Drug design: Le contrôle LUMO du pharmacophore neuroleptique

The aromatic ring of the antagonist of the dopaminergic receptor behaves as an electron acceptor within its interactions with the receptor. The energy of the lower unoccupied molecular orbital (ϵ_LUMO) is correlated with the biological activity for different series of neuroleptic compounds. The principle of interaction LUMO antagonist—HOMO receptor (Principle La—Hr), presented previously for the phenothiazine series, is extended to various series of antagonists of the dopaminergic receptor: thioxanthenes, butyrophenones, benzisoxazoles and benzamides.The Principle La—Hr is refined on a model series of 16 phenothiazines by a multilinear regression giving the biological activity versus 3 variables, with a stepwise procedure. The variable ϵ_LUMO has the strongest contribution, the aliphatic amine chain has a moderate contribution and the variation of lipophilicity induced by the substituent of the aromatic ring in position 2 has only a very weak contribution. The correlation is used to predict, with success, the relative activity of two new phenothiazines: mesoridazine and thioridazine.     

Synthesis and selective human monoamine oxidase inhibition of 3-carbonyl, 3-acyl, and 3-carboxyhydrazido coumarin derivatives

Several 3-carbonyl (1-26), 3-acyl (27-52), and 3-carboxyhydrazido (53-58) coumarins have been synthesized in high yields (72-99%) and tested in vitro for their human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitory activity. Different substituents on the coumarin nucleus were evaluated for their effect on biological activity and isoform selectivity. Substitution at position C7 of the 3-ethyl ester coumarin ring, or the introduction of a hydrazido substituent at C3, were important to obtain highly potent and selective hMAO-B inhibitors with IC₅₀ values in the nanomolar range. Some derivatives were also submitted to a stability test and showed no chemical cleavage in vitro.     

Benzoyl and/or benzyl substituted 1,2,3-triazoles as potassium channel activators. VIII

This paper reports the preparation of new benzoyl and/or benzyl substituted 1,2,3-triazole derivatives and their pharmacological evaluation as potential BK channel openers, as a part of a research program which hypothesized a pharmacophoric structure containing the 1,2,3-triazole ring. The synthetic procedures consist essentially with the 1,3-dipolar cycloaddition of aryl or benzyl azides to the asymmetric alkyne benzoylacetylene to give the wished 4-benzoyl-1,2,3-triazole isomers in larger amount. The pharmacological results show that the 1-(2-hydroxybenzyl)-4-benzyl-1H-1,2,3-triazole possesses high vasorelaxing activity involving the opening of the BK channels. Therefore the structure-activity relationships concerning this pharmacophoric structure confirm the usefulness of a phenolic function in the ortho position of the aromatic ring and would suggest a 1,2,3-triazole model bearing benzyl substituents. In addition such substituents appear more flexible and able to take different conformations with respect to phenyl groups which have higher trend to coplanar conformations.     

Antifungal agents. Part 4: Synthesis and antifungal activities of novel indole[1,2-c]-1,2,4-benzotriazine derivatives against phytopathogenic fungi in vitro

A series of novel indole[1,2-c]-1,2,4-benzotriazine derivatives were obtained by a modified Sandmeyer reaction in the presence of tert-butylnitrite (t-BuONO). As compared with hymexazol, a commercially available agricultural fungicide, at the concentration of 50 μg/mL, two indole[1,2-c]-1,2,4-benzotriazines, 5h and 5k, exhibited the more promising and pronounced antifungal activities in vitro against five phytopathogenic fungi. It clearly demonstrated that introduction of appropriate substituents on the indolyl ring of indole[1,2-c]-1,2,4-benzotriazine (5a) would lead to the more potent derivatives.     

Ligand-based virtual screening procedure for the prediction and the identification of novel β-amyloid aggregation inhibitors using Kohonen maps and Counterpropagation Artificial Neural Networks

In this work we have developed an in silico model to predict the inhibition of β-amyloid aggregation by small organic molecules. In particular we have explored the inhibitory activity of a series of 62 N-phenylanthranilic acids using Kohonen maps and Counterpropagation Artificial Neural Networks. The effects of various structural modifications on biological activity are investigated and novel structures are designed using the developed in silico model. More specifically a search for optimized pharmacophore patterns by insertions, substitutions, and ring fusions of pharmacophoric substituents of the main building block scaffolds is described. The detection of the domain of applicability defines compounds whose estimations can be accepted with confidence.     

10H-Phenothiazines: a new class of enzyme inhibitors for inflammatory diseases

The phenothiazine nucleus is known for their inhibitory activity towards the regulatory enzymes that are contributing to diseases such as asthma, autoimmune diseases including allergic rheumatoid and encephalomyelitis. In this study a number of substituted phenothiazines were synthesized and screened for their biological activity against the regulatory enzymes involved in inflammatory diseases. Our results show that the newly synthesized compounds 4a-c and 5a-c exhibited promising target specific enzyme inhibition against phosphodiesterase, prostaglandin dehydrogenase and superoxide dismutase activity depending on steric factors of the molecules.     

New condensed pyrroles of potential biological interest syntheses and structure-activity relationship studies

The Pyrrole derivatives Ia-d were prepared and utilized for the preparation of pyrrolo[2,3-d]pyrimidine derivatives IIa-c, III, IVa-e, V and VIIIa-c; pyrrolo[3,2-e]tetrazolo[1,5-c]pyrimidine VI and pyrrolo[4,3e][1,2,4]triazolo[1,5-c]pyrimidine derivative derivatives VIIa-c. These some newly synthesized compounds were examined for their in vitro antimicrobial activity and in vivo anti-inflammatory. Result indicated that these compounds showed promising anti-inflammatory activity in comparison to ibuprofen (the standard anti-inflammatory drug). The structure-activity relationships (SAR) and anti-inflammatory activities of these compounds are also discussed in this paper.     

Synthesis and pharmacological evaluations of novel 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as a new class of anti-cancer agents

The synthesis of novel 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives has been carried out using trifluoroacetic anhydride/phosphoric acid mediated C-C bond forming reaction as a key step. This method does not require the use of environmentally harmful AlCl₃ or moisture sensitive acid chloride. A number of compounds containing the benzooxazinone moiety attached to a five-membered central heterocyclic ring was synthesized and tested for their anti-cancer properties in vitro against three cell lines e.g. A549 (lung), DLD-1 (colorectal adenocarcinoma) and MV4-11 (acute myeloid leukemia). Some of them showed anti-cancer activities along with a number of reference compounds tested. Few of them showed promising anti-leukemic properties. A brief Structure-Activity-Relationship study within the series is presented. An imidazole derivative 9c containing benzene ring with a para-CF₃ group at C-2 position was identified as a potent anti-leukemic agent.     

Anticancer and radio-sensitizing evaluation of some new thiazolopyrane and thiazolopyranopyrimidine derivatives bearing a sulfonamide moiety

Recently, it has been reported that compounds bearing a sulfonamide moiety posses many types of biological activities, including anticancer activity. There are a variety of mechanisms for their anticancer activity, and the most prominent mechanism is the inhibition of carbonic anhydrase (CA) isozymes. The present work reports the synthesis of some new thiazolo[4,5-b]pyrane, thiazolo[4,5-b]pyrano[2,3-d]pyrimidine derivatives bearing a sulfonamide moiety. The design of the structures of these compounds complies with the general pharmacophoric requirements for CA inhibiting anticancer drugs. The newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Most of the screened compounds showed interesting cytotoxic activities compared to doxorubicin as a reference drug. Compounds 5, 6, 10 and 12 (IC₅₀ values 39.4 μM, 41.6 μM, 35.72 μM and 34.64 μM, respectively) exhibited higher cytotoxic activities than the reference drug doxorubicin (IC₅₀ = 71.8 μM). Additionally, the previously mentioned compounds were evaluated again for their ability to enhance the cell killing effect of γ-radiation.     

Synthesis and antifungal activity of some substituted phenothiazines and related compounds

Several phenothiazines and related compounds were synthesized and their antifungal activity was evaluated in vitro. The results observed for α-chloro-N-acetyl phenothiazine led us to choose this compound as a lead in the search of antifungal agents.     

Synthesis and anticonvulsant activity of novel 2,6-diketopiperazine derivatives. Part 1: perhydropyrrole[1,2-a]pyrazines

A number of novel pyrrole[1,2-a]pyrazine derivatives were synthesized and evaluated in in vivo animal models of epilepsy. Among them, several compounds displayed promising seizure protection in the maximal electroshock seizure (MES), subcutaneous metrazol seizure (scMET), 6 Hz and pilocarpine-induced status prevention (PISP) tests, with ED₅₀ values comparable to the reference anticonvulsant drugs (AEDs). A critical influence of the stereochemistry and conformational preferences of the pyrrole[1,2-a]pyrazine core on in vivo pharmacological activity was observed. The mechanism of the anticonvulsant action of the agents synthesized is most probably not via inhibition of the voltage-dependent sodium (Na⁺) currents.     

A molecular electrostatic potential study of phenothiazine dopaminergic antagonists

The recognition of the dopaminergic receptor by antagonists has been studied for a set of phenothiazine compounds. This study was based on molecular electrostatic potential (MEP) calculations. The first step of the recognition involves the interaction of the nitrogen atom of the chain fragment of the series of phenothiazines: promazines, perazines and phenazines. The second step involves the adaptation of the aromatic fragment deduced from the examination of the molecular orientation vector. The simultaneous influences of the orientation vector and of a binding step parameter, the energy of the lower unoccupied molecular orbital (LUMO), on the variation of activity of a series of promazines were studied.The variations of the structural parameters which induce a counterclockwise rotation of the orientation vector, in a range of about 70 degrees, are related to activity increases.     

Physicochemical profile of macrolides and their comparison with small molecules

Macrolides are stereospecific macrolactones of high molecular weights. Herein, 600 mostly semisynthetic macrolides are compared with 50,000 small non-macrolide synthetic molecules in terms of measured physicochemical properties in order to assess the drug-likeness and developability chances of macrolides. The pre-selected set of diverse macrolides is comprised mostly of derivatives of clarithromycin and azithromycin cores. Lipophilicity (CHI logD), affinity for immobilized artificial membranes (CHI IAM), human serum albumin (HSA) and α(1)-acid glycoprotein (AGP) plasma protein bindings (PPB), DMSO precipitative solubility as well as artificial membrane permeability (AMP) have been determined by high-throughput screening methods. It has been found that macrolides and small molecules have similar lipophilicity profiles, though macrolides show weaker PPB and have better solubility than small discovery molecules. However, macrolides are poorly permeable and have high affinity for immobilized artificial membranes signifying their strong interaction with biological phospholipids. In order to retain the drug-like profile, the design of novel macrolide molecules should be focused on optimisation of macrolide cores, that is macrolactone moiety with sugars and other small substituents avoiding large substituents and flexible linkers such as in conjugate derivatives.     

Antimalarial activity of imidazo[2,1-a]isoindol-5-ol derivatives and related compounds

The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorporation of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC₅₀ values as low as 60 nM and a certain efficacy in vivo by reducing parasitemia in Plasmodium berghei mouse models.     

New quinoxalinecarbonitrile 1,4-di-N-oxide derivatives as hypoxic-cytotoxic agents

We report the synthesis and biological in vitro activities of 16 new 2-quinoxalinecarbonitrile 1,4-di-N-oxides. These compounds present new basic lateral chains (piperazines and anilines) in the 3 position as well as different substituents in the 6 and/or 7 positions of the quinoxaline ring. Among piperazine derivatives, 4b (a 7-chloro-3-(4-methylpiperazin-1-yl) derivative) was the most potent (P = 0.5 x10(-6) M). In general, aniline derivatives were more potent and selective than the former, compound 12b (with a 4-(methylphenyl)amino moiety in the 3 position and a chlorine atom in the 7 position) being the best one (P = 3 x 10(-6) 16).     

Synthesis and anti-mycobacterial activities of triazoloquinolones

A number of quinolone derivatives have been reported to possess anti-mycobacterial activity. Generally. Mycobacterium tuberculosis isolates expressing resistance to both isoniazid and rifampin are susceptible to fluoroquinolones. Benzotriazole is a hetero-bicyclic aromatic ring endowed with interesting chemical and biological properties and pharmacological activities. In a preliminary study we have recently reported the activity of triazolo[4,5-h]quinolone-carboxylic acids, a new class of benzotriazole derivatives active against multi-drug resistant M. tuberculosis (MDR-Mtb). In this study we confirm that this novel class of quinolones is endowed with a selective anti-mycobacterial activity, coupled with absence of cytotoxicity.The SAR analysis of the new derivatives in comparison with the previous series shows that the methyl group is the most effective substituent in both N-3 and N-9 positions of the ring system.     

Heterocyclic analogs of benzanilide derivatives as potassium channel activators. IX

On the basis of our previous works, addressed to synthesise new activators of BK potassium channels, and of many suggestions from the international literature, a simple pharmacophoric model, consisting of two suitably substituted phenyl rings bound to various kinds of linkers, was hypothesised. In particular, the effectiveness of the amidic linker was demonstrated, since several benzanilide derivatives showed interesting BK-opener properties. As a development of these benzanilides, in this work we introduced heterocyclic substituents, replacing the aryl ring on the acid side or on the basic one of the amide linker of the above pharmacophore. The pharmacological results indicated some relevant remarks about the structural requirements, needed for a satisfactory BK-opener activity. In particular, the presence of a phenolic function, with a possible H-bond donor role, has been confirmed. Furthermore, the presence of nitrogen heterocycles on the acid side of the amide linker seems to be a negative requirement, while furan and thiophene were well tolerated. On the contrary, the introduction of insaturated heterocyclic rings (pyridine and thiazole) on the basic side of the amide linker, led to satisfactory biological activity, while the presence of aliphatic heterocycles lowered the pharmacological effect.     

Design and synthesis of spiro derivatives of parthenin as novel anti-cancer agents

Several novel spiro derivatives of parthenin (1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene-γ-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their in vitro cytotoxicity against three human cancer cell lines viz., SW-620, DU-145 and PC-3. In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of α,β-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with in vivo and western blotting experiments has been described.     

Imidazo-thiazine, -diazinone and -diazepinone derivatives. Synthesis, structure and benzodiazepine receptor binding.

In our search for new compounds acting on benzodiazepine receptors among the fused 2-thiohydantoin derivatives, a series of arylidene imidazo[2,1-b]thiazines was synthesized. The 1,2- and 2,3- cyclized derivatives of mono- and di-substituted Z-5-arylidene-2-thiohydantoins were examined (the X-ray crystal structure of Z-2-cinnamylidene-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one was determined) and compared with the diphenyl derivatives. To investigate the influence of the type of annelated ring on the biological activity, imidazo[2,1-b]pyrimidinone and imidazo[2,1-b]diazepinone derivatives were obtained. The method used in annelation (1,2- and 2,3-cyclized isomers with the exception of fused arylidene imidazothiazines), the substitution pattern (arylidene towards diphenyl) as well as the character of the annelated ring had minor influence on the benzodiazepine receptor affinity of the investigated compounds. It appears that the greatest influence on the biological activity has the character and position of the substituents on the arylidene ring.