2‐Phenyl‐5‐(trichloromethyl)‐1,3,4‐oxadiazoles, A new class of antimalarial substances

Abstract

An investigation of hybrids of 2,5‐dimethyl‐1,3,4‐oxadiazole (I) and α,α,α,α',α',α'‐hexachloro‐p‐xylene (Hetol®) (II) as potential antimalarial agents led to the synthesis of representative 2‐phenyI‐5‐(trichloromethyl)‐1,3,4‐oxadiazoles (VIa‐f, VIII‐X) and related trichloromethyl 1,2,4‐oxadiazole, 1,3,4‐oxadiazoles, and 1,3,4‐thiadiazole (VII, XIII‐XV). Treatment of the appropriately substituted benzoic: acid hydrazides (IVa‐f) with trichloroacetic anhydride afforded the intermediate 1‐benzoyl‐2‐(triehloroacetyl)hydrazines (Va‐f) which were cyclized to the desired 5‐(chlorophenyl, tolyl, or α,α,α‐trifluorotolyl)‐2‐(trichloromethyl)‐1,3,4‐oxadiazoles (VIa‐f) (44–66%) in situ utilizing phosphorous oxychloride. Chlorination of the 5‐tolyl‐2‐(trichloromethyl)‐1,3,4‐oxadiazoles (VId‐f) afforded 2‐(trichloromethyl)‐5‐(α,α,α‐trichloro‐m‐ and p‐tolyl)‐1,3,4‐oxadiazole (VIII and IX) and 2‐(α,α,α,α',α',α'‐hexachloro‐3,5‐xylyl)‐5‐(trichloromethyl)‐1,3,4‐oxadiazole (X) in 23–56% yield. Each of the 2‐phenyl‐5‐(trichloromethyl)‐1,3,4‐oxadiazoles (VIa‐f, VIII‐X) was active against Plasmodium berghei in mice when administered in single 160 or 640 mg./kg. subcutaneous doses or given orally by drug‐diet for 6 days at doses of 29–336 mg./kg./day. The 2‐(trichloromethyl)‐5‐(α,α,α‐trichlorotolyl)‐1,3,4‐oxadiazoles (VIII‐X) were the most active compounds prepared and exhibited activity against P. berghei comparable with Hetol®. Structure‐activity relationships are discussed.

1,2,4- and 1,3,4-Oxadiazoles as Scaffolds in the Development of Antiparasitic Agents

“…One advantage of this protocol is the possibility of synthesizing 1,2,4-oxadiazoles (63) just by using amidoximes (62) instead of hydrazides, keeping the same experimental procedure (Scheme 13). 52 Rouhani et al 53 utilized ultrasound irradiation to react aromatic carboxylic acids (64) and acenaphthoquinone (65), obtaining 1,3,4-oxadiazoles (67). The reaction was carried out in the presence of (N-isocyanimino)triphenylphosphorane (66) and acetonitrile as solvent.…”

“…An early work by Hutt et al 64 described the synthesis of a series of differently substituted 2-trichloromethyl-5-phenyl-1,3,4-oxadiazoles. The compounds were inspired by the chemical structure of 1,4-bis-(trichloromethyl) benzene (76, hetol), based on previous reports of its antimalarial activity in infected monkeys.…”

“…The events of cure are represented by C (n), while the deaths due to drug toxicity are represented by T (n), where n = frequency. 64 More recently, Balaji et al 66 reported the synthesis and antimalarial evaluation of 20 novel 1,3,4-oxadiazole derivatives. The compounds were assayed against chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) strains of P. falciparum.…”

Some Features of Liquid Crystalline Oxadiazoles

“…For instance, the 1,2,4-oxadiazole systems is used in the Oxolamine which is a cough suppressant. Oxadiazoles are antibacterial, antimalarial, anti-inflammatory, antifungal and anticonvulsant (see for instance, [32] and [33]). Recently [34], some 2,5-substituted diphenyl-1,3,4-oxadiazoles have been studies for their biological activities of the −N=C−O− grouping.…”

Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties

“…Therefore, the sulfonamide moiety is a crucial functionality because of its wide variety of pharmacological activities. In addition to various pharmacological applications of 2,5-disubstituted-1,3, 4-oxadiazoles [9 -13], the 2-phenyl -5-(trichloromethyl)-1,3,4-oxadiazole has been reported [14] as a potent antimalarial agent.…”