Synthesis of Functionalised Chromonyl‐pyrimidines and Their Potential as Antimycobacterial Agents

Abstract

Drug-resistant strains of Mycobacterium tuberculosis are on the rise and have resulted in an urgent need to develop new tuberculosis (TB) drugs. Herein, the development of chromonylpyrimidines as a new TB drug scaffold is presented. A library of eleven chromonyl-pyrimidines was synthesised, from which lead compound 6-((2-amino-6-methylpyrimidin-4-yl)amino)-3benzoyl-2-phenyl-4H-chromen-4-one (MIC = 36 μM against M. tuberculosis) was identified. A second-generation library of seven aryl-substituted chromonyl-pyrimidines was then prepared, with six chromonyl-pyrimidines exhibiting an improved M. tuberculosis growth inhibition (MIC = 12.5 μM). From this work, the potential of chromonyl-pyrimidines as therapeutics for TB is demonstrated.[a] Dr.

Assessment of the Antimicrobial and Antiproliferative Activities of Chloropyrazine-Tethered Pyrimidine Derivatives: In Vitro, Molecular Docking, and In-Silico Drug-Likeness Studies

“…The presence of heterocyclic substituents, independent of their position as well as nonsubstitution was detrimental (Figures 3 and 4). Among the bioisosteres (35)(36)(37)(38)(39)(40), the activity was found to be >200 µM. Irrespective of the incorporation of various heterocycles, the activity was not found to be improved over standard ciprofloxacin.…”

“…The different chloropyrazine-tethered pyrimidine derivatives (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) were obtained by the condensation of chloropyrazinyl chalcones (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) with guanidine hydrochloride (Scheme 1) using a base catalyst (KOH) in yields ranging from 56-92%. The molecular structures of the chloropyrazine-tethered pyrimidine hybrids were disentangled using FT-IR and 1 H NMR spectral data and are presented in our previous paper [55].…”

“…Many substituted pyrazine derivatives were reported with potential antibacterial [6][7][8][9][10][11], antifungal [12][13][14][15], anticancer [16][17][18][19][20][21], antioxidant [22][23][24][25], and antitubercular [9,[26][27][28] activities. Similarly, pyrimidine-based compounds also showed excellent antimicrobial (antibacterial and antifungal) [29][30][31][32][33], antimycobacterial [34][35][36][37][38], antioxidant [39][40][41][42], cytotoxic and anticancer [42][43][44][45][46][47][48][49][50][51][52], and antiviral…”

“…In our previous study, we reported the antimicrobial and antiproliferative activities of chloropyrazine-linked 1,5-benzothiazepine hybrids [54]. Considering the significant biological activities of pyrimidine derivatives, previously we synthesized and evaluated the antitubercular activity of chloropyrazine-tethered pyrimidine hybrids (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) [55]. These derivatives (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) are analogues of chloropyrazine-linked 1,5-benzothiazepine hybrids where the pyrimidine ring replaces the 1,5-benzothiazepine motif with the other parts of the compounds being the same (Figure 2).…”

“…Considering the significant biological activities of pyrimidine derivatives, previously we synthesized and evaluated the antitubercular activity of chloropyrazine-tethered pyrimidine hybrids (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) [55]. These derivatives (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) are analogues of chloropyrazine-linked 1,5-benzothiazepine hybrids where the pyrimidine ring replaces the 1,5-benzothiazepine motif with the other parts of the compounds being the same (Figure 2). Here, we report the antimicrobial as well as the antiproliferative activities of chloropyrazine-tethered pyrimidine hybrids with the aim to develop potent antimicrobial and antiproliferative hybrids.…”