Rational Drug Design, Synthesis and Biological Evaluation of Dihydrofolate Reductase Inhibitors as Antituberculosis Agents

Tawari, Nilesh R.; Bag, Seema; Raju, Archana; Lele, Arundhati C.; Bairwa, Ranjeet; Ray, Mukti Kanta; Rajan, M. G. R.; Nawale, Laxman; Sarkar, Dhiman; Degani, Mariam S.

doi:10.4155/fmc.15.48

Cited by 12 publications

(13 citation statements)

References 23 publications

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“…20 Simultaneously, the Pharmacophore Alignment and Scoring Engine (PHASE) module of Schrödinger suite was used to align the 26 in-house Mtb DHFR inhibitors, having 2,4-diaminotriazine scaffold, 11 and identify additional features. The designed derivatives were docked into Mtb DHFR active site to investigate the in-silico binding interactions.…”

Section: Methodsmentioning

confidence: 99%

“…10 Our research group has been actively involved in the synthesis of several novel, diverse inhibitors of DHFR for Mtb 11,12 and opportunistic pathogens, [13][14][15] including Mycobacterium avium. 16,17 Additionally, we have isolated Mtb DHFR enzyme from recombinant Saccharomycescerevisiae strains and purified it using a novel affinity column.…”

Section: Introductionmentioning

confidence: 99%

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2016

IJPSR

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A series of 2,4-diaminotriazines were synthesized as Mycobacterium tuberculosis(Mtb) dihydrofolatereductase (DHFR) inhibitors. These derivatives were evaluated in whole cells by employing resazurinmicrotitre plate assay (REMA) against MtbH 37 Rv. Further, these were tested against other gram positive and gram negative bacterial strains to check specificity for Mtb. Cytotoxicity assessment was performed using HepG2 cell line and the compounds were found to be non-cytotoxic. The results indicated that some of the derivatives exhibited promising activity. The most active compound in the REMA assay was selected for DHFR enzyme assay against both the Mtb and human enzymes. The enzyme assay results indicated that this derivative exhibited selectivity towards the pathogenic enzyme. The most active compound in the whole cell assay against MtbH 37 Rv showed low cytotoxicity, was specific towards Mtb and displayed selectivity in the DHFR enzyme assay. Thus this study provides promising insight for design of potent and selective Mtb DHFR inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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2016

IJPSR

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“…10 Our research group has been actively involved in the search of DHFR inhibitors and has synthesized several novel, diverse inhibitors of DHFR for Mtb 11,12 and opportunistic pathogens, 13−15 including Mycobacterium avium.…”

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confidence: 99%

“…These studies resulted in hits with Mtb inhibition in the micromolar range. 12 This encouraged us to focus our efforts toward strategically modifying the diamino triazine scaffold, using various molecular modeling techniques, with the goal to achieve submicromolar activity. The current work therefore deals with identification of pharmacophoric features using the interactions of known DHFR inhibitors and alignment of our earlier developed analogues.…”

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confidence: 99%

“…Therefore, diamino substituted ring features were short-listed for manual pharmacophore generation (Figure 1c). Simultaneously, Pharmacophore Alignment and Scoring Engine (PHASE) module of Schrodinger suite was used to align the 26 inhouse Mtb DHFR inhibitors, having 2,4-diamino triazine scaffold, 12 and identify additional features, which could enhance the activity. It was observed that the phenyl ring, which is directly attached to the triazine ring, shows a good overlap in the alignment (Figure 1b).…”

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Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors

Lele

Raju

Khambete

et al. 2015

ACS Med. Chem. Lett.

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We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H 37 Rv and Dormant stage H 37 Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb was evaluated by testing against other bacterial strains. Some derivatives showed promising activity along with low cytotoxicity. The most potent compound in the whole cell assay (MIC 0.325 μM against H 37 Rv) showed selectivity in the enzyme assay and exhibited synergy with second line anti-TB agent p-amino salicylic acid. This study therefore provides promising molecules for further development as antituberculosis DHFR inhibitors.

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Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors

Shelke

Degani

Raju

et al. 2016

Archiv der Pharmazie

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Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38-90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5-125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design.

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Rational Drug Design, Synthesis and Biological Evaluation of Dihydrofolate Reductase Inhibitors as Antituberculosis Agents

Abstract: This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.

Cited by 12 publications

References 23 publications

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Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors

Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors

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