Ionel I. Mangalagiu

New pyridazine derivatives : Synthesis, chemistry and biological activity

In this paper we report a feasible study concerning synthesis, structure and biological activity of some new pyridazine derivatives. Syntheses have been done both under classical conditions and microwave [in liquid phase and interphasic transfer catalysis (PTC)]. The MW induced a remarkable acceleration for the [3+2] dipolar cycloaddition reaction of pyridazinium ylides to activated alkenes and alkynes, the yields were increased in some cases, and the amount of used solvents decrees in liquid phase (while PTC do not use solvents). Consequently, these types of reactions could be considered environmentally friendly. The in vitro antibacterial and antifungal activities of the newly obtained diazine compounds were tested, some of the compounds have proved to have a remarkable activity against Gram positive germs, the results on Sarcinia luteea being spectacular.

Synthesis and antituberculosis activity of some new pyridazine derivatives. Part II.

A series of eighteen novel compounds with pyridazine moiety were synthesized and their in vitro antituberculosis activities have been evaluated. A fast, general, and facile method for preparation of pyridazine derivatives in moderate to excellent yields is presented. Three compounds were found to be moderate active against Mycobacterium tuberculosis. Correlation of structure-biological activity has been done.

Synthesis and antimicrobial activity of some new pyridazine derivatives

Five new pyridazine derivatives (1 salt and 4 pyrrolopyridazine cycloadducts) were prepared and tested in vitro as antimicrobial compounds. Some of them have proved to have a remarkable activity against different micro organisms (germs and fungi). The influence of microwave irradiation concerning cycloaddition reactions of pyridazinium ylides was studied. Stereo- and regiochemistry involved in these reactions are also discussed.

Diazinium salts with dihydroxyacetophenone skeleton: Syntheses and antimicrobial activity.

Herein we report a feasible study concerning syntheses, structure and antimicrobial activity of some new diazinium salts with dihydroxyacetophenone skeleton. A fast, general, environmentally friendly, and facile method for preparation of diazinium salts under microwave and ultrasounds irradiation is presented. Antimicrobial tests prove that some diazine compounds have a remarkable activity against different microorganisms (germs and fungi), the pyrimidine derivatives being more active. Correlations between structure and antimicrobial activity are reported.

A facile synthesis of pyridazinone derivatives under ultrasonic irradiation.

A new, efficient and general method for preparation of N-substituted-pyridazinones using ultrasound irradiation is reported. Under ultrasound the reaction time decreases substantially, the yields are high and the reaction conditions are mild. It was noticed that substituents at the 3-(6)-position of pyridazone heterocycle have a substantial influence on the reactivity, while the effect of the substituents at the 1-(2)-position seems to be of minor importance. A comparative study of the reactions performed under ultrasound conditions versus at room temperature has been done.

An efficient and selective way to new highly functionalized coronands or spiro derivatives using ultrasonic irradiation.

A new, selective, straightforward and general method for preparation of highly functionalized coronands or spiro derivatives bearing 1,2-dihydroxyacetophenone unit, under conventional conditions and ultrasonic irradiation, is reported. The reaction setup involves only one step, acylation of an α-chloro-3,4-dihydroxyacetophenone with phthaloyl dichloride derivatives. 1,3- and 1,4-Phthaloyl dichloride derivatives leads to coronands only, while 1,2-phthaloyl dichlorides lead either to coronands or to spiro derivatives. A feasible explanation for the different behavior between conventional and ultrasound methods could be the different reaction mechanism involved in the two procedures: tetrahedral nucleophilic substitution under conventional conditions and radical substitution under ultrasound. Ultrasound induces a remarkable acceleration of the reactions (from days to minutes) and, most significantly, the yields are twice as high. A feasible explanation for the efficiency of the reactions under ultrasonic irradiation is presented.

Ultrasound assisted reactions of steroid analogous of anticipated biological activities.

A new, fast, efficient and general method for preparation of steroid analogous of anticipated biological activity under ultrasound irradiation and classical heating is reported. The reaction pathway involves two steps: quaternization of phthalazine heterocycle followed by a 3+2 dipolar cycloaddition of cycloimmonium ylides to dienophiles. Under ultrasound the reaction time decreases substantially, the yields are higher, the reaction conditions are milder. A comparative study ultrasound verses classical heating has been done.

Antimycobacterial activity of nitrogen heterocycles derivatives: Bipyridine derivatives. Part III [13,14]

Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts. These data indicate that mono-indolizine mono-salt 6d is a potent compound against both replicating and non-replicating Mycobacterium tuberculosis, is active against both extracellular and intracellular organisms, has a bacteriostatic mechanism of action and has basically no toxicity. We see no influence concerning the anti-TB activity of the fused-pyridine substituents.

Ultrasound and microwave assisted synthesis of isoindolo-1,2-diazine: A comparative study

A comparative study, ultrasound (US) versus microwave (MW) versus conventional thermal heating (TH), for synthesis of isoindolo-1,2-diazine is described. The reaction pathway is fast, efficient and straight applicable, involving a Huisgen [3+2] dipolar cycloaddition of cycloimmonium ylides to 1,4-naphthoquinone. A feasible reaction mechanism for the obtaining of the fully aromatized tetra- and penta- cyclic isoindolo-1,2-diazine is presented. Under US irradiation the yields are much higher (sometimes substantially, by almost double), the reaction time decreases substantially, the reaction conditions are milder. The use of a generator with a higher nominal power induces higher yields and short reaction times. Overall the use of US it proved to be more efficient than MW or TH. A feasible explication for US efficiency is presented.

New indolizines with phenanthroline skeleton: Synthesis, structure, antimycobacterial and anticancer evaluation.

We report herein a feasible study concerning the design, synthesis, structure and in vitro antimycobacterial and anticancer activity of two new classes (containing four and five fused rings) of indolizine with phenanthroline skeleton. The preparation is straight and efficient, involving a Huisgen [3+2] dipolar cycloaddition of cycloimmonium ylides to alkynes or alkenes dipolarophiles. The cycloaddition reactions are highly stereo- or regioselective, according with the dipolarophiles nature. The structure of the new compounds was assigned unambiguously, X-ray analysis including. The primary antimycobacterial screening reveals that one of the thirteen tested compounds had a good activity against Mycobacterium tuberculosis H37Rv under aerobic conditions. The antiproliferative evaluation against a NCI 60 human tumor cell line panel, revealed that two indolizine with phenanthroline skeleton exhibit a selective and significant antitumor growth inhibitory activity against Breast Cancer (MCF7 and T-47D) and a slightly moderate activity against some forms of Leukemia, Non-Small Cell Lung Cancer, Renal Cancer and Breast Cancer (MDA-MB-468). The X-ray diffraction study of the indolizines with phenanthroline skeleton prove a flat coplanar structure which, corroborated with their anticancer activity, allow us to suggest that an interaction with DNA (via an intercalation mechanism) would be reasonable.