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Molecules 2017, 22(10), 1592; doi:10.3390/molecules22101592

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

1
School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
2
Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Sungai Long campus, Kajang 43000, Selangor, Malaysia
3
School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan 750021, China
4
KeyLaboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 4 September 2017 / Revised: 19 September 2017 / Accepted: 20 September 2017 / Published: 22 September 2017
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [2679 KB, uploaded 25 September 2017]   |  

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 μg/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. View Full-Text
Keywords: anti-tuberculosis; 2,4-diaminopyrimidine derivatives; synthesis anti-tuberculosis; 2,4-diaminopyrimidine derivatives; synthesis
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MDPI and ACS Style

Ouyang, Y.; Yang, H.; Zhang, P.; Wang, Y.; Kaur, S.; Zhu, X.; Wang, Z.; Sun, Y.; Hong, W.; Ngeow, Y.F.; Wang, H. Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities. Molecules 2017, 22, 1592.

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