Design, synthesis, in vitro and in silico evaluations of new isatin-triazine- aniline hybrids as potent anti- Alzheimer multi-target directed lead compounds.

Multi target directed ligands (MTDLs) are one of the promising tools for treatment of complex disease like Alzheimer's disease (AD). In this study, using rational design, we synthesized new 15 hybrids of the s-triazine, isatin and aniline derivatives as anti- AD compounds. The design was as way as that new compounds could had anti cholinesterase (ChE), antioxidant and biometal chelation ability. In vitro biological evaluation against ChE enzymes showed that these molecules were excellent inhibitors with IC50 values ranging from 0.2 nM to 734.5 nM for acetylcholinesterase (AChE), and 0.02 µM to 1.92 µM for butyrylcholinesterase (BChE). Among these compounds, 8 l with IC50 AChE = 0.7 nM, IC50 BChE = 0.09 µM and 8n with IC50 AChE = 0.2 nM, IC50 BChE = 0.03 µM were the most potent compounds. In silico studies showed that these molecules had key and effective interactions with the corresponding enzymes residues. The molecules with hydroxyl group on aniline moiety had also good antioxidant activity with EC50 values ranging from 64.2 µM to 103.6 µM. The UV-Vis spectroscopy study revealed that molecule 8n was also able to chelate biometals such as Zn2+, Cu2+and Fe2+ properly. It was concluded that these molecules could be excellent lead compounds for future studies.

Bioinformatic analysis of highly consumed phytochemicals as P-gp binders to overcome drug-resistance.

Background and purpose: P-glycoprotein (P-gp) is an adenosine triphosphate (ATP)-dependent membrane efflux pump for protecting cells against xenobiotic compounds. Unfortunately, overexpressed P-gp in neoplastic cells prevents cell entry of numerous chemotherapeutic agents leading to multidrug resistance (MDR). MDR cells may be re-sensitized to chemotherapeutic drugs via P-gp inhibition/modulation. Side effects of synthetic P-gp inhibitors encouraged the development of natural products. Experimental approach: Molecular docking and density functional theory (DFT) calculations were used as fast and accurate computational methods to explore a structure binding relationship of some dietary phytochemicals inside distinctive P-gp binding sites (modulatory/inhibitory). For this purpose, top-scored docked conformations were subjected to per-residue energy decomposition analysis in the B3LYP level of theory with a 6-31g (d, p) basis set by Gaussian98 package. Findings/Results: Consecutive application of computational techniques revealed binding modes/affinities of nutritive phytochemicals within dominant binding sites of P-gp. Blind docking scores for best-ranked compounds were superior to verapamil and rhodamine-123. Pairwise amino acid decomposition of superior docked conformations revealed Tyr303 as an important P-gp binding residue. DFT-based induced polarization analysis revealed major electrostatic fluctuations at the atomistic level and confirmed larger effects for amino acids with energy-favored binding interactions. Conformational analysis exhibited that auraptene and 7,4',7'',4'''-tetra-O-methylamentoflavone might not necessarily interact to P-gp binding sites through minimum energy conformations. Conclusion and implications: Although there are still many hurdles to overcome, obtained results may propose a few nutritive phytochemicals as potential P-gp binding agents. Moreover; top-scored derivatives may have the chance to exhibit tumor chemo-sensitizing effects.

In silico repurposing of CNS drugs for multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease affecting numerous people worldwide. While the relapsing subtypes of MS are to some extent treatable, the disease remains incurable leading to progressive disability. Limited efficacy of current small molecule drugs necessitates development of efficient and safe MS medications. Accordingly, drug repurposing is an invaluable strategy that recognizes new targets for known drugs especially in the field of poorly addressed therapeutic areas. Drug discovery largely depends on the identification of potential binding molecules to the intended biomolecular target(s). In this regard, current study was devoted to in silico repurposing of 263 small molecule CNS drugs to achieve superior binders to some MS-related targets. On the basis of molecular docking scores, thioxanthene and benzisothiazole-based antipsychotics could be identified as potential binders to sphingosine-1-phosphate lyase (S1PL) and cyclophilin D (CypD). Tightest interaction modes were observed for zuclopenthixol-S1PL (ΔGb -7.96 kcal/mol) and lurasidone-CypD (ΔGb -8.84 kcal/mol) complexes. Molecular dynamics (MD) simulations proved the appropriate and stable accommodation of top-ranked drugs inside enzyme binding sites during 100 ns. Hydroxyethyl piperazine of zuclopenthixol and benzisothiazole of lurasidone flipped inside the binding pocket to interact with adjacent polar and apolar residues. Solvent accessible surface area (SASA) fluctuations confirmed the results of binding trajectory analysis and showed that non-polar hydrophobic interactions played significant roles in acquired stabilities. Our results on lurasidone binding pattern were interestingly in accordance with previous reports on X-ray structures of other norbornane maleimide derivatives as CypD inhibitors. According to this, Asn144, Phe102 and Phe155 served as important residues in providing stable binding pose of lurasidone through both exo and endo conformations. Although experimental results are necessary to be achieved, the outcomes of this study proposed the potentiality of some thioxanthene and benzisothiazole-based antipsychotics for binding to S1PL and CypD, respectively, as MS-related targets.

Structural Insight into Privileged Heterocycles as Anti-Trypanosoma cruzi and brucei Agents.

Trypanosomiasis is caused by parasitic protozoan trypanosomes in vertebrates. T. cruzi and T. brucei are causative agents of Chagas disease (CD) and Human African Trypanosomiasis (HAT), respectively. These life-threatening diseases are a serious threat to public health, with considerable incidence in sub-Saharan African and continental Latin America countries. Although WHO validated mitigated number of HAT cases in Togo (June 2020) and Cote d'Ivoire (December 2020), serious efforts need to be performed for the elimination of the disease. Antigenic variation of trypanosomal parasites provides a major bottleneck for developing effective vaccines. In the absence of human vaccines or chemoprophylaxis, the control of trypanosomatid infections may be envisaged through the eradication of vectors, management of animal reservoirs, and chemotherapy. A small number of chemical agents are currently available for antitrypanosomal treatments, and most of them are associated with toxicity, lack of efficacy, and non-oral route of administration. Given the restricted applicability of current medications, numerous efforts have been made for the synthesis and biological evaluation of heterocyclic scaffolds as antitrypanosomal candidates. In light of the above considerations, we were prompted to describe chemical diversity within privileged 5- membered heterocycles (imidazoles, thiazoles, triazoles and tetrazoles) as antitrypanosomal agents. The main purpose of the study was to throw light on the structure-activity relationship (SAR) of the relevant structures. To capture the recent structural diversity within reported cases, small molecules that belonged to the recent 7-year period (2015-2021) have been discussed. The available medications have also been briefly reviewed.

In silico target specific design of potential quinazoline-based anti-NSCLC agents.

Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In spite of great advances, treatment of the disease is a medical challenge. Epidermal-growth factor receptor (EGFR) has been taken as a promising cell surface target to develop anti-NSCLC therapies. The main bottleneck to attain clinical efficacy with current EGFR tyrosine kinase inhibitors (EGFR-TKIs) is the rapid spread of oncogenic mutations. Numerous efforts have been made for the synthesis of diverse EGFR-TKIs against resistance-conferring mutations. One of the best strategies to design potent agents would be to explore existing anti-NSCLC drugs at the nonclinical development stage and prioritize privileged structural patterns. Within current study, conformational stability of clinically frequent EGFR mutants (G719S, T790M, L858R and a double mutant form L858R/T790M) were validated via DynaMut and missense3D computational servers. Subsequently, structure activity relationship (SAR) and scaffold similarity inquiry were used to rationally propose a few erlotinib analogues. Intended molecules were subjected to molecular docking and top-scored binders were further analyzed through 50-ns all atom molecular dynamics (MD) simulations to infer the dynamic behavior. The aim was to offer potential binders to overwhelm clinically frequent EGFR-TK mutants. The linear interaction energy (LIE) method was applied to compute the binding free energies between EGFR and intended ligands. For this purpose, MD-based conformational sampling of ligand-enzyme complexes and ligand-water associations were used to acquire thermodynamic energy averages. Though mechanistic details are to be explored, results of the current study identify synthetically accessible quinazoline small molecules with potential affinity toward frequent EGFR-TK mutants.[Figure: see text]Communicated by Ramaswamy H. Sarma.

HIGHLIGHTSConsecutive in silico procedure on a few rationally designed erlotinib analogues introduced two molecules with high theoretical affinity to clinically frequet mutant EGFRs (6a and 22a).MD simulations of top-ranked docked molecules were indicative of tight packed complexes and showed that mutant EGFR backbones were stable upon binding to probable inhibitors.The results of LIE method confirmed binding patterns of intended ligands and showed the dominance of van der Waals over electrostatic interactions in ligand-enzyme complexes.In overall it might be deduced that central quinazoline ring had more binding contributions toward EGFR active site in 22a.Regarding SASA distribution patterns, it might be inferred that the simulation time of 50 ns could screen equilibrated complex systems.

Synthesis, antileishmanial activity and molecular modeling of new 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives.

Due to the lack of effective vaccine(s) against leishmania and also pharmacokinetics issues of current drugs, it is necessary to discover new antileishmanial agents. Within this particular study, a series of novel 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives were synthesized (yields 69-84%) and evaluated as antileishmanial compounds (1-11). Synthetic derivatives were subjected to in vitro antileishmanial assessment against Leishmania major promastigotes by colorimetric MTT assay. Compounds 3 (IC50 38.54 µg/mL), 5 (IC50 84.75 µg/mL) and 10 (IC50 70.31 µg/mL) exhibited higher activities after 48 h but were less potent than amphotericin B (IC50 0.19 µg/mL). Antileishmanial activities indicated priority of 5-methyl-4-phenyl thiazole over furyl methyl substituents and 4-phenyl thiazole on thiourea nitrogen. N-myristoyltransferase (NMT) was selected as a validated L. major target for molecular docking studies. In silico results indicated the contribution of hydrophobic, π-stacking and H-bond interactions in binding to target. Most of the synthesized derivatives had lower binding affinities to human NMT (hNMT) than leishmanial enzyme. Docking conformations of top-ranked selective binders (compounds 3 and 5) were subjected to 50 ns MD simulations inside L. major HMT (LmNMT) active site. MD trajectories were used to extract RMSD, RMSF, Rg and durability of intramolecular/intermolecular H-bonds of the complex. It was observed that compound 3 escaped from LmNMT binding site during simulation period and no stable complex could be envisaged. Unlike 3, compound 5 attained stable binding conformation with converged stability parameters. Although mechanistic details for antileishmanial effects of synthesized derivatives are to be explored, current results may be implicated in further structure-guided approach toward potent antileishmanial agents.

In silico screening and molecular dynamics simulations toward new human papillomavirus 16 type inhibitors.

Background and purpose: Human papillomavirus (HPV) is known as the main reason for cervical cancer. According to carcinogenic risk, HPV can be located into two classes, counting the low-risk virus, which is the main cause of genital warts and low-grade cervical epithelial lesions. HPV-16 is one of the high-risk HPV subtypes in the spectrum of cervical diseases. Experimental approach: The PubChem database was screened in order to identify potential anti-HPV hits followed by ADMET predictions. Then, molecular docking was performed to improve the accuracy of screening and also to find the details of the interactions of the hit compounds with the active site. Finally, molecular dynamic (MD) simulations and free binding energy on top-ranked structures CID_73212812, CID_91059286, CID_69838075, cidofovir, and jaceosidin were carried out with protein to compute the interaction energies and stability of the top-ranked compounds at the active site. Findings/Results: Based on molecular docking studies, three compounds including CID_73212812, CID_91059286, and CID_69838075 exhibited the best results among compounds against the E6 protein of HPV-16. Furthermore, RMSD, RMSF, hydrogen binds, Rg, and energy analysis during MD simulation certainly indicated the stable binding of selected compounds with E6 protein of HPV-16 active site. Conclusion and implications: Docking and MD results revealed that hydrophobic contacts and optimum hydrogen bonds were determinant factors in the interactions of hits and the E6 protein of HPV-16. In addition, the binding energy portions exposed that Van der Waals and non-polar interactions were fundamental factors in the molecule binding.

In silico identification of potential Hsp90 inhibitors via ensemble docking, DFT and molecular dynamics simulations.

The molecular chaperone heat shock protein 90 (Hsp90) has emerged as one of the most exciting targets for anticancer drug development and Hsp90 inhibitors are potentially useful chemotherapeutic agents in cancer. Within the current study, Hsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 structure query to find similar compounds (≥ 78%). Obtained small molecules (1-29) with defined similarity cut-off were docked into ensemble of Hsp90-α NTDs. Docked complexes were ranked on the basis of binding modes and Gibbs free energies as Hsp90 binders (cut-off point; ΔGb ≤ -12 kcal/mol). Top-ranked compounds were subjected to energy decomposition analysis per residue of binding pocket via density functional theory (DFT) calculations in B3LYP level of theory. Subsequent MD simulations of the top-ranked complexes were performed for 100 ns to explore the stable binding modes during a reasonable period in explicit water. Results of molecular docking and intermolecular binding analysis indicated that H-bond, hydrophobic and salt bridge interactions were determinant forces in complex formation. Compounds 19 and 20 were well accommodated in binding pocket of Hsp90 via relatively varied conformations. It was revealed that Asn51 and Phe138 were key residues that interacted stably to 19 and 20. Although primary mechanism of action for proposed molecules are unknown and yet to be explored, results of the present study revealed key structural features for future structure-guided optimization toward potent inhibitors of Hsp90-α NTD. HighlightsHsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 based structure query to afford potential enzyme inhibitors 19 and 20.Quantum chemical calculations confirmed docking results and verified pivotal role of a conserved residues (Asn51, Leu103, Phe138 and Tyr139) in making effective hydrogen bonds.MD simulations of top-ranked docked derivatives revealed the achievement of stable binding modes with less conformational variation of 20 than 19 in the active site of Hsp90-α NTD.H-bond, hydrophobic contacts and salt bridge interactions were determinant forces in binding interactions of in silico hits.Resorcinol and isoxazole were important structural motifs of in silico hits in binding to the active site of Hsp90-α NTD.Communicated by Ramaswamy H. Sarma.

Synthesis of new 2-aminothiazolyl/benzothiazolyl-based 3,4-dihydropyrimidinones and evaluation of their effects on adenocarcinoma gastric cell migration.

Gastric cancer is one of the malignant tumors of the gastrointestinal tract that, despite its decrease in recent years, is still the fourth most common cancer and the second leading cause of cancer-related death. Various strategies including chemotherapy are used to keep cancer cells from spreading and induce apoptotic death in them. Recent studies have shown that dihydropyrimidinones (DHPMs) are privileged structures in medicinal chemistry due to their pharmacological effects. A number of new 2-aminothiazolyl/benzothiazolyl derivatives of 3,4-DHPMs (3-8) were synthesized and structurally identified, and then their effects on the migration behavior of human AGS cells (gastric cancer cells) were investigated. Molecular docking and molecular dynamics (MD) simulations were applied to explore binding potential and realistic binding model of the assessed derivatives through identification of key amino acid residues within L5/α2/α3 allosteric site of kinesin 5 (Eg5) as a validated microtubule-dependent target for monastrol as a privileged DHPM derivative.

Identification of potential antileishmanial agents via structure-based molecular simulations.

Leishmaniasis is a parasitic disease with frequent annual incidence. An important issue in chemotherapy is the emergence of resistance, toxicity and lack of cost-effectiveness within current drugs. Therefore, it is of utmost importance to design effective drugs against disease. Current contribution was devoted to the in-silico analysis of binding a few flavonoids/alkaloids to relevant leishmanial targets. Docking scores were used to prioritize acquired affinities and top ranked binders were subjected to subsequent 100-ns MD simulation in explicit water. Binding trajectories revealed the tightest interaction modes for two flavonoid molecules (acerosin and nevadensin) in the uracil DNA glycolase (UDG) active site. Acerosin showed less conformational changes whereas, nevadensin interacted stably during longer simulation time. Conserved interactions of Gln205 and His331 to acerosin indicated their dominant biological role in complex stability. No conserved residues were perceived for nevadensin interactions and a completely new and stable binding conformation could be retrieved after 12 ns simulation. Moreover; acerosin was subjected to DFT analysis for pairwise decomposition evaluations of interacted residues. Although primary mechanisms of action are yet to be discovered, UDG may be a promising target for developing antileishmanial flavonoids.

Response Surface Study on Molecular Docking Simulations of Citalopram and Donepezil as Potent CNS Drugs.

Computer-aided drug design provides broad structural modifications to evolving bioactive molecules without an immediate requirement to observe synthetic restraints or tedious protocols. Subsequently, the most promising guidelines with regard to synthetic and biological resources may be focused on upcoming steps. Molecular docking is common in-silico drug design techniques since it predicts ligand-receptor interaction modes and associated binding affinities. Current docking simulations suffer serious constraints in estimating accurate ligand-receptor binding affinities despite several advantages and historical results. Response surface method (RSM) is an efficient statistical approach for modeling and optimization of various pharmaceutical systems. With the aim of unveiling the full potential of RSM in optimizing molecular docking simulations, this study particularly focused on binding affinity prediction of citalopram-serotonin transporter (SERT) and donepezil-acetyl cholinesterase (AChE) complexes. For this purpose, Box-Behnken design of experiments (DOE) was used to develop a trial matrix for simultaneous variations of AutoDock4.2 driven binding affinity data with selected factor levels. Responses of all docking trials were considered as estimated protein inhibition constants with regard to validated data for each drug. The output matrix was subjected to statistical analysis and constructing polynomial quadratic models. Numerical optimization steps to attain ideal docking accuracies revealed that more accurate results might be envisaged through the best combination of factor levels and considering factor interactions. Results of the current study indicated that the application of RSM in molecular docking simulations might lead to optimized docking protocols with more stable estimates of ligand-target interactions and hence better correlation of in-silico in-vitro data.

Identification of a potential SARS-CoV2 inhibitor via molecular dynamics simulations and amino acid decomposition analysis.

Considering lack of validated therapeutic drugs or vaccines against contagious SARS-CoV2, various efforts have been focused on repurposing of existing drugs or identifying new agents. In an attempt to identify new and potential SARS-CoV2 inhibitors targeting specific enzyme of the pathogen, a few induced fit models of SARS-CoV2 main protease (Mpro) including N-aryl amide and aryl sulfonamide based fragments were subjected to a multi-step in silico strategy. Sub-structure query of co-crystallographic fragments provided numerous ZINC15 driven commercially available compounds that entered molecular docking stage to find binding interactions/modes inside Mpro active site. Docking results were reevaluated through time dependent stability of top-ranked ligand-protease complexes by molecular dynamics (MD) simulations within 50 ns. Relative contribution of interacted residues in binding to the most probable binding pose was estimated through amino acid decomposition analysis in B3LYP level of theory with Def2-TZVPP split basis set. In confirmation of docking results, MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔGb -9.18 kcal/mol) into Mpro active site. H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of in silico hit. Quantum chemical calculations confirmed MD results and proved the pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772. Drug-like physicochemical properties as well as desirable target binding interactions nominated ZINC_252512772 as a desirable in silico hit for further development toward SARS-CoV2 inhibitors. HighlightsA few N-aryl amide/aryl sulfonamide based fragments were subjected to a multi-step in silico strategy to afford potential SARS-CoV2 Mpro inhibitors.MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔGb -9.18 kcal/mol) into Mpro active site.H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of in silico hit.Quantum chemical calculations confirmed MD results and proved pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772.Communicated by Ramaswamy H. Sarma.

In silico design of peptide inhibitors of tubulin: amyloid-ß as a lead compound.

Microtubule is one of the most studied targets in cancer research. Stabilizing and destabilizing of the microtubule by targeting its building block tubulin are common mechanisms of microtubule targeting agents. Cancer associates inversely with Alzheimer's disease (AD). So the rate of developing AD is significantly slower in patients with cancer and vice versa. Amyloid-ß (Aß) peptide inhibits tubulin polymerization and induces apoptotic death of cancer cells. We studied the interactions of Aß with tubulin using protein-protein docking and MD simulation. Aß bond to the vicinity of the vinblastine binding site and interacted with the H6-H7 loop. Interaction of Aß with H6-H7 loop blocked nucleotide exchange and may be attributed as a possible reason for blocking of tubulin polymerization. We designed new Aß-based peptidic inhibitors of tubulin using visual inspection and alanine scanning method. P1 (FRHYHHFFELV) and P9 (HYHHF) bound efficiently to tubulin and also interacted with the H6-H7 loop. Obtained results indicated that proposed peptides could potentially inhibit nucleotide exchange as Aß.Communicated by Ramaswamy H. Sarma.

Synthesis and antileishmanial effect of a few cyclic and non-cyclic n-aryl enamino amide derivatives.

BACKGROUND AND PURPOSE: The prevalence of leishmaniasis is reported in more than 98 countries and Iran is one of the endemic areas. There is no vaccine for this disease and few effective drugs are available to treat it. Moreover, drug resistance to the disease is increasing. During the past decade, several in vitro and in vivo studies have been performed on dihydropyrimidine derivatives as antileishmanial agents. EXPERIMENTAL APPROACH: In the present project, a few 6-methyl-4-aryl-N-aryl dihydropyrimidinone/thiones (A7-A11) and N-heteroaryl-3-(para-methoxy benzyl) amino but-enamides (A1-A6) were synthesized, structurally characterized, and finally subjected to in vitro anti-leishmanial effect against Leishmania major promastigotes. FINDINGS / RESULTS: Results of the study showed that compound A10, 4-(3-chlorophenyl)-6-methyl-N-phenyl- 2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, exhibited superior anti-leishmanial effect with IC50 value of 52.67 µg/mL (more active than standard drug Glucantim® with IC50 71000 ± 390 µg/mL). CONCLUSION AND IMPLICATIONS: It was demonstrated that some dihydropyrimidine thiones were able to inhibit Leishmania major promastigotes. Structure-activity relationship evaluations indicated that more electron-poor rings such as isoxazole afforded higher activity within A1-A6 series and in these derivatives, N-benzothiazole rings reinforced anti-leishmanial activity concerning thiazole. It was also observed that higher anti-parasite activities of A10 and A11 concerning A7-A9 might be related to the incorporation of the sulfur atom into C2 position, replacement of N-thiazole carboxamide by N-phenyl carboxamide on C5 position of dihydropyrimidine ring, and also replacement of para with meta-substituted phenyls within C4 of dihydropyrimidine ring. The results may help unveil new 4-aryl-5-carboxamide dihydropyrimidines as potential anti-leishmanial agents and their further structural modification toward more potent derivatives.

Synthesis and biological assessment of ciprofloxacin-derived 1,3,4-thiadiazoles as anticancer agents.

The quinolone-3-carboxylic acid scaffold is essential structure for antibacterial activity of fluoroquinolones such as ciprofloxacin. Modification of 3-carboxylic functionality in this structure can be used for switching its activity from antibacterial to anticancer. Accordingly, a series of C-3 modified ciprofloxacin derivatives containing N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-carboxamide moiety was synthesized as novel anticancer agents. Most of compounds showed significant activity against MCF-7, A549 and SKOV-3 cancer cells in the MTT assay. In particular, compounds 13a-e and 13g were found to be as potent as standard drug doxorubicin against MCF-7 cell line (IC50s = 3.26-3.90 µM). Furthermore, the 4-fluorobenzyl derivatives 13h and 14b with IC50 values of 3.58 and 2.79 µM exhibited the highest activity against SKOV-3 and A549 cells, being as potent as doxorubicin. Two promising compounds 13e and 13g were further tested for their apoptosis inducing activity and cell cycle arrest. Both compounds could significantly induce apoptosis in MCF-7 cells, while compound 13e was more potent apoptosis inducer resulting in an 18-fold increase in the proportion of apoptotic cells at the IC50 concentration in MCF-7 cells. The cell cycle analysis revealed that compounds 13e and 13g could increase cell portions in the sub-G1 phase, inducing oligonucleosomal DNA fragmentation and apoptosis confirmed by comet assay.

Synthesis and cytotoxic effect of a few N-heteroaryl enamino amides and dihydropyrimidinethiones on AGS and MCF-7 human cancer cell lines.

BACKGROUND AND PURPOSE: Cancer prevalence has increased in the last century posing psychological, social, and economic consequences. Chemotherapy uses chemical molecules to control cancer. New studies have shown that dihydropyrimidinethione (DHPMT) derivatives have the potential of being developed into anticancer agents. EXPERIMENTAL APPROACH: New derivatives of DHPMTs and a few acyclic bioisosters were synthesized via Biginelli reaction and assessed for their toxicity against gastric (AGS) and breast cancer (MCF-7) cell lines through MTT method. FINDINGS / RESULTS: Chemical structures of all synthesized N-heteroaryl enamino amides and DHPMTs were confirmed by spectroscopic methods. Result of biological assessment exhibited that none of the tested agents was more cytotoxic than cis-platin against AGS and MCF-7 cell lines and compound 2b was the most cytotoxic agent against AGS (IC50 41.10 µM) and MCF-7 (IC50 75.69 µM). Cytotoxic data were mostly correlated with the number of H-bond donors within gastric and breast cancer cells. CONCLUSION AND IMPLICATIONS: It was realized that DHPMTs were able to inhibit the growth of cancer cells much better than acyclic enamino amides and moreover; N-(4-methylbenzothiazol-2-yl) DHPMT derivative (2b) supposed possible interaction with a poor electron site of target due to the lipophilic nature of benzothiazole ring and also less electron rich nature than isoxazole. Similar scenario was observed with acyclic enamino amides in which incorporation of sulfur and nitrogen containing heterocycles doubled the cytotoxic effects. Results of the present contribution might assist in extending the scope of DHPMTs as privileged medicinal scaffolds.

Synthesis, cytotoxic assessment, and molecular docking studies of 2,6-diaryl-substituted pyridine and 3,4- dihydropyrimidine-2(1H)-one scaffolds.

Cancer is one of the main global health problems. In order to develop novel antitumor agents, we synthesized 3,4-dihydropyrimidine-2(1H)-one (DHPM) and 2,6-diaryl-substituted pyridine derivatives as potential antitumor structures and evaluated their cytotoxic effects against several cancer cell lines. An easy and convenient method is reported for the synthesis of these derivatives, employing cobalt ferrite (CoFe 2 O 4 @SiO 2 -SO 3 H) magnetic nanoparticles under microwave irradiation and solvent-free conditions. The structural characteristics of the prepared nanocatalyst were investigated by FTIR, XRD, SEM, and TGA techniques. In vitro cytotoxic effects of the synthesized products were assessed against the human breast adenocarcinoma cell line (MCF-7), gastric adenocarcinoma (AGS), and human embryonic kidney (HEK293) cells via MTT assay. The results indicated that compound 4r (DHPM derivative) was the most toxic molecule against the MCF-7 cell line (IC 50 of 0.17 µg/mL). Moreover, compounds 4j and 4r (DHPM derivatives) showed excellent cytotoxic activities against the AGS cell line, with an IC 50 of 4.90 and 4.97 µg/mL, respectively. Although they are pyridine derivatives, compounds 5g and 5m were more active against the MCF-7 cell line. Results showed that the candidate compounds exhibited low cytotoxicity against HEK293 cells. The kinesin Eg5 inhibitory potential of the candidate compounds was evaluated by molecular docking. The docking results showed that, among the pyridine derivatives, compound 5m had the most free energy of binding (-9.52 kcal/mol) and lowest Ki (0.105 µM), and among the pyrimidine derivatives, compound 4r had the most free energy of binding (-7.67 kcal/mol) and lowest Ki (2.39 µM). Ligand-enzyme affinity maps showed that compounds 4r and 5m had the potential to interact with the Eg5 binding site via H-bond interactions to GLU116 and GLY117 residues. The results of our study strongly suggest that DHPM and pyridine derivatives inhibit important tumorigenic features of breast and gastric cancer cells. Our results may be helpful in the further design of DHPMs and pyridine derivatives as potential anticancer agents.

Synthesis and cytotoxicity evaluation of novel cyclic/non-cyclic N-aryl enamino amides against human cancer cell lines.

BACKGROUND AND PURPOSE: Considering the undesirable consequences of prevalent cancer diseases, design and development of potent and selective anticancer chemotherapeutics is a major concern. Several studies have unraveled the potential of dihydropyrimidinone (DHPM) scaffold toward generating anticancer agents. EXPERIMENTAL APPROACH: In the present work, a series of new dihydropyrimidinethiones (DHPMTs) along with a few acyclic enamino amides were synthesized and evaluated for their cytotoxic activity against human gastric (AGS), liver (Hep-G2), and breast (MCF-7) cancer cell lines. FINDINGS/RESULTS: Among the assessed compounds, one of the DHPMT derivatives (compounds, one of the DHPMT derivatives (compound 5: 4-(3- fluorophenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-ttrahydropyrimidine-5-carboxamide) exhibited superior cytotoxicity in all of the target cell lines (AGS, IC50 9.9 µM; MCF-7, IC50 15.2 µM; and Hep-G2, IC50 40.5 µM). Cytotoxicity assessments showed that non-cyclic enamino amides exhibited weaker activities when compared to cyclic analogues (DHPMs). CONCLUSION AND IMPLICATIONS: DHPMTs were better cytotoxic agents than non-cyclic enamino amides. Structure activity relationship studies guided us toward the design of DHPMT derivatives with OH and NH groups particularly on meta position of 4-phenyl ring and hydrophobic bulky substituents on carboxamide side chain within the structure. Possible interaction with the hydrophobic site(s) of the cellular target was supposed. The results of this study emphasized the potential role of DHPMTs and their optimized derivatives as privileged medicinal scaffolds to inhibit the growth of gastric, breast, and liver cancer cells.

Insights into the current status of privileged N-heterocycles as antileishmanial agents.

Leishmania, one of the most important neglected tropical diseases, is endemic in several regions of the world and hence regarded as a serious threat to public health. Major difficulties with current chemotherapeutic agents raise issues such as toxicity, resistance, cost and other side effects. These issues necessitate development of potentially new chemical entities against diverse leishmanial species. Numerous natural and synthetic new antileishmanial molecules have been described for disease management. Careful inspection of scientific reports revealed that considerable amount of promising antileishmanial agents belonged to the nitrogen-containing heterocycles such as quinoline, triazole, pyrazole, imidazole, indole, pyrimidine, ß-carboline, quinoxaline, quinazoline and benzimidazole. In this regard, enormous chemical data provide the opportunity for systematic elucidation of structural requirements against different leishmanial species. Within this representation, insights into the current status of privileged N-heterocycles as antileishmanial agents with particular emphasis on structure activity relationships are reviewed.

Design, synthesis and evaluation of cytotoxic, antimicrobial, and anti-HIV-1 activities of new 1,2,3,4-tetrahydropyrimidine derivatives.

A series of new 1,2,3,4-tetrahydropyrimidine (THPM) derivatives were designed and synthesized within a one-pot three component Biginelli reaction. The structures of compounds were characterized by FT-IR, 1HNMR, mass spectroscopy, and elemental analysis. All synthesized derivatives were screened for their cytotoxic, antimicrobial, and anti-HIV activities. Due to significant cytotoxic and antimicrobial effects of 1,2,3,4-THPM scaffold, in this study, cytotoxic and antimicrobial activities of synthesized derivatives were evaluated on two cell lines and four bacterial strains. Compounds 4e and 4k showed highest cytotoxic activity against HeLa and MCF-7 cell lines. In addition, 4c and 4d were most active against MCF-7 and HeLa cell lines, respectively. Among the compounds, 4e revealed high antimicrobial activity against four strains. According to the results, 4e possessing m-bromophenyl group at C-4 position of THPM exhibited the highest cytotoxic and antimicrobial effects. Also, all the newly synthesized compounds were evaluated for their anti-HIV-1 assay. Compounds 4l and 4a indicated remarkable anti-HIV-1 activity. It is concluded from cytotoxic, antimicrobial, and anti-HIV-1 activities that the 1,2,3,4-tertahydropyrimidines may serve as hit compounds for development of new anticancer small-molecules.