Antimalarial activity and docking studies of novel bi-functional hybrids derived from 4-aminoquinoline and 1,3,5-triazine against wild and mutant malaria parasites as pf-DHFR inhibitor

Bhat, Hans Raj; Singh, Udaya Pratap; Gahtori, Prashant; Ghosh, Surajit Kumar; Gogoi, Kabita; Prakash, Anil; Singh, R. K. P.

doi:10.1039/c2ra21915h

Cited by 50 publications

(23 citation statements)

References 23 publications

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“…[(η 6 -p-Cymene)-RuCl 2 ] 2 was prepared according to a published procedure. 18 Solvents and other reagents were purchased from various suppliers and were used without additional purification. Elemental analysis was carried out with an Elemental Vario EL III microanalyzer.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Strong in Vitro Cytotoxic Potential of New Ruthenium–Cymene Complexes

et al. 2015

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Two p-cymenerutheniumchlorido complexes with thiourea derivative of 7-chloroquinoline (C1) and pyridine-3-imidazole (C2) were synthesized starting from [(η 6 -p-cymene)RuCl 2 ] 2 and corresponding ligands. The structures of complexes were determined with elemental analysis and IR, ESIMS, 1 H and 13 C{ 1 H} NMR, and 2D 1 H− 15 N correlation NMR spectroscopy. Cytotoxic activities examined by the MTT assay were performed in five human neoplastic cell lines (HeLa, K562, A549, MDA-MB-231, EA.hy926) and one nontumor human fetal lung fibroblast cell line (MRC-5). Tested complexes exhibited low micromolar activities with IC 50 in the range 11.03−56.45 μM, while ligands L1 and L2 were significantly less active. Complex C1 showed cytoselective activity toward the K562 cell line (IC 50 = 11.03 ± 1.39 μM) and was 3 times less active against the nontumor MRC-5 cell line. Flow cytometry analysis indicated that complexes C1 and C2 after 24 h treatment caused a concentration-dependent increase of the apoptotic sub-G1 fraction (up to 18.4%), comparable to cis-diamminedichloridoplatinum(II) (cisplatin, CDDP), although without other substantial alterations of the cell cycle. A drug-accumulation and DNA-binding study performed by ICP-MS in the K562 cell line revealed that complex C1 had a high intracellular uptake (1.38 μg Ru/10 6 cells), which significantly exceeded the intracellular uptake levels of CDDP (0.29 μg Pt/10 6 cells) and C2 (0.08 μg Ru/10 6 cells). However, both ruthenium complexes C1 and C2 bind to cellular DNA less efficiently in comparison to CDDP. The structure−activity relationship clearly suggested that introduction of a 7-chloroquinoline moiety in the ruthenium(II)-p-cymene complex significantly contributed to the intracellular uptake of C1 and higher cytotoxicity and cytoselectivity.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Strong in Vitro Cytotoxic Potential of New Ruthenium–Cymene Complexes

et al. 2015

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“…Multiple computational approaches like ab initio molecular orbital and density functional theory calculations, along with the molecular electrostatic potential analysis, and molecular docking were also utilized by our research group for the design of 1H-imidazole-2,4-diamine derivatives as potential inhibitors of PfDHFR enzyme (Adane & Bharatam, 2011). Many scientific groups have also identified many novel classes of PfDHFR inhibitors such as 2,4-diaminopyrimidines (Falco, Goodwin, Hitchings, Rollo, & Russell, 1951), 2-amino-1,4-dihydro-4,4,7,8-tetramethyl-s-triazino(1,2-a)benzimida zole and Trp-P-2 series (Toyoda et al, 1997), 5-Benzyl-2,4-diamonopyrimidines (Sirichaiwat et al, 2004), novel biguanide analogs (RJF001302, RJF00670 and RJF00719) (Dasgupta et al, 2009), 2-methyl-6-ureido-4-quinolinamides (Madapa et al, 2009, 4-anilinoquinoline triazines , 1,2,3-Triazole tethered β-lactam and 7-chloroquinoline bifunctional hybrids , hybrid phenylthiazolyl-1,3,5-triazine derivatives (Gahtori et al, 2012), 4-aminoquinoline and 1,3,5-triazine derivatives Bhat et al, 2013), and 2-Aminopyrimidinebased 4-aminoquinoline antiplasmodial agents (Singh, Kaur et al, 2012). More recently, our research group has implemented computer-aided methods for the design of new class of S-benzylated guanylthiourea compounds (Figure 1), which were synthesized later and tested for their biological activity.…”

Section: Introductionmentioning

confidence: 99%

Origins of the specificity of inhibitor P218 toward wild-type and mutantPfDHFR: a molecular dynamics analysis

Abbat

Jain

Bharatam

2014

Journal of Biomolecular Structure and Dynamics

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Molecular dynamics simulations were performed to evaluate the origin of the antimalarial effect of the lead compound P218. The simulations of the ligand in the cavities of wild-type, mutant Plasmodium falciparum Dihydrofolate Reductase (PfDHFR) and the human DHFR revealed the differences in the atomic-level interactions and also provided explanation for the specificity of this ligand toward PfDHFR. The binding free energy estimation using Molecular Mechanics Poisson-Boltzmann Surface Area method revealed that P218 has higher binding affinity (~ -30 to -35 kcal/mol) toward PfDHFR (both in wild-type and mutant forms) than human DHFR (~ -22 kcal/mol), corroborating the experimental observations. Intermolecular hydrogen bonding analysis of the trajectories showed that P218 formed two stable hydrogen bonds with human DHFR (Ile7 and Glu30), wild-type and double-mutant PfDHFR's (Asp54 and Arg122), while it formed three stable hydrogen bonds with quadruple-mutant PfDHFR (Asp54, Arg59, and Arg122). Additionally, P218 binding in PfDHFR is stabilized by hydrogen bonds with residues Ile14 and Ile164. It was found that mutant residues do not reduce the binding affinity of P218 to PfDHFR, in contrast, Cys59Arg mutation strongly favors inhibitor binding to quadruple-mutant PfDHFR. The atomistic-level details explored in this work will be highly useful for the design of non-resistant novel PfDHFR inhibitors as antimalarial agents.

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“…In this regard, derivatives of 1,3,5‐triazine have received considerable attention . 1,3,5‐Triazines have various pharmacological activities, such as antibacterial, antifungal, antimalarial, antidiabetic and anticystic fibrosis effects. Moreover, 1,3,5‐triazine exerts anticancer effects by inhibiting PI3K/mTOR, Rad6 ubiquitin conjugating enzyme and human epidermal growth factor receptor tyrosine kinases (EGFR‐TKs) …”

Section: Introductionmentioning

confidence: 99%

Novel 1,3,5‐triazine derivatives exert potent anti‐cervical cancer effects by modulating Bax, Bcl2 and Caspases expression

Wang

et al. 2017

Chem Biol Drug Des

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This study aimed to develop novel 1,3,5-triazine derivatives as potent anti-cervical cancer agents. The compounds were synthesized in short steps with an excellent yield and characterized via various spectroscopic and analytical methods. A structure-activity relationship study suggested that electron-withdrawing substituents showed greater anticancer activity than electron-donating groups. Compound 7p (p-fluoro) showed the highest activity against cervical cancer cells. In a nude mouse xenograft model inoculated with HeLa cells, 7p showed dose-dependent inhibition of cervical tumour growth. Histopathological examination of excised tumour-bearing tissues showed that 7p improved the microstructure in a dose-dependent manner. Compound 7p also increased the proportions of HeLa cells in G0/G1 and S-phase and significantly decreased that of G2/M-phase. The effects of 7p on C-caspase-3, C-caspase-9, Bcl-2 and Bax expression in HeLa cells were also determined.

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Antimalarial activity and docking studies of novel bi-functional hybrids derived from 4-aminoquinoline and 1,3,5-triazine against wild and mutant malaria parasites as pf-DHFR inhibitor

Abstract: Antimalarial activity and docking studies of novel bifunctional hybrids derived from 4-aminoquinoline and 1,3,5-triazine against wild and mutant malaria parasites as pf-DHFR inhibitor

Cited by 50 publications

References 23 publications

Strong in Vitro Cytotoxic Potential of New Ruthenium–Cymene Complexes

Strong in Vitro Cytotoxic Potential of New Ruthenium–Cymene Complexes

Origins of the specificity of inhibitor P218 toward wild-type and mutantPfDHFR: a molecular dynamics analysis

Novel 1,3,5‐triazine derivatives exert potent anti‐cervical cancer effects by modulating Bax, Bcl2 and Caspases expression

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