Synthesis and evaluation of 4-quinazolinone compounds as potential antimalarial agents

Abstract

Febrifugine is an alkaloid isolated from Dichroa febrifuga as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug. As part of an ongoing malaria chemotherapy project, novel febrifugine analogues were designed and synthesized. Lower toxicity of these newly designed compounds was achieved by reducing or eliminating the tendency to form chemically reactive and toxic intermediates. New compounds possess excellent in vivo antimalarial activity and most of them become less toxic than the natural product febrifugine. Some of the compounds possess a therapeutic index over ten times superior to that of febrifugine and the commonly used antimalarial drug chloroquine. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.

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“…On standing for 1 h, solidification occur, the product was filtered off, washed with water and dried. (6)(7)(8)(9)(10)(11)(12)(13)(14): To a solution of the appropriate acetophenones (0.01mol) dissolved in ethanol (20ml), was added different substituted 3-amino-2-phenylquinazolin-4-one derivative (5a-5c) (0.01mol) and pH of the resultant solution was adjusted to 4.0-4.5 using glacial acetic acid. The resulting mixture was refluxed for 2-3 h. The solid thus obtained was filtered and purified by column chromatographic method using n-hexane/ethyl acetate (75:25) as eluents.…”

“…The in silico pharmacokinetic properties of the designed quinazoline analogues (6)(7)(8)(9)(10)(11)(12)(13)(14) were estimated by means of molecular weight, dipole moment, H-bond donors, H-bond acceptors, QPlogP o/w, QPlogS, QlogBB, human oral absorption, and polar surface area (PSA), molecular surface descriptors (solvent accessible surface area) and other parameters such as wiener index (WI) were also determined using QikProp (version9.2) module of Schrödinger. As well as the Lipinski' rule of five was to filter molecules with filter for drug-like properties has also been estimated.…”

“…Unless otherwise stated, the following conditions were employed in all experiments. Target compounds (6)(7)(8)(9)(10)(11)(12)(13)(14) were suspended in aqueous solution of carboxymethyl cellulose (CMC, 0.5% w/v) and administered orally at a dose level of 10mg/kg of synthesized compounds (6)(7)(8)(9)(10)(11)(12)(13)(14), respectively. Control animals were similarly treated with aqueous solution of carboxymethyl cellulose (CMC, 0.5% w/v).…”

“…Structures of the ligands 2,3-disubstituted quinazolinone derivatives containing Schiff bases (6)(7)(8)(9)(10)(11)(12)(13)(14) were drawn by using chemdraw ultra 8.0 and the three-dimensional structures of the compounds were constructed using the Maestro interface. All 3D ligands were subjected to energy minimization and optimization using Ligprep module.…”

“…Quinazolin-4(3H)-one represents a versatile lead molecule for the design of potential bioactive agents [1][2][3][4][5][6][7] and the pharmaceuticals containing quinazolinone nucleus show varied biological activities as different substitution patterns results in diverse biological properties [8][9][10] . Number of quinazoline derivatives with different substitutions at 2,3,4,6 positions have been reported and studied as antitumor 11 , antibacterial 12 , anticonvulsant 13 , antimalarials 14 and antiviral agents 15 as shown in Table 1.…”