Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline‐7‐Acetic Acid Derivatives With Amino Acid Moieties

Abstract

The theophylline-7-acetic acid (7-TAA) scaffold is a promising novel lead compound for antimycobacterial activity. Here, we derive a model for antitubercular activity prediction based on 14 7-TAA derivatives with amino acid moieties and their methyl esters. The model is applied to a combinatorial library, consisting of 40 amino acid and methyl ester derivatives of 7-TAA. The best three predicted compounds are synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them are stable, non-toxic against human cells and show antimycobacterial activity in the nanomolar range being 60 times more active than ethambutol.

Clinical and social aspects of dysmenorrhea development

“…As shown in the scheme (Fig. 1), the reaction of 8-brom-7ethylxanthines (1,2) [7,8] with an excess of the corresponding aminoalkanoic acid in an aqueous DMF medium in the presence of an equimolar (in relation to the amino acid) amount of baking soda leads to the formation of the corresponding 7-ethylxanthinyl-8-aminoalkanoic acids (3)(4)(5)(6)(7)(8)(9)(10).…”

“…Synthesis of 7-ethylxanthinyl-8-aminoalkanoic acids (3)(4)(5)(6)(7)(8)(9)(10). A mixture of 0.01 mol of 8-brom-7-ethylxanthine 1 or 2, 0.025 mol of the corresponding amino acid, 2.1 g (0.025 mol) of NaHCO 3 , 15 ml of water and 25 ml of DMF are boiled for 6 hours, cooled; 50 ml of water are added, then the mixtures are filtered.…”

“…Despite their effectiveness, they cause a number of side effects, and thus the search for new antimicrobial and antifungal agents is currently one of the problems of pharmaceutical science of current interest. Literary data suggest that xanthine derivatives exhibit activity in relation to some strains of pathogenic microorganisms and fungi [1][2][3][4][5][6].…”

Recent Synthetic Approaches Towards Biologically Potent Derivatives/Analogues of Theophylline

“…in 2014 and Stavrakov et al . in 2016 extended the idea of purine‐based structural scaffold of theophylline and devised the synthesis of 7‐theophylline acetamides 174 (28–96%) from amino acids as potentially active anti‐mycobacterial candidates. In their work, amide linkage was developed by the reaction of theophylline‐7‐acetic acid 172 with amino acid derivatives 173 in the presence of N ‐ethyl‐ N′ ‐dimethyl amino propylcarbodiimide (EDCI) together with N ‐hydroxybenzotriazole (HOBT).…”

“…again in 2015 proposed the synthesis of acetamides of theophylline‐7‐acetic acid but in different mode. In their previous work , the synthesis of required product was achieved by coupling of theophylline‐7‐acetic acid 172 with various amino acid derivatives 173 under suitable reaction conditions. In this work, to accomplish the synthesis of theophylline‐7‐acetamides 199 , firstly, N ‐chloroacetyl amino acid methyl ester 197 was synthesized by carrying out the treatment of amino acid methyl ester hydrochloride 196 with chloroacetyl chloride in the presence of K 2 CO 3 that was then reacted with deprotonated theophylline 198 and furnished the required derivatives 199 in 76–82% yields (Scheme ).…”