Publications by authors named "Mehdi Khoshneviszadeh"

49 Publications

The natural-based optimization of kojic acid conjugated to different thio-quinazolinones as potential anti-melanogenesis agents with tyrosinase inhibitory activity.

Bioorg Med Chem 2021 Apr 27;36:116044. Epub 2021 Jan 27.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Melanin pigment and melanogenesis are a two-edged sword. Melanin has a radioprotection role while melanogenesis has undesirable effects. Targeting the melanogenesis pathway, a series of kojyl thioether conjugated to different quinazolinone derivatives were designed, synthesized, and evaluated for their inhibitory activity against mushroom tyrosinase. All the synthesized compounds were screened for their anti-tyrosinase activity and all derivatives displayed better potency than kojic acid as the positive control. In this regard, 5j and 5h as the most active compounds showed an IC value of 0.46 and 0.50 µM, respectively. In kinetic evaluation against tyrosinase, 5j depicted an uncompetitive inhibition pattern. Designed compounds also exhibited mild antioxidant capacity. Moreover, 5j and 5h achieved good potency against the B16F10 cell line to reduce the melanin content, whilst showing limited toxicity against malignant cells. The proposed binding mode of new inhibitors evaluated through molecular docking was consistent with the results of structure-activity relationship analysis.
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http://dx.doi.org/10.1016/j.bmc.2021.116044DOI Listing
April 2021

Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met.

Sci Rep 2021 Feb 11;11(1):3644. Epub 2021 Feb 11.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibitory activity of all synthesized compounds against c-Met kinase was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay at the concentration range of 5-25 µM. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential. They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 µM. Synthetic compounds showed antiproliferative effects against lung (EBC-1) and pancreatic cancer cells (AsPc-1, Suit-2 and Mia-PaCa-2) expressing different levels of c-Met, with IC values as low as 3.0 µM measured by sulforhodamine B assay. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and also induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They also inhibited PDGFRA and FLT3 at 25 µM among a panel of 16 kinases. Molecular docking and dynamics simulation studies corroborated the experimental findings and revealed possible binding modes of the select derivatives with target receptor tyrosine kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers.
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http://dx.doi.org/10.1038/s41598-021-83069-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878917PMC
February 2021

Design, synthesis, in vitro and in silico studies of novel Schiff base derivatives of 2-hydroxy-4-methoxybenzamide as tyrosinase inhibitors.

Drug Dev Res 2020 Dec 19. Epub 2020 Dec 19.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Due to the fact that tyrosinase is responsible for biosynthesis and regulation of melanins and browning food products, tyrosinase inhibitors can be favorable agents in cosmetics and medicinal industries. A series of novel 2-hydroxy-4-methoxybenzohydrazide were designed, synthesized, and their new application as tyrosinase inhibitors was also disclosed. Based on in vitro tyrosinase inhibitory assay, 4d as the strongest inhibitor of tyrosinase with an IC value of 7.57 μM showed approximately 2.5-fold better inhibition than kojic acid as positive control followed by two compounds 4b (IC = 8.19 ± 0.25 μM) and 4j (IC = 8.92 ± 0.016) which displayed preferable tyrosinase inhibitory activity. Detailed investigations on the mechanism of action of the 4d reported mix type of inhibition. More importantly, molecular modeling assessments proposed the ability of 4d for potential interaction with Cu (metal)-His (residue) within tyrosinase active site. Overall, 4d is a promising candidate for the development of anti-tyrosinase agents.
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http://dx.doi.org/10.1002/ddr.21771DOI Listing
December 2020

Anti- activity of 5-oxo-hexahydroquinoline derivatives: synthesis, and evaluations, and molecular docking analysis.

Res Pharm Sci 2020 Aug 28;15(4):367-380. Epub 2020 Aug 28.

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.

Background And Purpose: The aim of this study was to evaluate the and anti- () effect of 5-oxo-hexahydroquinoline compounds. Moreover, molecular docking study of the compounds into the active site of enoyl-acyl carrier protein reductase (ENR) as a necessary enzyme for the vitality of apicoplast was carried out.

Experimental Approach: A number of 5-oxo-hexahydoquinoline derivatives (Z1-Z4) were synthesized. The tachyzoites of RH strain were treated by different concentrations (1-64 μg/mL) of the compounds. The viability of the encountered parasites with compounds was assessed using flow cytometry and propidium iodide (PI) staining. Due to the high mortality effect of Z3 and Z4 , their chemotherapy effect was assessed by inoculation of tachyzoites to four BALB/c mice groups ( = 5), followed by the gavage of various concentrations of the compounds to the mice. Molecular docking was done to study the binding affinity of the synthesized 5-oxo-hexahydroquinolines into ENR enzyme active site byusing AutoDock Vina® software. Docking was performed by a Lamarckian Genetic Algorithm with 100 runs.

Findings / Results: Flow cytometry assay results indicated compounds Z3 and Z4 had relevant mortality effect on parasite tachyzoites. Besides, experiments were also performed and a partial increase of mice longevity between control and experiment groups was recorded. Molecular docking of Z3 and Z4 in the binding site of ENR enzyme indicated that the compounds were well accommodated within the binding site. Therefore, it could be suggested that these compounds may exert their anti- activity through the inhibition of the ENR enzyme.

Conclusion And Implications: Compounds Z3 and Z4 are good leads in order to develop better anti- agents as they demonstrated both and inhibitory effects on tachyzoites viability and infection. Further studies on altering the route of administration along with additional pharmacokinetics evaluations are needed to improve the anti- impacts of 5-oxo-hexahydroquinoline compounds.
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http://dx.doi.org/10.4103/1735-5362.293515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714012PMC
August 2020

Novel 2-amino-1,4-naphthoquinone hybrids: Design, synthesis, cytotoxicity evaluation and in silico studies.

Bioorg Med Chem 2020 11 28;28(21):115718. Epub 2020 Aug 28.

Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

In the present work, a novel series of 2-amino-1,4-naphthoquinones bearing oxyphenyl moiety (5a-5m) were designed and synthesized via a two-step route and evaluated for their in vitro cytotoxic activity against three different cancer cell lines (MCF-7, HL-60 and U937) and normal human cell line (HEK-293) by MTT assay. Compounds 5b (4-nitro-benzyl-) and 5k (4-bromo-benzyl-) were identified to possess the highest cytotoxic activity against MCF-7 cancerous cells (IC values of 27.76 and 27.86 μM, respectively). At the same time, none of the compounds exert significant toxicity against HEK-293 normal human kidney cells. Cell cycle analysis showed that the selected derivatives increased the population of MCF-7 cells in the S phase at 25 and 50 μM concentrations. Annexin V-FITC/PI staining assay also confirmed that compounds 5b and 5k induced apoptosis in the cell death pathway. Molecular docking and molecular dynamics studies were also performed to evaluate the probable interactions between the hybrids and human ATP binding domain of topo IIα protein. Our findings may provide new insight for further development of novel naphthoquinone-containing compounds.
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http://dx.doi.org/10.1016/j.bmc.2020.115718DOI Listing
November 2020

Design and Synthesis of Novel 1-hydroxy-2,4,5-triaryl Imidazole Derivatives as Anti-cytokine Agents.

Iran J Pharm Res 2020 ;19(1):181-191

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Among recent advances in the identification of anti-inflammation agents, anti-cytokines (like Interleukin-1), related to p38 MAPK families play an important role; Here in we designed new effective and low toxic anti-cytokine agents based on 1-hydroxy-2,4,5-triaryl imidazole derivatives. The reaction of oximoinoketone intermediate with ten different aromatic aldehyde and ammonium acetate in refluxing acetic acid condition give imidazole derived product, the IL-1β inhibitory assay were performed on Human PBMCs (peripheral blood mononuclear cells) using an enzyme-linked immunosorbent assay (ELISA) kit and then in computational part the binding mode of the best compound was accomplished by docking in Crystal structure of p38 MAP kinase (PDB ID: 1A9U) compared with SB202190 as standard drug. All compounds were synthesized and evaluated in biological assay showing the inhibitory activity from 28% to 82% compared to SB202190 and binding mode analysis revealed that the hydrogen-bond interactions with residues (Met109, Val30) were key point in inhibitor binding. Compound clearly proved the best inhibitory action and could be further utilized for designing newer anti-cytokine agents and p38α MAP kinase potentially inhibitory action.
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http://dx.doi.org/10.22037/ijpr.2019.1100909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462483PMC
January 2020

4H-benzochromene derivatives as novel tyrosinase inhibitors and radical scavengers: synthesis, biological evaluation, and molecular docking analysis.

Mol Divers 2020 Jul 18. Epub 2020 Jul 18.

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

A series of ethyl 2-amino-4H-benzo[h]chromene-3-carboxylate derivatives, having phenyl ring with diverse substituents at C position of 4H-benzochromene nucleus, were synthesized via one-pot three-component reaction between various aromatic aldehydes, α-naphthol, and ethyl cyanoacetate. The synthesized compounds were screened for their antityrosinase activity. Compound 4i, bearing 4-dimethylamino substitution on C-phenyl ring, was the most potent tyrosinase inhibitor (IC = 34.12 μM). The inhibition kinetic analysis of 4i indicated that the compound was a competitive tyrosinase inhibitor. Compounds 4a, 4g, 4i and 4j were the effective radical scavengers with ECs in the range of 0.144-0.943 mM. According to the in silico drug-like and ADME predictions, 4i can be considered as a suitable candidate. Molecular docking results confirmed that the derivative was well accommodated within the mushroom tyrosinase binding site. Therefore, 4i can be introduced as a novel tyrosinase inhibitor that might be a promising lead in medicine, cosmetics, and food industry.
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http://dx.doi.org/10.1007/s11030-020-10123-0DOI Listing
July 2020

Kojic acid-natural product conjugates as mushroom tyrosinase inhibitors.

Eur J Med Chem 2020 Sep 16;201:112480. Epub 2020 Jun 16.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

As part of our effort to develop potential tyrosinase inhibitors, we have conjugated the well-known tyrosinase inhibitor kojic acid (KA) with several phenolic natural products such as umbelliferone, sesamol, thymol, carvacrol, eugenol, isoeugenol, vanillin, isovanillin, and apocynin that some reports have shown their activity on tyrosinase enzyme. The designed compounds were synthesized using click reaction and 1,2,3-triazole formation. All compound showed potent anti-tyrosinase activity significantly higher than KA. The best activities were observed with apocynin and 4-coumarinol analogs (10c and 16c) displaying IC values of 0.03 and 0.02 μM, respectively. The potency of 16c was >460-times more than that of KA. Cell-based assays against B16F10 and HFF cells revealed that the representative compounds can efficiently suppress the melanogenesis without significant toxicity on cells.
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http://dx.doi.org/10.1016/j.ejmech.2020.112480DOI Listing
September 2020

1,2,3-Triazole-linked 5-benzylidene (thio)barbiturates as novel tyrosinase inhibitors and free-radical scavengers.

Arch Pharm (Weinheim) 2020 Oct 8;353(10):e2000058. Epub 2020 Jul 8.

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

In this study, benzyl-1,2,3-triazole-linked 5-benzylidene (thio)barbiturate derivatives 7a-d and 8a-h were designed as potential tyrosinase inhibitors and free-radical scavengers. The twelve derivatives were synthesized via the [3+2] cycloaddition reaction of the corresponding benzyl azide as a dipole and the corresponding alkyne as a dipolarophile in the presence of copper(I) species, generated in situ from copper(II)/ascorbate. The thiobarbiturate derivative 8h and the barbiturate derivative 8b bearing 4-fluoro and 4-bromo groups on the benzyl-triazole moiety were found to be the most potent tyrosinase inhibitors with IC values of 24.6 ± 0.9 and 26.8 ± 0.8 μM, respectively. Almost all the compounds showed a good radical scavenging activity with EC values in the range of 29.9-324.9 μM. Derivatives 7a, 8f, and 8h were the most potent free-radical scavengers with EC values of 29.9 ± 0.8, 36.8 ± 0.9, and 39.2 ± 1.1 μM, respectively. The kinetic analysis revealed that compound 8h was a mixed-type tyrosinase inhibitor. The molecular docking analysis indicated that 8b and 8h were well accommodated in the active site of the tyrosinase enzyme and possessed the most negative binding energy values of -8.55 and -8.81 kcal/mol, respectively. Moreover, it was found that the two residues, Asn81 and Glu322, played a significant role in forming stable enzyme-inhibitor complexes.
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http://dx.doi.org/10.1002/ardp.202000058DOI Listing
October 2020

A Series of Benzylidenes Linked to Hydrazine-1-carbothioamide as Tyrosinase Inhibitors: Synthesis, Biological Evaluation and Structure-Activity Relationship.

Chem Biodivers 2020 Aug 3;17(8):e2000285. Epub 2020 Aug 3.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, 71348, Shiraz, Iran.

Tyrosinase is a type 3 copper enzyme responsible for skin pigmentation disorders, skin cancer, and enzymatic browning of vegetables and fruits. In the present article, 12 small molecules of 2-benzylidenehydrazine-1-carbothioamide were designed, synthesized and evaluated for their anti-tyrosinase activities followed by molecular docking and pharmacophore-based screening. Among synthesized thiosemicarbazone derivatives, one compound, (2E)-2-[(4-nitrophenyl)methylidene]hydrazine-1-carbothioamide, is the strongest inhibitor of mushroom tyrosinase with IC of 0.05 μM which demonstrated a 128-fold increase in potency compared to the positive control. Kinetic studies also revealed mix type inhibition by this compound. Docking studies confirmed the complete fitting of the synthesized compounds into the tyrosinase active site. The results underline the potential of 2-benzylidenehydrazine-1-carbothioamides as potent pharmacophore to extend the tyrosinase inhibition in drug discovery.
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http://dx.doi.org/10.1002/cbdv.202000285DOI Listing
August 2020

5-Oxo-hexahydroquinoline Derivatives and Their Tetrahydroquinoline Counterparts as Multidrug Resistance Reversal Agents.

Molecules 2020 Apr 16;25(8). Epub 2020 Apr 16.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz 71348-53734, Iran.

Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason of chemotherapy failure in many patients and is often related to overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of modulation of the activity of these transporters might be effective in overcoming MDR. In this study, a new set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole moiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of these 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human uterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the most potent compounds in induction of apoptosis and alterations of cell cycle was examined in these cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was evaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental non-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds and with 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties, respectively, and their tetrahydroquinoline counterparts and significantly blocked P-gp efflux, induced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However, only and compounds were relatively selective against cancer and MDR cells as compared to non-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline and 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in drug resistant cancers.
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http://dx.doi.org/10.3390/molecules25081839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221826PMC
April 2020

Synthesis, biological evaluation and molecular docking analysis of vaniline-benzylidenehydrazine hybrids as potent tyrosinase inhibitors.

BMC Chem 2020 Dec 7;14(1):28. Epub 2020 Apr 7.

1Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

In this work, 11 novel compounds based on vaniline and benzylidenehydrazine structure were synthesized with various substituents on phenyl aromatic ring of the molecule and evaluated as tyrosinase inhibitors. These new derivatives showed significant anti-tyrosinase activities, among which demonstrated to be the most potent compound, with IC values of 1.58 µM . The structure-activity relationship study of the novel constructed analogs was fully discussed. Kinetic study of compound showed uncompetitive inhibition towards tyrosinase. Furthermore, the high potency of was supported theoretically by molecular docking evaluations.
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http://dx.doi.org/10.1186/s13065-020-00679-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137441PMC
December 2020

Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands.

Bioorg Chem 2020 04 4;97:103649. Epub 2020 Feb 4.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that effects 50 million people worldwide. In this review, AD pathology and the development of novel therapeutic agents targeting AD were fully discussed. In particular, common approaches to prevent Aβ production and/or accumulation in the brain including α-secretase activators, specific γ-secretase modulators and small molecules BACE1 inhibitors were reviewed. Additionally, natural-origin bioactive compounds that provide AD therapeutic advances have been introduced. Considering AD is a multifactorial disease, the therapeutic potential of diverse multi target-directed ligands (MTDLs) that combine the efficacy of cholinesterase (ChE) inhibitors, MAO (monoamine oxidase) inhibitors, BACE1 inhibitors, phosphodiesterase 4D (PDE4D) inhibitors, for the treatment of AD are also reviewed. This article also highlights descriptions on the regulator of serotonin receptor (5-HT), metal chelators, anti-aggregants, antioxidants and neuroprotective agents targeting AD. Finally, current computational methods for evaluating the structure-activity relationships (SAR) and virtual screening (VS) of AD drugs are discussed and evaluated.
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http://dx.doi.org/10.1016/j.bioorg.2020.103649DOI Listing
April 2020

One-pot synthesis of thioxo-tetrahydropyrimidine derivatives as potent β-glucuronidase inhibitor, biological evaluation, molecular docking and molecular dynamics studies.

Bioorg Med Chem 2020 04 6;28(7):115359. Epub 2020 Feb 6.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

A series of N,N-diethyl phenyl thioxo-tetrahydropyrimidine carboxamide have been synthesized and investigated for their β-glucuronidase inhibitory activities. All molecules exhibited excellent inhibition with IC values ranging from 0.35 to 42.05 µM and found to be even more potent than the standard d-saccharic acid. Structure-activity relationship analysis indicated that the meta-aryl-substituted derivatives significantly influenced β-glucuronidase inhibitory activities while the para-substitution counterpart outperforming moderate potency. The most potent compound in this series was 4g bearing thiophene motif with IC of 0.35 ± 0.09 µM. To verify the SAR, molecular docking and molecular dynamics studies were also performed.
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http://dx.doi.org/10.1016/j.bmc.2020.115359DOI Listing
April 2020

Prediction of cytotoxic activity of a series of 1H-pyrrolo[2,3-b]pyridine derivatives as possible inhibitors of c-Met using molecular fingerprints.

J Recept Signal Transduct Res 2019 Aug 28;39(4):295-303. Epub 2019 Oct 28.

Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA.

Cancer is a leading cause of death all over the world. HGF/MET signaling pathway is involved in many cancers and its inhibition has great potential as an effective therapeutic intervention. A series of 1H-pyrrolo [2,3-b]pyridine derivatives has recently been identified with cytotoxic activity, and most of them exhibited considerable potencies with IC values under 10 µM. The present study was carried out with the specific aim to shed light upon the quantitative structure activity relationship (QSAR) to design and predict the activity of new potent inhibitors using molecular fingerprints and some 2D and 3D descriptors. The built model was statistically significant in terms of = 0.90 and = 0.91 values. Fingerprint PubchemFP759 (1-chloro-2-methylbenzene) was the most effective fragment in the biological activity and just appeared in the most active compound 7j with a pIC value of 8.0. A similarity search study was applied based on compounds 7c and 17e, with reported inhibitory activity against c-Met kinase, which showed that also other compounds could possess similar effects against c-Met enzyme. The most promising compound 7g-cl was subjected to docking and molecular dynamics simulation. Two hydrogen bonds between Lys1110, Met1160, and 7g-cl were stable during the equilibrium time range. The suggested modifications might be considered in future studies to design more efficient anticancer agents.
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http://dx.doi.org/10.1080/10799893.2019.1676258DOI Listing
August 2019

Developing a multiplex real-time PCR with a new pre-enrichment to simultaneously detect four foodborne bacteria in milk.

Future Microbiol 2019 07 1;14:885-898. Epub 2019 Aug 1.

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

The aim of this study is to formulate a new single nonselective pre-enrichment medium (ELSS) that can support the concurrent growth of four major foodborne pathogens containing O157: H7, . , . and . serovar Entertidis to develop a multiplex TaqMan Real-time PCR (mRT-PCR). The mRT-PCR with a new pre-enrichment was carried out for simultaneous detection and quantification of these foodborne bacteria. By using mRT-PCR after 16 h pre-enrichment in ELSS, the detection limit of each pathogen was 1 CFU/25 ml contaminated milk, as well as inclusivity and exclusivity reached 100%. The mRT-PCR assay with pre-enrichment step is a fast and reliable technique for detecting single or multiple pathogens in food products.
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http://dx.doi.org/10.2217/fmb-2019-0044DOI Listing
July 2019

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities.

Med Chem 2020 ;16(7):892-902

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti- tyrosinase agents.

Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated.

Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site.

Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex.

Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.
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http://dx.doi.org/10.2174/1573406415666190724142951DOI Listing
January 2020

5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer's disease modifying agents.

Mol Divers 2020 Aug 20;24(3):641-654. Epub 2019 Jul 20.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

In this study, new derivatives of 5,6-diphenyl triazine-thio methyl triazole hybrid were designed, synthesized and evaluated as multifunctional agents for Alzheimer's disease. Among all synthesized compounds, 4a and 4h showed the best inhibitory activities against BACE1 (40% and 37.5% μM inhibition at 50 µM, respectively). Molecular docking studies showed that compound 4a occupied the entire BACE1 enzyme and the thio triazine fragment deeply penetrates into S2 binding site via two hydrogen bonds with Thr72 and Gln73 amino acids. Different aromatic moieties occupy S'2 pocket via hydrophobic interactions. 6-Phenyl ring also had a potential hydrophobic interaction with S1 pocket. In vitro ChE inhibitory assay demonstrated that most of the derivatives exhibited more selectivity toward BuChE than AChE. 4c as the most potent BuChE inhibitor displayed an IC value of 6.4 µM, and 4b exhibited AChE inhibitory activity with 25.1% inhibition at 50 μM. Further, molecular docking studies revealed that the thiazolidinones moiety plays a key role in the inhibition mechanism by well fitting into the enzyme bounding pocket. Moreover, molecular docking study of 4a, 4b and 4c with ChE active site was also performed.
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http://dx.doi.org/10.1007/s11030-019-09970-3DOI Listing
August 2020

Novel morpholine containing cinnamoyl amides as potent tyrosinase inhibitors.

Int J Biol Macromol 2019 Aug 29;135:978-985. Epub 2019 May 29.

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. Hence, tyrosinase inhibitors are important in the fields of medicine, cosmetics and agriculture. In this study, novel N-(2-morpholinoethyl)cinnamamide derivatives bearing different substituents on phenyl ring were designed, synthesized and evaluated for their tyrosinase diphenolase inhibitory activity. The compounds were found to be better tyrosinase inhibitors (ICs were in micro molar range) than cinnamic acid. (E)-3-(3-chlorophenyl)-N-(2-morpholinoethyl)acrylamide (B6) exhibited the highest inhibition with IC value of 15.2 ± 0.6 μM which was comparable to that of kojic acid. The inhibition kinetic analysis of B6 indicated that the compound was a mixed-type tyrosinase inhibitor. In silico ADME prediction indicated that B6 might show more skin penetration than kojic acid. Molecular docking analysis confirmed that the active inhibitors well accommodated in the mushroom tyrosinase active site and it was also revealed that B6 formed the most stable drug-receptor complex with the target protein. Therefore, cinnamamide B6 could be introduced as a potent tyrosinase inhibitor that might be a promising lead in cosmetics, medicine and food industry.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.05.201DOI Listing
August 2019

Click chemistry-assisted synthesis of novel aminonaphthoquinone-1,2,3-triazole hybrids and investigation of their cytotoxicity and cancer cell cycle alterations.

Bioorg Chem 2019 07 30;88:102967. Epub 2019 Apr 30.

Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

A series of 12 novel 1,4-naphthoquinone-1,2,3-triazole hybrids were designed and synthesized through copper-catalyzed click reaction of 2-(prop-2-ynylamino)naphthalene-1,4-dione (3) and different azidomethyl-benzene derivatives. The synthesized compounds were assessed for their anticancer activity against three cancer cell lines (MCF-7, HT-29 and MOLT-4) by MTT assay. The results showed that the majority of the synthesized compounds displayed cytotoxic activity. Derivatives 6f and 6h, bearing 4-trifluoromethyl-benzyl and 4-tert-butyl-benzyl groups, respectively, as well as intermediate 3 demonstrated good cytotoxic potential against all tested cancer cell lines, among which compound 6f showed the highest activity. Flow cytometric analysis revealed that compounds 3, 6f and 6h arrested cell cycle at G0/G1 phase in MCF-7 cells. Therefore, synthesized aminonaphthoquinone-1,2,3-triazole derivatives can be introduced as promising molecules for further development as potential anticancer agents.
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http://dx.doi.org/10.1016/j.bioorg.2019.102967DOI Listing
July 2019

Veratric acid derivatives containing benzylidene-hydrazine moieties as promising tyrosinase inhibitors and free radical scavengers.

Bioorg Med Chem 2019 06 10;27(12):2644-2651. Epub 2019 Apr 10.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. A series of veratric acid derivatives containing benzylidene-hydrazine moieties with different substitutions were synthesized and their inhibitory effect on mushroom tyrosinase and free radical scavenging activity were evaluated. The results indicated that N'-(4-chlorobenzylidene)-3,4-dimethoxybenzohydrazide (D5) and N'-(2,3-dihydroxybenzylidene)-3,4-dimethoxybenzohydrazide (D12) showed the highest tyrosinase inhibitory activity with IC values of 19.72 ± 1.84 and 20.63 ± 0.79 μM, respectively, that were comparable with the IC value of kojic acid (19.08 ± 1.21 μM). D12 was also a potent radical scavenger with EC value of 0.0097 ± 0.0011 mM. The free radical scavenging activity of D12 was comparable with the standard quercetin. The inhibition kinetic analyzed by Lineweaver-Burk plots revealed that compound D5 was a competitive tyrosinase inhibitor. Molecular docking study was carried out for the derivatives demonstrating tyrosinase inhibitory activity. D5 and D12 possessed the most negative estimated free energies of binding in mushroom tyrosinase active site. Therefore, D5 and D12 could be introduced as potent tyrosinase inhibitors that might be promising leads in medicine, cosmetics and food industry.
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http://dx.doi.org/10.1016/j.bmc.2019.04.016DOI Listing
June 2019

Multi-target inhibitors against Alzheimer disease derived from 3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy methyl-1,2,3-triazole: Design, synthesis and biological evaluation.

Bioorg Chem 2019 03 29;84:363-371. Epub 2018 Nov 29.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Alzheimer's disease (AD) is a complex neurological disorder with diverse underlying pathological processes. Several lines of evidence suggest that BACE1 is a key enzyme in the pathogenesis of AD and its inhibition is of particular importance in AD treatment. Ten new 3-hydrazinyl-1,2,4-triazines bearing pendant aryl phenoxy methyl-1,2,3-triazole were synthesized as multifunctional ligands against AD. We show that compounds containing Cl and NO groups at the para position of the phenyl ring, namely compounds 7c (IC = 8.55 ± 3.37 µM) and 7d (IC = 11.42 ± 2.01 µM), possess promising BACE1 inhibitory potential. Furthermore, we assessed the neuroprotective activities of 7c and 7d derivatives in PC12 neuronal cell line, which showed moderate protection against amyloid β peptide toxicity. In addition, compound 7d demonstrated metal chelating activity and moderate antioxidant potential (IC = 44.42 ± 7.33 µM). Molecular docking studies of these molecules revealed high-affinity binding to several amino acids of BACE1, which are essential for efficient inhibition. These results demonstrate that 1,2,4-triazine derivatives bearing an aryl phenoxy methyl-1,2,3-triazole have promising properties as therapeutic agents for AD.
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http://dx.doi.org/10.1016/j.bioorg.2018.11.038DOI Listing
March 2019

1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design, synthesis and biological evaluation.

Bioorg Chem 2019 02 31;82:414-422. Epub 2018 Oct 31.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3-triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (ICs = 0.06-6.80 µM), being superior to reference drug, kojic acid. In particular, the naphthyloxy analogs 6o and 6p were found to be 31-155 times more potent than kojic acid. The metal-binding study of selected compound 6o revealed that the prototype compound possesses metal-chelating ability, particularly with Cu ions. The promising compounds 6o and 6p had acceptable safety profile as demonstrated by cytotoxicity assay against melanoma (B16) cell line and Human Foreskin Fibroblast (HFF) cells.
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http://dx.doi.org/10.1016/j.bioorg.2018.10.069DOI Listing
February 2019

5-Oxo-hexahydroquinoline derivatives as modulators of P-gp, MRP1 and BCRP transporters to overcome multidrug resistance in cancer cells.

Toxicol Appl Pharmacol 2019 01 2;362:136-149. Epub 2018 Nov 2.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Multidrug resistance (MDR) in cancer cells is often associated with overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2). Modulators of these transporters might be helpful in overcoming MDR. Moreover, exploiting collateral sensitivity (CS) could be another approach for efficient treatment of cancer. Twelve novel 5-oxo-hexahydroquinoline derivatives bearing different aromatic substitutions at C, while having 2-pyridyl alkyl carboxylate substituents at the C were synthesized and evaluated for MDR reversal activity by flow cytometric determination of rhodamine 123, calcein and mitoxantrone accumulations in P-gp, MRP1 and BCRP-overexpressing cell lines, respectively. Furthermore, to confirm the P-gp inhibitory activity, the effect of compounds on the reduction of doxorubicin's IC of drug-resistant human uterine sarcoma cell line, MES-SA/DX5, was evaluated. Compounds D6, D5 and D3 (bearing 3-chlorophenyl, 2,3-dichlorophenyl and 4-chlorophenyl substituents at C position of 5-oxo-hexahydroquinoline core) were the most potent P-gp, MRP1 and BCRP inhibitors, respectively, causing significant MDR reversal at concentrations of 1-10 μM. Additionally, D4 (containing 3-flourophenyl) was the most effective MRP1-dependent CS inducing agent. Overall, chlorine containing compounds D6, C4 and D3 were capable of significant inhibition of all 3 important efflux pumps in cancer cells. Moreover, D6 also induced CS triggered by reducing glutathione efflux. In conclusion, some of the 5-oxo-hexahydroquinoline derivatives are effective efflux pump inhibitors capable of simultaneously blocking 3 important ABC transporters involved in MDR, and represent promising agents to overcome MDR in cancer cells.
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http://dx.doi.org/10.1016/j.taap.2018.10.025DOI Listing
January 2019

5-Oxo-hexahydroquinoline: an attractive scaffold with diverse biological activities.

Mol Divers 2019 May 2;23(2):471-508. Epub 2018 Nov 2.

Medicinal and Natural Products, Chemistry Research Center, Shiraz University of Medical Sciences, P.O. Box 71345-3388, Shiraz, Iran.

5-Oxo-hexahydroquinoline (5-oxo-HHQ) represents a biologically attractive fused heterocyclic core. Various synthetic analogs of 5-oxo-HHQ have been synthesized and assessed for different biological activities. Some derivatives have exhibited myorelaxant, analgesic, anticancer, antibacterial, antifungal, antitubercular, antimalarial, antioxidant, anti-inflammatory, multidrug resistance reversal, anti-Alzheimer, neuroprotective, antidiabetic, antidyslipidemic and antiosteoporotic activities. This review provides a comprehensive report regarding the preparation and pharmacological characterization of 5-oxo-HHQ derivatives that have been reported so far. This information will be beneficial for medicinal chemists in the field of drug discovery to design and develop new and potent therapeutical agents bearing the 5-oxo-HHQ nucleus.
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http://dx.doi.org/10.1007/s11030-018-9886-4DOI Listing
May 2019

Synthesis of New Benzimidazole-1,2,3-triazole Hybrids as Tyrosinase Inhibitors.

Chem Biodivers 2018 Jul 21;15(7):e1800120. Epub 2018 Jun 21.

Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, P.O. Box 14155, 6451, Tehran, Iran.

A novel series of benzimidazole-1,2,3-triazole hybrids containing substituted benzyl moieties were designed, synthesized and evaluated for their inhibitory activity against mushroom tyrosinase. The results indicated that 2-(4-{[1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-1H-benzimidazole (6g) and 2-(4-{[1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-1H-benzimidazole (6h) exhibited effective inhibitory activity with IC values of 9.42 and 10.34 μm, respectively, comparable to that of kojic acid as the reference drug (IC = 9.28 μm). Kinetic study of compound 6g confirmed mixed-type inhibitory activity towards tyrosinase indicating that it can bind to free enzyme as well as enzyme-substrate complex. Also, molecular docking analysis was performed to determine the binding mode of the most potent compounds (6g and 6h) in the active site of tyrosinase. Consequently, 6g and 6h derivatives might serve as promising candidates in cosmetics, medicine or food industry, and development of such compounds may be of an interest.
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http://dx.doi.org/10.1002/cbdv.201800120DOI Listing
July 2018

Design, synthesis, cytotoxicity evaluation and docking studies of 1,2,4-triazine derivatives bearing different arylidene-hydrazinyl moieties as potential mTOR inhibitors.

Res Pharm Sci 2018 Feb;13(1):1-11

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.

Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. , and exhibited good cytotoxic activity on both cell lines with an IC range of 6.42 - 20.20 μM. In general, substitution of a five-membered heterocyclic ring containing NO, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, , was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity.
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http://dx.doi.org/10.4103/1735-5362.220962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772076PMC
February 2018

Synthesis and structure-activity relationship study of multi-target triazine derivatives as innovative candidates for treatment of Alzheimer's disease.

Bioorg Chem 2018 04 16;77:223-235. Epub 2018 Jan 16.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

The complex pathogenesis of Alzheimer's disease (AD) requires using multi-target ligands (MTLs) for disease management. We synthesized, characterized and evaluated a series of novel triazine analogues as MTLs for AD. The biological screening results indicated that most of our compounds displayed potent inhibitory activities against β-site APP-cleaving enzyme 1 (BACE1) using a FRET-based assay. Compounds 6c and 6m were found to possess significant BACE1 inhibitory properties with IC values of 0.91 (±0.25) µM and 0.69 (±0.20) µM, respectively. DPPH radical scavenging activity evaluation showed that compounds with hydroxyl and pyrrole moieties had antioxidant effects. Docking evaluations provided insight into enzyme inhibitory interactions of novel synthesized compounds with the BACE1 active site involving a critical role for Gln73 and/or Phe108 alongside of Asp32. Metal chelation tests confirmed that compound 6m is a chelator for Fe, Fe, Zn, Cu. Moreover 6m as the most potent BACE1 inhibitor did not show any toxicity against PC12 neuronal cells. These findings demonstrate the high potential of triazine scaffolds in the design of MTLs for treatment of AD.
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http://dx.doi.org/10.1016/j.bioorg.2018.01.017DOI Listing
April 2018

Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer's disease.

Eur J Med Chem 2017 Dec 28;141:690-702. Epub 2017 Sep 28.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Alzheimer's disease (AD) is a neurodegenerative disorder known for the presence of amyloid beta plaques resulting from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. We developed and synthesized, through click reactions, a new family of iminochromene carboxamides containing different aminomethylene triazole. The BACE1 inhibition, neuroprotective capacity and metal chelation of these derivatives make them ideal candidates against AD. Most of the synthesized compounds were shown to have potent BACE1 inhibitory activity in a FRET assay, with an IC value of 2.2 μM for the most potent compound. Moreover, molecular modeling evaluation of these BACE1 inhibitors demonstrates the vital role of the amine and amide linkers through hydrogen bond interactions with key amino acids in the BACE1 active site. Our in vitro neuroprotective evaluations in PC12 neuronal cells of Aβ-induced neuroprotection demonstrated promising activity for most of the compounds as neuroprotective agents. Based on our findings, we propose that introduction of a phthalimide substitute on the triazole ring shown to be interesting multifunctional lead compound worthy of further study.
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http://dx.doi.org/10.1016/j.ejmech.2017.09.057DOI Listing
December 2017

In Silico Screening of IL-1β Production Inhibitors Using Chemometric Tools.

Iran J Pharm Res 2017 ;16(2):513-524

Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

The IL-1β plays a major role in inflammatory disorders and IL-1β production inhibitors can be used in the treatment of inflammatory and related diseases. In this study, quantitative relationships between the structures of 46 pyridazine derivatives (inhibitors of IL-1β production) and their activities were investigated by Multiple Linear Regression (MLR) technique Stepwise Regression Method (ES-SWR). The genetic algorithm (GA) has been proposed for improvement of the performance of the MLR modeling by choosing the most relevant descriptors. The results show that eight descriptors are able to describe about 83.70% of the variance in the experimental activity of the molecules in the training set. The physical meaning of the selected descriptors is discussed in detail. Power predictions of the QSAR models developed were evaluated using cross-validation, and validation through an external prediction set. The results showed satisfactory goodness-of-fit, robustness and perfect external predictive performance. The applicability domain was used to define the area of reliable predictions. Furthermore, the screening technique was applied in order to predict the structure and potency of new compounds of this type using the proposed QSAR model.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603860PMC
January 2017