Pyrrolo[2,1-a]isoquinoline scaffold in drug discovery: Advances in synthesis and medicinal chemistry

Pyrrolo[2,1-a]isoquinoline (PIq) is a nitrogen heterocyclic scaffold of diverse alkaloids endowed with several biological activities, including antiretroviral and antitumor activities. Several 5,6-dihydro-PIq (DHPIq) alkaloids, belonging to the lamellarins' family, have proved to be cytotoxic to tumor cells, as well as reversers of multidrug resistance. In this review, we provide an overview of the main achievements over the last decade in the synthetic approaches to access libraries of PIq compounds along with a survey, as comprehensive as possible, of bioactivity, mechanism of action, pharmacophore and structure-activity relationships of synthetic analogs of DHPIq-based alkaloids. The focus is mainly on the potential exploitation of the (DH)PIq scaffold in design and development of novel antitumor drugs. © 2019 © 2019 Newlands Press

AZEPINO [4,3-b]INDOLE DERIVATIVES AS SELECTIVE INHIBITORS OF HUMAN BUTYRYLCHOLINESTERASE WITH PROTECTIVE EFFECTS AGAINST NMDA-INDUCED NEUROTOXICITY

Neurodegeneration in Alzheimer’s disease (AD), is a devastating disorder accounting for the majority of the dementias.1 Despite the advances achieved over the last two decades in the understanding of the pathogenic mechanisms underlying AD, only a few drugs are currently available, which include AChE inhibitors (rivastigmine, galantamine, and donepezil), for the symptomatic relief of mild to moderate AD, and the N-methyl-D-aspartate receptor antagonist memantine.2 Previously, we reported the inhibitory activities of cholinesterases (ChEs) by a number of derivatives of annulated tetrahydroazocino-indoles, which preferentially inhibited AChE over BChE, with potency in the low micromolar range.3 New 6-substituted 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one (THAI) derivatives have been synthesized and evaluated for their activity as ChEs’ inhibitors. The most potent compounds have been identified among 6-(2-phenylethyl)-THAI derivatives, and in particular compounds 12b and 12d proved to be highly potent inhibitors of human BChE (IC50 = 13 and 1.8 nM, respectively), with 1000-fold selectivity over AChE. Structure-activity relationships revealed critical features (e.g., ring fusion [4,3-b], integrity of the lactam CONH function) and favorable physicochemical properties of the 6-(2-phenylethyl) group (i.e., optimal position, size and lipophilicity of phenyl substituents). Interestingly, 12b increased the viability of SH-SY5Y cells pre-treated with 250 μM NMDA, with significant effects (P<0.05) at concentrations ranging from 0.5 to 5 μM. These findings suggest that THAI can be used as a scaffold for developing new drug leads for the treatment of Alzheimer-type neurodegeneration syndrome

Nigral cell loss produced by infusion of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP+) are potential endogenous neurotoxins causing nigral cell death from Parkinson's disease. We now report the effects of 7 days unilateral supranigral infusion in rats of four isoquinoline derivatives, namely N-n-propylisoquinolinium (N-Pr-IQ+), N-methyl-6,7-dimethoxyisoquinolinium (N-Me-6,7-diOMe-IQ+), 6,7-dimethoxy-1-styryl-3,4-dihydroisoquinoline (6,7-diOMe-1-S-3,4-DHIQ) and 1,2,3,4-tetrahydroisoquinoline (THIQ) compared to MPP+. MPP+ (33 nmol/24h)-infused rats showed a marked reduction in motor activity and displayed ipsilateral postural asymmetry. Administration of apomorphine or (+)-amphetamine to these animals produced robust contralateral and ipsilateral rotations, respectively. In contrast, rats infused with the isoquinoline derivatives (150 nmol/24h) did not show spontaneous or drug-induced motor changes. Infusion of MPP+ decreased the number of tyrosine hydroxylase (TH)-positive cells in the ipsilateral substantia nigra pars compacta (SNc) by approximately 90%. Infusion of N-Me-diOme-IQ+ and THIQ produced approximately 42% and 20% ipsilateral SNc cell loss, respectively, but N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ did not alter SNc cell numbers. MPP+ markedly depleted the dopamine (DA, 95%), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) content of the ipsilateral striatum. N-Me-diOMe-IQ+ and THIQ also reduced the DA content of the ipsilateral striatum by approximately 39% and 20% respectively, but N-Pr-IQ+ and 6,7-diOme-1-S-3,4-DHIQ did not deplete striatal DA content. The isoquinoline derivatives slightly reduced (N-Me-diOMe-IQ+ and THIQ) or had no effect (N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ) on DOPAC or HVA levels. In conclusion, some isoquinoline derivatives that are substrates for the dopamine re-uptake system and inhibitors of mitochondrial function, are toxic to nigral dopaminergic neurones. Chronic exposure to endogenous or exogenous isoquinoline derivatives might contribute to cell death in Parkinson's disease

Physicochemical properties and antimicrobial activity of new spirocyclic thieno[2,3-d]pyrimidin-4(3H)-one derivatives

(figure presented) A number of 6'-methylidene-2,3-dihydro-1H-spiro[pyridine-4,5'-thieno[2,3-d]pyrimidin]-4'(3'H)-one derivatives, obtained as major products of a domino reaction between 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidines and electron-deficient alkynes, were characterized for their acid-base properties and lipophilicity and evaluated for the antimicrobial activity against a number of clinical isolates of bacterial and fungal strains. The cytotoxicity against four tumor cell lines was also screened for some compounds. The dissociation constants (pKa) and partition coefficients (log P) in 1-octanol–water system were determined using a potentiometric technique. The negative difference between the observed and calculated log P values could be explained in the light of the conformational rigidity. Most of the studied compounds showed a moderate and selective activity against Gram-positive bacteria strains (S. agalactiae, E. faecalis, S. epidermidis), whereas did not exhibit any effect against Gram-negative bacteria and fungi at the maximum test concentration (500 μM). Implications of the physicochemical properties in modulating the antimicrobial activity and cytotoxicity of the examined spirocyclic thieno[2,3-d]pyrimidin-4(3H)-one derivatives are also discussed. © 2017 Springer Science+Business Media New York

Reductive domino reaction to access chromeno[2,3-c]isoquinoline-5-amines with antiproliferative activities against human tumor cells

An interaction of homophthalonitrile with salicylaldehydes proceeds as a novel domino reaction and results in the formation of nineteen 12H-chromeno[2,3-c]isoquinoline-5-amine derivatives. Four new bonds and two cycles are forged in a single synthetic operation, employing cheap and eco-friendly ammonium formate, acting both as a catalyst and a reducing agent. The in vitro cytotoxicity tests revealed antiproliferative activities against five human tumor cell lines, including the cisplatin-resistant ovarian carcinoma one (A2780cp8), with inhibitory potency data (IC50) in the low micromolar range in most cases. Molecular docking calculations and fluorescence quenching studies revealed possible binding properties with DNA of the active compounds. © 2020 Elsevier Inc