren‐1yl)‐picolinamide compounds have been investigated spectroscopically for their photophysical properties and metal ion sensing abilities. Two sets of regioisomers were selected based on their molar absorptivities and fluorescence quantum yields and classified into two series I methoxy group at meta‐ and para‐ position of phenyl ring, and series II methyl group at meta‐ and para‐ position of phenyl ring. Additionally, for better understanding on structure‐property relationship, a comparison study with C‐10 unsubstituted compound was also conducted. All compounds exhibited characteristic absorption and emission responses only towards Cu2+ and Fe3+ ions among all the screened metals. While the reference compound and those with methoxy substituent displayed a fluorescence turn‐off behaviour, compounds with methyl groups showed fluorescence turn‐on response through excimer formation at ∼550 nm in the presence of Cu2+ and Fe3+. Sensing studies were performed to elucidate structure‐property relationship and to obtain limits of detection, binding constants and fluorescence quenching constants. Temperature‐dependent fluorescence studies were performed to distinguish the type of excimers produced by two compounds in series II with the metal ions.

Unveiling the Full Potential of 2-aryl-1H-phenanthro [9,10-d] imidazoles as Cytotoxic Agents vs AGS, HepG2 and MCF-7 Cell lines

A few 2-aryl-1H-phenanthro [9,10-d] imidazoles were synthesized and assessed for their cytotoxicity against MCF-7, HepG2, and AGS cell lines using MTT assay. Cellular assessments showed that phenanthroimidazoles were extremely potent cytotoxic agents (sub-nanomolar IC50s). Maximum effect was recorded for para-N-phenyl acetamide containing derivative against AGS cells (IC50=0.07 nM). It was also revealed that phenanthroimidazole derivatives showed better cytotoxicity against MCF-7 and AGS cells when compared to HepG2 cells. Minimum cytotoxicity was reported for para-methylphenyl derivative within HepG2 cancer cells (IC50 7608.07 nM). Structure activity relationship studies indicated that incorporation of nitrogen/oxygen containing polar groups such as N-acetyl or nitro into para/meta positions of phenyl ring significantly enhanced the cytotoxicity against AGS cells. Similar trend was observed in meta-nitro derivatives vs MCF-7 cells. It was revealed that even the least potent compound exhibited cytotoxic activity in the range of low micromolar IC50. Results of this study proposed 2-aryl-1H-phenanthro [9,10-d] imidazoles as privileged structures for further in vivo studies.

Evaluation of N-aryl-β-alanine derivatives as anticancer agents in triple-negative breast cancer and glioblastoma in vitro models

Synthesis of β-amino acid derivatives containing hydrazone and azole moieties is described. For this purpose, the appropriate hydrazide was treated with aromatic aldehydes, ketones and phenyl iso(thio)cyanates to obtain the desired outcome. The synthesized target compounds were evaluated for their anticancer properties. The assay displayed 3,3′-((2,6-diethylphenyl)azanediyl)bis(N′-(benzylidene)propanehydrazide) to possess the convincing anticancer effect against triple-negative breast cancer cells in vitro. To further study the anticancer properties of compounds containing a hydrazone moiety in breast cancer, series of previously and newly prepared dihydrazones were investigated. It was determined that derivatives with the bis(N′-(4-bromobenzylidene) fragment in the structure are exclusively cytotoxic to cancer cells. The most active compounds against both cell lines were those containing electron withdrawing 4-BrPh or 4-ClPh moieties, together with either chlorine, bromine or iodine groups in para position of phenyl ring. Selected two representative compounds showed migrastatic activity in MDA-MB-231 cell line, where both of them reduced the growth of breast cancer and glioblastoma cell 3D cultures and inhibited cell colony formation. 2009 Elsevier Ltd. All rights reserved.

Molecular docking analysis of selected pyrimidine derivatives with human cyclin-dependent kinase 2.

A series of pyrimidine were synthesized, characterized and evaluated for their antioxidant properties using the human cyclin-dependent kinase-2 protein model. Data shows that the pyrimidine derivatives (compound ID 4G) with para fluoro groups substitution at phenyl ring attached to the 4th position (IC50: 98.5µg/ml), compound 4B bearing hydroxy group at para position of phenyl ring (IC50: 117.8 µg/ml) have significant antioxidant activity. Docking data infer that compounds 4c, 4a, 4h and 4b possess binding energy (-7.9, -7.7, -7.5 and -7.4 kcal.mol-1) with 1HCK (PDB ID) receptor.

Synthesis and Biological Evaluation of Tetrahydropyrimidine and Dihydropyridine Derivatives Against Leishmania Major.

A number of tetrahydropyrimidines and their bioisosteric dihydropyridines bearing chloro substituent at various positions of phenyl ring in C4 of main scaffolds were designed, synthesized and evaluated for antileishmanial activity. The antileishmanial activity of the synthesized compounds was evaluated against promastigote and amastigote forms. Moreover, molecular docking studies of the compounds in pteridine reductase 1 (PTR1) pocket were carried out to describe the results of biological experiments. The compounds exhibited moderate to good antileishmanial activity against promastigote and amastigote forms. Among the screened compounds, 1d and 2c were found as the most potent compounds against promastigote form with EC50 values of 15.5 and 10.5µM, respectively. Compounds 2a and 2c were the most potent compounds against amastigote form with EC50 values of 5.4 and 2.2µM, respectively. According to structure-activity relationship (SAR) studies, the chloro substituent in different positions of phenyl ring at C4 of 1,2,3,4-tetrahydropyrimidine (THPM) and 1,4-dihydropyridine (DHP) rings and also the length of the chain belonging to the ester groups could be important for antileishmanial activity of these compounds. Most of these compounds exhibited low cytotoxicity against macrophages. Compounds 1h, 2a, 2b and 2c revealed higher activity than glucantime while all compounds showed lower activity toward amphotericine B. Docking studies showed that the synthesized compounds were fit well in the PTR1 pocket. Compounds 1h and 2c indicated the highest score docking among screened compounds in PTR1 enzyme.