Formamidines with antinociceptive and antiinflammatory activities

Pursuing our investigations on 7-amino-2,3-polymethyleneindole derivatives, a set of 7-(dimethylaminomethylene)-amino-2,3-polymethyleneindoles, together with some other aryl or cycloalkyl substituted formamidines, were prepared and tested for analgesic and antiinflammatory activities. Several compounds resulted endowed with one or both of these activities; the indole derivatives 1 and 2 exhibited a good degree of both of them

Amides and formamidines with antinociceptive activity: note II

Forty amides, formamidines and trifluoromethylsulfonylamides bearing on the nitrogen a cyclohexyl residue, eventually 2-substituted, were prepared and tested for analgesic activity against a chemical stimulus. Good activity was exhibited by amides 9, 11 and 28, by formamidine 34, as well as by triflyamide 40. Eleven additional compounds exhibited a moderate activity

Cyclopentenyl ethylamines active on CNS

Two new cyclopentenylethylamines were prepared and were submitted to a pharmacological screening together with some others previously described and now reprepared. All compounds exhibited different degrees of depressive activity on CNS and good analgesic activity. Compound 5, bearing a phenyl group on the carbon atom to which the amino group is connected, appears rather interesting being the most active as analgesic and the least toxic. Compounds 2 and 3 are able to antagonize in a certain degree lethal doses of physostigmine and also, respectively, of pentylenetetrazole and strychnine

Further Quinolizidine Derivatives as Antiarrhythmic Agents- 3

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1- (quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4, 1, 6, and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC50 = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5, which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation

Benzimidazole derivatives endowed with potent antileishmanial activity

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC50values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles

Quinolizidine-Derived Lucanthone and Amitriptyline Analogues Endowed with Potent Antileishmanial Activity

Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against Leishmania tropica and L. infantum promastigotes. All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety. All compounds displayed activity against both species of Leishmania with IC50 values in the low micromolar range, resulting in several fold more potency than miltefosine, comparable to that of lucanthone, and endowed with substantially lower cytotoxicity to Vero-76 cells, for the best of them. Thus, 4-amino-1-(quinolizidinylethyl)aminothioxanthen-9-one (14) and 9-(quinolizidinylmethylidene)fluorene (17), with selectivity index (SI) in the range 16\u201324, represent promising leads for the development of improved antileishmanial agents. These two compounds also exhibited comparable activity against intramacrophagic amastigotes of L. infantum. Docking studies have suggested that the inhibition of trypanothione reductase (TryR) may be at the basis (eventually besides other mechanisms) of the observed antileishmanial activity. Therefore, these investigated derivatives may deserve further structural improvements and more in-depth biological studies of their mechanisms of action in order to develop more efficient antiparasitic agents

Novel organotins as antitumor agents

Metal complexes and organo-metallic compounds have a growing importance in medicine, particularly in oncology. Cisplatin is among the most widely used anticancer agents, but other platinum (PtII) complexes are being introduced in the therapy of tumours. Cell resistance to cisplatin and its analogues is the main reason for treatment failure and clinical relapse. In order to overcome this issue, novel PtII and PtIV as well as non-platinum metal complexes have been developed, with encouraging results. Organotin derivatives have caught much attention during the last two decades for their potential biocidal activities. In recent years several organotin compounds have been synthesised, some with interesting cytotoxic properties. Little is known about the exact mechanisms by which these agents induce cell growth inhibition, although macromolecular synthesis and mitochondrial energy metabolism appear to be the targets. This article will focus on the relevance of organotin derivatives as very promising potential candidates in anticancer therapy