Antimalarial evaluation and docking studies of hybrid phenylthiazolyl-1,3,5-triazine derivatives: A novel and potential antifolate lead for Pf-DHFR-TS inhibition

Gahtori, Prashant; Ghosh, Surajit Kumar; Parida, Pratap; Prakash, Anil; Gogoi, Kabita; Bhat, Hans Raj; Singh, Udaya Pratap

doi:10.1016/j.exppara.2011.12.014

Cited by 68 publications

(30 citation statements)

References 18 publications

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“…Some are also used for the treatment of HIV infection [4][5][6]. Several workers have investigated s-triazine derivatives in the scope of potential therapeutic agents for diseases due to bacteria [7][8][9][10], cancer [11][12][13], antitumor [14,15], and malaria [16,17]. This literature survey led us to consider the s-triazine system as a possible scaffold.…”

Section: Introductionmentioning

confidence: 98%

Synthesis, characterization, and antimicrobial screening of s-triazines linked with piperazine or aniline scaffolds

Lakum

Desai

Chikhalia

2013

Heterocyclic Communications

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Two series of s-triazines linked with piperazine or aniline scaffolds (4a-i and 5a-j) were synthesized and evaluated for their in vitro biological efficacy against Gram positive and Gram negative bacteria (Klebsiella pneumoniae MTCC 109, Pseudomonas aeruginosa MTCC 741, Staphylococcus aureus MTCC 96, Bacillus cereus MTCC 619) and fungi (Candida albicans MTCC 183 and Aspergillus niger MTCC 282) using a broth dilution technique. Compounds most active against certain bacteria and fungi are 4e, 4g, 4i, 5d, and 5i.

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Section: Introductionmentioning

confidence: 98%

Synthesis, characterization, and antimicrobial screening of s-triazines linked with piperazine or aniline scaffolds

Lakum

Desai

Chikhalia

2013

Heterocyclic Communications

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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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“…It is used to predict the preferred orientation, affinity and activity of ligands (small molecules) into the active site of target protein through a process involving series of steps. In continuation of our research endeavour on discovery of novel anti-infective agents from 1,3,5-triazines (Gahtori et al 2009; Singh et al 2011; Bhat et al 2011; Gahtori et al 2012a; Gahtori et al 2012b; Gahtori and Ghosh et al 2012; Ghosh et al 2012; Bhat et al 2012, Singh et al 2012). We have tried to work out the inhibitory effect of hybrid phenylthiazole-1,3,5-triazines on the candida albicans cytosolic leucyl-tRNA synthetase editing domain through molecular docking studies to elucidate probable mechanism of action of 1,3,5-triazine as antifungal agent.…”

Section: Introductionmentioning

confidence: 99%

Hybrid phenylthiazole and 1,3,5-triazine target cytosolic leucyl-tRNA synthetase for antifungal action as revealed by molecular docking studies

Singh

Bhat

Gahtori

et al. 2013

In Silico Pharmacol.

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BackgroundLeucyl-tRNA synthetase (LeuRS) is one of the essential enzymes belonging to the family of aminoacyl-tRNA synthetases (aaRSs), which executes the translation of genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs. This process is very crucial for survival of micro-organism and thus the inhibition of LeuRS offered a novel and lucrative target for developing new antimicrobials.FindingsDocking studies using hybrid phenylthiazole-1,3,5-triazine derivatives revealed that these molecules acted as probable inhibitors of candida albicans cytosolic leucyl-tRNA synthetaseConclusionThe conjugates of phenylthiazole and 1,3,5-triazine can act as lead molecules towards the development of potential leucyl-tRNA synthetase inhibitors on the basis of molecular docking runs, which contribute to the possible mechanism of antifungal activity of these analogues.

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Antimalarial evaluation and docking studies of hybrid phenylthiazolyl-1,3,5-triazine derivatives: A novel and potential antifolate lead for Pf-DHFR-TS inhibition

Cited by 68 publications

References 18 publications

Synthesis, characterization, and antimicrobial screening of s-triazines linked with piperazine or aniline scaffolds

Synthesis, characterization, and antimicrobial screening of s-triazines linked with piperazine or aniline scaffolds

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

Hybrid phenylthiazole and 1,3,5-triazine target cytosolic leucyl-tRNA synthetase for antifungal action as revealed by molecular docking studies

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