A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability. Bioorg Med Chem Lett

Medicinal Chemistry Group, Institut Pasteur Korea, Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 02/2012; 22(7):2522-6. DOI: 10.1016/j.bmcl.2012.01.133
Source: PubMed


Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.

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Available from: Sung-Jun Han, Aug 05, 2014
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    • "Recently, an appropriately functionalized dihydropyrimidine analogue of novel 4-aryl-5-isopropoxy- carbonyl-6-methyl-3,4-dihydropyrimidinones emerged as an anti-microbiological agent [5]. A novel 3,4- dihydropyrimidin-2(1H)-one was reported to inhibit HIV-1 replication with improved metabolic stability [6], and its special structure was found to occur naturally in marine alkaloid batzelladines; these are the first "
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    ABSTRACT: A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones (DHPMs) through Biginelli reaction by the condensation reaction of aldehydes, β-ketoesters and urea/thiourea employing p-dodecylbenzenesulfonic acid (DBSA) as a recyclable catalyst under solvent-free condition at 80 °C is described. Furthermore, a series of indeno[1,2-d]pyrimidines have also been synthesized using the same conditions by the Biginelli-like reaction of 2H-indene-1,3-dione, with urea/thiourea and aromatic aldehyde. All the products in both reactions obtained in good to excellent yields by proceeding through a simple and efficient procedure. All the synthesized compounds structure has been established by advanced spectroscopic data
    Full-text · Article · Jul 2014
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    ABSTRACT: Dihydropyrimidines received considerable attention over the last few decades due to their interesting pharmacological properties like, antimicrobial, anti-tuberculosis, antiinflammatory, calcium-channel blockers, mitotic inhibitions, anti-cancer activities, etc. In this chapter, we reviewed recent developments of DHPMs in the field of medicinal chemistry and pharmacology.
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    ABSTRACT: The application of bioisosteres in drug discovery is a well-established design concept that has demonstrated utility as an approach to solving a range of problems that affect candidate optimization, progression, and durability. In this chapter, the application of isosteric substitution is explored in a fashion that focuses on the development of practical solutions to problems that are encountered in typical optimization campaigns. The role of bioisosteres to affect intrinsic potency and selectivity, influence conformation, solve problems associated with drug developability, including P-glycoprotein recognition, modulating basicity, solubility, and lipophilicity, and to address issues associated with metabolism and toxicity is used as the underlying theme to capture a spectrum of creative applications of structural emulation in the design of drug candidates.
    No preview · Chapter · Jan 2013
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