Chemical and Biological Studies on 1,2-Dihydro-s-triazines. III. Two-Component Synthesis^1,2

Expeditious synthesis and biological evaluation of novel 2,N6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as potential antimalarials

“…Chemistry N 1 -Aryl-1,2-dihydro-1,3,5-triazine-4,6-diamines (11), such as cycloguanil, are generally made in two steps from dicyandiamide (7) and an aniline (8) under acidic conditions to first generate arylbiguanides (9) which are then reacted with an appropriate carbonyl compound (10) in the presence of an acid catalyst to give the 1,2-dihydro-1,3,5-triazine-4,6-diamine (11) substituted at N-1 and C-2 [15,16]. The arylbiguanide (9) may be isolated before further reaction, or the two-step procedure may be performed in the same reaction vessel (Scheme 1).…”

“…When employing this methodology for the synthesis of flexible cycloguanil analogues, as depicted in Scheme 2, instead of obtaining exclusively the cycloguanil-like structures (15), one often obtains the related isomer (16) which has the tether attached to N-6 [17]. Closer inspection of the mechanism of the cyclisation reaction offers a plausible explanation (Scheme 2).…”

“…Although 2,N 6 -disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines (16) have been reported by other workers [15,16,19] as inter alia anticoccidial agents [17]; anthelmintics [17]; topical antiseptic agents [20]; antiviral agents [21]; antibacterial agents [21,22]; herbicides [23]; and for treating pathophysiological conditions arising from inflammatory responses [24]; they have never, to the best of our knowledge, been tested for their antimalarial properties. We were interested in investigating this series of compounds for their antimalarial activity and embarked on the synthesis of a small collection of compounds of general structure 16.…”

“…The mixture was allowed to cool down to w90 C (caution being exercised to prevent solidification of the reaction mixture), at which point 1,4-dioxane (3 ml/mmol amine hydrochloride) was added. To this solution of the biguanide salt (14) was added the aldehyde or Table 1 Antimalarial data for 2,N 6 -disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines (16 …”

Chemical and Biological Studies on 1,2-Dihydro-s-triazines XVIII: Synthesis of 1-(5,6- and 5,'7-Dichloro-2-naphthyl) Derivatives and Related Compounds as Candidate Antimalarial and Antitumor Agents

“…On the other hand, the standard three-component synthesis Hiith 5,7-dichloro-2-naphthylamine hydfochloride did produce a small amount of gua+dinoquinazo-line HIb. HCl, which made it preferable to obtain dihydrotriazine Ib .HCl via the two-component synthesis (8) starting from biguanide Ilb-HCI. An authentic specimen of 1llb.HCl was synthesized conveniently uiu the recently described (4) modified three-component synthesis, wherein only a limited amount of acid is used at the outset of the reaction.…”