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Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities.

ABSTRACT: Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level. In the current study, we designed and synthesized a series of mt-DHFR inhibitors that contain a 2,4-diaminopyrimidine core with side chains to occupy the glycerol binding site with proper hydrophilicity for cell entry, and tested their anti-tubercular activity against Mtb H37Ra. Among them, compound 16l showed a good anti-TB activity (MIC = 6.25 ?g/mL) with a significant selectivity against vero cells. In the molecular simulations performed to understand the binding poses of the compounds, it was noticed that only side chains of a certain size can occupy the glycerol binding site. In summary, the novel synthesized compounds with appropriate side chains, hydrophobicity and selectivity could be important lead compounds for future optimization towards the development of future anti-TB drugs that can be used as monotherapy or in combination with other anti-TB drugs or antibiotics. These compounds can also provide much information for further studies on mt-DHFR. However, the enzyme target of the compounds still needs to be confirmed by pure mt-DHFR binding assays.

SUBMITTER: Ouyang Y

PROVIDER: S-EPMC6151568 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities.

Ouyang Yifan Y Yang Hao H Zhang Peng P Wang Yu Y Kaur Sargit S Zhu Xuanli X Wang Zhe Z Sun Yutong Y Hong Wei W Ngeow Yun Fong YF Wang Hao H

Molecules (Basel, Switzerland) 20170922 10

Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, bu ...[more]

PMID: 28937657

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Project description:The present pathway involves synthesis of isonicotinohydrazide derivatives using isoniazid and diversely substituted aldehydes in the presence of EtOH and catalytic amount of glycerol based carbon sulfonic acid catalyst. The developed pathway has so many merits like excellent yields (91–98%), short reaction time (4–10 min), easy reaction set up, no need of column chromatography, large substrate scope, easily recyclable and reusable catalyst. The synthesized compounds were screened for antimicrobial and anti-tubercular activity and it was observed that compounds possessed high biological potency against the Gram positive and Gram negative bacterial and fungal strains. Regarding anti-tubercular activity, compound 3m exhibited high % inhibition against Mycobacterium tuberculosis H37RV strain. Based on the outcome of in vitro studies, all the synthesized compounds were docked against E. coli (1KZN), C. albicans (1IYL), and M. tuberculosis H37Rv strain (2NSD). The synthesized derivatives were docked within the binding site of 1KZN, and 1IYL. However, with 2NSD, apart from 3h, all the derivatives displayed interaction within the binding cavity of the protein. All the crucial interactions with Asn46, Asp73, and Arg136 in 1KZN, His227, Leu451 in 1IYL, and Tyr158 in 2NSD were witnessed in the top-scored docked candidates. Molecular docking studies revealed the importance of the substitution at R position on isonicotinohydrazide scaffold. The nitrogen atoms of hydrazide moiety were involved in forming hydrogen bonding with the active site amino acids, and the substitution at the R position occupy the hydrophobic position in the binding pocket. Also, the functional groups present on the substituted R position were involved in forming hydrogen bonding with the crucial active site residues. Graphical abstract Synthesis of isonicotinohydrazide analogs and their in vitro and in silico studies.Image 1 Highlights • Isonicotinohydrazide analogs were synthesized in excellent yields (91–98%) in 4–10 min using glycerol based carbon-SO3H catalyst.• The synthesized compounds were screened for anti-microbial activity against bacterial and fungal strains.• The synthesized compounds were examined for anti-tubercular activity.• All the synthesized compounds (3a-o) were docked against 1KZN, 1IYL, and 2NSD proteins.

Dataset Information

Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities.

Publications

Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities.

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