1. Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors
Aleem Gangjee, Wei Li, Jie Yang, Roy L Kisliuk J Med Chem. 2008 Jan 10;51(1):68-76. doi: 10.1021/jm701052u. Epub 2007 Dec 12.
We designed and synthesized a classical antifolate N-{4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5 H-pyrrolo[3,2- d]pyrimidin-5-yl)methyl]benzoyl}- l-glutamic acid 4 and 11 nonclassical analogues 5- 15 as potential dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. The key intermediate in the synthesis was N-(4-chloro-6-methyl-5 H-pyrrolo[3,2- d]pyrimidin-2-yl)-2,2-dimethylpropanamide, 29, to which various 5-benzyl substituents were attached. For the classical analogue 4, the ester obtained from the N-benzylation reaction was deprotected and coupled with diethyl l-glutamate followed by saponification. Compound 4 was a potent dual inhibitor of human TS (IC 50 = 46 nM, about 206-fold more potent than pemetrexed) and DHFR (IC 50 = 120 nM, about 55-fold more potent than pemetrexed). The nonclassical analogues were marginal inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR.
2. Rigid Dipeptide Mimics: Synthesis of Enantiopure 5- and 7-Benzyl and 5,7-Dibenzyl Indolizidinone Amino Acids via Enolization and Alkylation of delta-Oxo alpha,omega-Di-[N-(9-(9-phenylfluorenyl))amino]azelate Esters
Felix Polyak, William D. Lubell J Org Chem. 1998 Aug 21;63(17):5937-5949. doi: 10.1021/jo980596x.
Azabicyclo[X.Y.0]alkane amino acids are tools for constructing mimics of peptide structure and templates for generating combinatorial libraries for drug discovery. Our methodology for synthesizing these conformationally rigid dipeptides has been elaborated such that alkyl groups can be appended onto the heterocycle to generate mimics of peptide backbone and side-chain structure. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/ketone alkylation/reductive amination/lactam cyclization sequence that furnished alkyl-branched azabicyclo[4.3.0]alkane amino acid. Enantiopure 5-benzyl-, 7-benzyl-, and 5,7-dibenzylindolizidinone amino acids 2-4 were stereoselectively synthesized via efficient reaction sequences featuring the alkylation of di-tert-butyl alpha,omega-di-[N-(PhF)amino]azelate delta-ketone 5. A variety of alkyl halides were readily added to the enolate of ketone 5 to provide mono- and dialkylated ketones 6 and 7. Hydride additions to 6 and 7, methanesulfonations, and intramolecular S(N)2 displacements by the PhF amine gave 5-alkylprolines that were converted by lactam cyclizations into 7- and 5-benzyl-, as well as 5,7-dibenzyl-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylate methyl esters 10, 11, and 14. Epimerization of the alkyl-branched stereocenter via an iminium-enaminium equilibrium proved effective for controlling diastereoselectivity in reductive aminations with 6 and 7 in order to furnish 5-alkylprolines that were similarly converted to 7- benzyl- and 5,7-dibenzylindolizidinone N-(BOC)amino esters 10 and 14. Ester hydrolysis with hydroxide ion and potassium trimethylsilanolate then gave enantiopure indolizidinone amino acids 2-4. Epimerization at C-9 of benzylindolizidinone amino esters was also used to provide alternative diastereomers of 10, 11, and 14. This practical methodology for introducing side-chain groups onto the heterocycle with regioselective and diastereoselective control is designed to enhance the use of alkyl-branched azabicycloalkane amino acids for the exploration of conformation-activity relationships of various biologically active peptides.
3. Exploring the ability of dihydropyrimidine-5-carboxamide and 5-benzyl-2,4-diaminopyrimidine-based analogues for the selective inhibition of L. major dihydrofolate reductase
Maria Bibi, et al. Eur J Med Chem. 2021 Jan 15;210:112986. doi: 10.1016/j.ejmech.2020.112986. Epub 2020 Nov 4.
To tackle leishmaniasis, search for efficient therapeutic drug targets should be pursued. Dihydrofolate reductase (DHFR) is considered as a key target for the treatment of leishmaniasis. In current study, we are interested in the design and synthesis of selective antifolates targeting DHFR from L. major. We focused on the development of new antifolates based on 3,4-dihydropyrimidine-2-one and 5-(3,5-dimethoxybenzyl)pyrimidine-2,4-diamine motif. Structure activity relationship (SAR) studies were performed on 4-phenyl ring of dihydropyrimidine (26-30) template. While for 5-(3,5-dimethoxybenzyl)pyrimidine-2,4-diamine, the impact of different amino acids (valine, tryptophan, phenylalanine, and glutamic acid) and two carbon linkers were explored (52-59). The synthesized compounds were assayed against LmDHFR. Compound 59 with the IC50 value of 0.10 μM appeared as potent inhibitors of L. major. Selectivity for parasite DHFR over human DHFR was also determined. Derivatives 55-59 demonstrated excellent selectivity for LmDHFR. Highest selectivity for LmDHFR was shown by compounds 56 (SI = 84.5) and 58 (SI = 87.5). Compounds Antileishmanial activity against L. major and L. donovani promastigotes was also performed. To explore the interaction pattern of the synthesized compounds with biological macromolecules, the docking studies were carried out against homology modelled LmDHFR and hDHFR targets.
