Antimalarial Activities of Polyhydroxyphenyl and Hydroxamic Acid Derivatives

Abstract

Several known mammalian ribonucleotide reductase inhibitors featuring a polyhydroxyphenyl and/or hydroxamate moiety as the active group were screened for potency in inhibiting growth of the malaria parasite Plasmodium falciparum. Compounds containing a 2,3- or 3,4-dihydroxyphenyl group as well as benzohydroxamate appear to be the most effective inhibitors of the malaria parasite.

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

“…Similar structures to hydroxyurea [101] such as acetohydroxamate [102], substituted benzohydroxamic acids [54] or even hydroxylamine, hydroquinones and hydrazine derivatives [103] have shown similar inhibition behaviour. Although some of them are structurally dissimilar, they all readily donate electrons that facilitate the quenching of the critical tyrosyl radical.…”

“…Most of these inhibitors are being tested in clinical trials and some of them have already been approved for the treatment of sickle cell anaemia and certain forms of cancer such as non-small cell lung cancer, adenocarcinoma of pancreas, bladder cancer, leukaemia and solid tumours [52]. Although less studied these inhibitors can also be used in anti-viral, anti-bacterial and anti-parasite therapies, and may be applied in the near future in the treatment of diseases such as AIDS [53] and malaria [54]. entire mRNA coding sequence.…”

Hydroxamic Acids as Pharmacological Agents

“…They are also capable of competing as siderophores for iron-(III) [9][10][11]. In the biomedical sciences, hydroxamic acids moieties are used in the design of therapeutics targeting cancer [12][13][14][15], cardiovascular diseases [16,17], HIV [18,19], Alzheimer's [20,21], malaria [22][23][24][25][26][27], allergic diseases [28][29][30], tuberculosis [31][32][33][34][35][36], metal poisoning [37][38][39][40], and ironoverload [41][42][43]. In addition, the hydroxamic acids have been employed as insecticides [44,45], antimicrobials [46][47][48][49][50][51][52][53], and plant growth regulators [54][55][56]…”

Synthesis of carbohydrate-based artificial siderophores and their biological applications

“…39 Retro-hydroxamate siderophores are analogues in which the position of the hydroxamate nitrogen and carbon are interchanged relative to their position in the natural siderophore and have found application as antimalarial agents. [40][41][42][43] The first synthetic analogues of hydroxamate siderophores based on methyl a-D-glucopyranoside, methyl a-D-galactopyranoside, methyl a-Dribopyranoside and methyl a-D-xylopyranoside were in fact retro-hydroxamates and were reported by Heggemann et al 15 The two hexoses were first protected with a trityl group at C-6, so that all four monosaccharides studied have only three free OH groups (OH-2, 3 and 4). The corresponding retro-trishydroxamates with different spacer groups were prepared by Steglich esterification with N-benzoyloxy-N-methylglutaric acid (30-33a), N-benzyloxy-N-methylsuccinic acid (30-33b), N-benzyloxy-N-methylglutaric acid (30-33c) and N-benzyloxy-N-butylglutaric acid (30d), using dicyclohexyl-carbodiimide (DCC) and N,N-dimethylaminopyridine (DMAP) in dichloromethane.…”