Synthesis and Antitrypanosomal and Mechanistic Studies of a Series of 2-Arylquinazolin-4-hydrazines: A Hydrazine Moiety as a Selective, Safe, and Specific Pharmacophore to Design Antitrypanosomal Agents Targeting NO Release

Abstract

Nitric oxide (NO) represents a valuable target to design antitrypanosomal agents by its high toxicity against trypanosomatids and minimal side effects on host macrophages. The progress of NO-donors as antitrypanosomal has been restricted by the high toxicity of their agents, which usually is based on NOheterocycles and metallic NO-complexes. Herein, we carried out the design of a new class of NO-donors based on the susceptibility of the hydrazine moiety connected to an electron-deficient ring to be reduced to the amine moiety with release of NO. Then, a series of novel 2-arylquinazolin-4-hydrazine, with the potential ability to disrupt the parasite folate metabolism, were synthesized. Their in vitro evaluation against Leishmania and Trypanosoma cruzi parasites and mechanistic aspects were investigated. The compounds displayed significant leishmanicidal activity, identifying three potential candidates, that is, 3b, 3c, and 3f, for further assays by their good antiamastigote activities against Leishmania braziliensis, low toxicity, non-mutagenicity, and good ADME profile. Against T. cruzi parasites, derivatives 3b, 3c, and 3e displayed interesting levels of activities and selectivities. Mechanistic studies revealed that the 2arylquinazolin-4-hydrazines act as either antifolate or NO-donor agents. NMR, fluorescence, and theoretical studies supported the fact that the quinazolin-hydrazine decomposed easily in an oxidative environment via cleavage of the N−N bond to release the corresponding heterocyclic-amine and NO. Generation of NO from axenic parasites was confirmed by the Griess test. All the evidence showed the potential of hydrazine connected to the electron-deficient ring to design effective and safe NO-donors against trypanosomatids.

Optimization of the 2-arylquinazoline-4(3H)one scaffold for a selective and potent antitrypanosomal agent: modulation of the mechanism of action through chemical functionalization

“…Selection of 2-aryl-functionalities (Scheme 1) was focused on those that led to the best activity/toxicity profile in the previous 2-arylquinazolin-4(3 H )-ones 1 and 2-arylquinazolin-4-hydrazine 2 : phenyl, 4-Cl-, 4-Br, 4-F-, and 4-Me-phenyl. 23,25 Other electron-deficient aryl-functionalities such as 3-chlorophenyl ( 3f ) or 3-bromophenyl ( 3g ), as aryl substitution at the 2-position, were also considered because an electron-deficient aryl group could favor the hypothesized bio-reduction of the nitro-moiety thanks to its ability to increase the electron-deficient character of the quinazoline core. 40–41 In addition, a 5-denitrofuryl derivative was synthesized to study the relevance of the nitro-group in the antitrypanosomal activity and mechanism of action ( 3h , Scheme 1).…”

“…2-Arylquinazolin-4-(furfurylidene)hydrazones 3a–h were prepared from their corresponding 2-aryl-quinazolin-4-hydrazines 2a–g following reported procedures with a few modifications 25,40,41 (Scheme 1). Then, hydrazine compounds 2a–g were reacted with the corresponding aldehyde, 5-nitrofurfural, or furfural (1.2 equiv.…”

“…Derivatives 3f , 3g , and 3h showed a clear predominance of the E -isomer (>95%). The 2-arylquinazolin-4-hydrazines 2a–g were prepared as described previously 25 from 2-aryl-quinazolin-4(3 H )-ones 1 . 44…”

“…45 dLeishmanicidal. 25 eLog P values were calculated from Swiss-ADME website. 53 fSolubility (μM) determined from UV-Vis spectroscopy.…”

“…14–18 Traditionally, pteridin and quinazolin scaffolds have been used as chemical platforms to design new antifolate agents as competitive inhibitors of DHFR and PTR1, and their derivatives have displayed significant antitrypanosomal activities with good inhibitory responses. 19–25…”