Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents

A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC₅₀) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC₉₀: 5.9 μg/mL) and cytotoxicity (CC₅₀: 14.27 μg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC₉₀: >20 μg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.     

Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and 17 (IC₅₀ = 4.49 μM/mL against HepG2, IC₅₀ = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC₅₀ = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.     

Selective leishmanicidal effect of 1,3,4-thiadiazole derivatives and possible mechanism of action against Leishmania species

With the aim of determining selectivity and the possible target(s) of nitroheteroaryl-1,3,4-thiadiazoles considered as possible leads for the development of anti-leishmanial agents, we studied 5-nitroimidazole, 5-nitrofuran and 5-nitrothiophene analogs of N-substituted-piperazinyl-1,3,4-thiadiazoles. We investigated 21 representative compounds 1-3(a-g) for the following properties: selectivity and efficiency against different Leishmania wild type species and intracellular parasite, toxicity against host cells and inhibition of topoisomerases I and II. Our results indicate that the nitroimidazole analogs 1a and 1f, and nitrofuran derivatives 2a, 2b, 2c, 2f, and 2g exhibited low toxicity against the host cells (IC₅₀ ? 80 μM), but high selectivity against intracellular amastigotes (selectivity index > 12). Leishmania topoisomerases revealed impressive sensitivity to the agents (%inhibition >50 at IC₅₀ doses of compounds against Leishmania). Our findings showed that at least part of leishmaniacidal effect of the compounds could be attributed to disruption DNA-relaxed activities of topoisomerases I and II, and cleavable-complex formation.     

Selective antagonists of mouse trace amine-associated receptor 1 (mTAAR1): discovery of EPPTB (RO5212773)

High throughput screening of the Roche compound library identified benzanilides such as 1 and 2 as antagonists of TAAR1. Optimisation of this hit series led to the first selective TAAR1 antagonist (N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide EPPTB (RO5212773, 9f) having IC₅₀ of 28 nM at mouse TAAR1.     

Synthesis and SAR investigations of novel 2-arylbenzimidazole derivatives as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists

Compounds containing 2-arybenzimidazole ring systems linked to arylpiperidines were synthesized and evaluated as MCH-R1 antagonists. The results of structure-activity relationship studies led to the identification of compound 4c as a potent MCH-R1 antagonist (IC₅₀ = 1 nM). This compound also has good metabolic stability, and favorable pharmacokinetic and brain penetration properties. However 4c was found to be potent inhibitor of the hERG potassium channel.     

Platinum(II) and palladium(II) complexes with (N,N') and (C,N,N')- ligands derived from pyrazole as anticancer and antimalarial agents: synthesis, characterization and in vitro activities

The study of the reactivity of three 1-(2-dimethylaminoethyl)-1H-pyrazole derivatives of general formula [1-(CH₂)₂NMe₂}-3,5-R₂-pzol] {where pzol represents pyrazole and RH (1a), Me (1b) or Ph (1c)} with [MCl₂(DMSO)₂] (MPt or Pd) under different experimental conditions allowed us to isolate and characterize cis-[M{κ²-N,N′-{[1-(CH₂)₂NMe₂}-3,5-R₂-pzol])}Cl₂] {MMPtPt (2a-2c) or Pd (3a-3c)} and two cyclometallated complexes [M{κ³-C,N,N′-{[1-(CH₂)₂NMe₂}-3-(C₅H₄)-5-Ph-pzol])}Cl] {MPt(II) (4c) or Pd(II) (5c)}. Compounds 4c and 5c arise from the orthometallation of the 3-phenyl ring of ligand 1c. Complex 2a has been further characterized by X-ray crystallography. Ligands and complexes were evaluated for their in vitro antimalarial against Plasmodium falciparum and cytotoxic activities against lung (A549) and breast (MDA MB231 and MCF7) cancer cellular lines. Complexes 2a-2c and 5c exhibited only moderate antimalarial activities against two P. falciparum strains (3D7 and W2). Interestingly, cytotoxicity assays revealed that the platinacycle 4c exhibits a higher toxicity than cisplatin in the three human cell lines and that the complex 2a presents a remarkable cytotoxicity and selectivity in lung (IC₅₀ = 3 μM) versus breast cancer cell lines (IC₅₀ > 20 μM). Thus, complexes 2c and 4c appear to be promising leads, creating a novel family of anticancer agents. Electrophoretic DNA migration studies in presence of the synthesized compounds have been performed, in order to get further insights into their mechanism of action.     

Dicarbonyliridium(I) complexes of pyridine ester ligands and their reactivity towards various electrophiles

The reaction of dimeric precursor [Ir(CO)₂Cl]₂ with two molar equivalent of the pyridine-ester ligands (L) like methyl picolinate (a), ethyl picolinate (b), methyl nicotinate (c), ethyl nicotinate (d), methyl isonicotinate (e) and ethyl isonicotinate (f) affords the tetra coordinated neutral complexes of the type [Ir(CO)₂ClL] (1a-f). The single crystal X-ray structure of 1d reveals that the Ir atom occupies the centre of an approximately square planar geometry with two CO groups cis- to each other. Intermolecular C-H?O and Ir?C interactions greatly stabilize the supramolecular structure of 1d in the solid state. The oxidative addition (OA) reactions of 1a-f with different electrophiles such as CH₃I, C₂H₅I and I₂ undergo decarbonylation of one CO group to generate the oxidized products of the type [Ir(CO)RClIL] where R = -CH₃ (2a-f); -C₂H₅ (3a-f) and [Ir(CO)ClI₂L] (4a-f). Kinetic study of the reaction of 1c-f with CH₃I indicates a first order reaction which follow the order 1d > 1c > 1f > 1e. All the synthesized complexes were characterized by elemental analyses, IR, and multinuclear NMR spectroscopy.     

Substituted imidazole derivatives as novel cardiovascular agents

A series of novel substituted imidazole derivatives were synthesized and have been screened in vivo for their hypotensive and acute toxicity activities. Out of seventeen compounds eight compounds (2b, 2c, 3b, 3c, 3f, 4a, 4b and 4c) have shown good hypotensive and bradycardiac responses. Compounds 3b, 3c, 3f and 4c have shown better activity than reference drug clonidine. All the compounds have shown ALD50 >1000 mg/kg with maximum in 2e and 4c (>1200 mg/kg).     

Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles

The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11-22 is described. Compounds 11-22 have been obtained by Friedländer-type reaction of 2-aminopyridine-3-carbonitriles 1-10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (11) [IC₅₀ (EeAChE: 14 nM); IC₅₀ (eqBuChE: 5.2 ??M]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (16) [IC₅₀ (EeAChE: 64 nM); IC₅₀ (eqBuChE: 9.6 ??M] showed that this compound is a mixed-type inhibitor (K_i = 69.2 nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11-22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K⁺-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11-22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.     

Antioxidant, anti-inflammatory and anti-hyperglycaemic activities of heterocyclic homoprostanoid derivatives

A series of 19 heterocyclic homoprostanoids were synthesized from easily available oleic and ricinoleic acids and evaluated for their possible antioxidant, anti-inflammatory and anti-hyperlipidaemic activities. Compounds with thioxo- and oxoimidazole ring (1) and (2) have shown potent antioxidant activity with IC₅₀ values 0.23 ± 0.09 and 0.41 ± 0.01 mM comparable with standard ascorbic acid. Compound (3) with a quinoxaline ring showed maximum inhibition of BSA denaturation at 1 mM concentration and comparable with standard diclofenac. Incorporation of electron withdrawing substitutions like chloro- and nitro-groups in the quinoxaline ring has resulted in an increase anti-inflammatory activity. Test compounds (3), (3a) and (3c) showed modest inhibition of DPP-IV in vitro. However, the unsubstituted quinoxaline (3) and substituted quinoxalines (3b and 3c) reduced plasma glucose levels indicating the presence of hypoglycemic activity.     

Synthesis, reactivities and catalytic carbonylation of rhodium(I) carbonyl complexes containing isomeric acetylpyridine ligands

[Rh(CO)₂Cl]₂ reacts with two mole equivalent of 2-acetylpyridine (a), 3-acetylpyridine (b) and 4-acetylpyridine (c) to afford chelate [Rh(CO)Cl(η²-N∩O)] (1a) and non-chelate [Rh(CO)₂Cl(η¹-N∼O)] (1b, 1c) complexes, where, N∩O = a, N∼O = b, c. Oxidative addition (OA) of 1a-1c with CH₃I and C₂H₅I yields penta coordinate rhodium(III) complexes, [Rh(COR)ClI(η²-N∩O)] {R = -CH₃ (2a); -C₂H₅ (3a)} and [Rh(COR)(CO)ClI(η¹-N∼O)] {R = -CH₃ (2b, 2c); -C₂H₅ (3b, 3c)}. Kinetic study for the reaction of 1a-1c with CH₃I indicates a pseudo-first order reaction. The catalytic activity of 1a-1c for the carbonylation of methanol to acetic acid and its ester was evaluated at different initial CO pressures 5, 10 and 20 bar at ∼25 °C and higher turn over numbers (TON = 1581-1654) were obtained compared to commercial Monsanto’s species [Rh(CO)₂I₂]⁻ (TON = 1000) under the reaction conditions: temperature = 130 ± 1 °C, pressure = 15-32 bar, rpm = 450, time = 1 h and catalyst: substrate = 1: 1900.     

An efficient route to substituted 1-silacyclopent-2-enes and 1-silacyclohex-2-enes via consecutive 1,2-hydroboration and 1,1-organoboration

The reaction of alkyn-1-yl(vinyl)silanes R₂Si(CCR¹)CHCH₂ [R = Me (1), Ph (2); R¹ = ^tBu (a), Ph (b), SiMe₃ (c)] with 9-borabicyclo[3.3.1]nonane in a 1:1 ratio affords the 1-silacyclopent-2-ene derivatives 4a-c (R = Me) and 5a-c (R = Ph) as a result of selective intermolecular 1,2-hydroboration of the vinyl group, followed by intramolecular 1,1-organoboration of the alkynyl substituent. The analogous reaction sequence converts the alkyn-1-yl(allyl)dimethylsilanes 3a,c into the 1-silacyclohex-2-ene derivatives 7a,c. All reactions were monitored by ²⁹Si NMR spectroscopy and the structural assignment of the final products was based on multinuclear magnetic resonance data (¹H, ¹¹B, ¹³C and ²⁹Si NMR). The molecular structure of 6a was determined by X-ray analysis.     

Structure-activity relationships and DNA binding properties of apoptosis inducing cytotoxic rhodium(III) polypyridyl complexes containing the cyclic thioether [9]aneS3

The Rh(III) polypyridyl complexes of the type [RhCl(pp)([9]aneS₃)]²⁺ [(pp) = 2,2′-bipyridine (bpy), 2,2′-bipyrimidine (bpm),1,10-phenanthroline (phen), pyrazino[2,3-f]quinoxaline (tap), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq), dipyrido[2,3-a:2′,3′-c]phenazine (dppz)] 2-7 have been prepared in a stepwise manner by treatment of RhCl₃ · 3H₂O with the appropriate polypyridyl ligand (pp) followed by 1,4,7-trithiacyclononane. Interactions of the polypyridyl complexes with DNA were investigated by CD and UV/visible spectroscopy and by gel electrophoresis. The dpq complex 6 cleaves DNA exiguously in the dark, but UV irradiation is required to induce nuclease activity for the bpy complex 2. Whereas 2 [IC₅₀ values: 12.8 (±0.2) and 4.4 (±0.1) μM] exhibits significantly higher cytotoxicities towards MCF-7 and HT-29 cells than 4 [IC₅₀ values: 36.3 (±6.0) and 72.2 (±8.0)], the activity of complexes in the series 4/6/7 correlates directly with the size of the polypyridyl ligand, as documented by their respective IC₅₀ values of 72.2 (±8.0), 20.9 (±2.8) and 7.4 (±2.2) towards HT-29 cells. Complexes of the nitrogen-rich ligands bpm (3) [IC₅₀ values: 1.7 (±0.5) and 1.9 (±0.1) μM] and tap (5) [IC₅₀ values: 11.5 (±0.6) and 7.6 (±4.8) μM] are considerably more potent than their bpy and phen counterparts 2 and 4. Measurement of the lactate dehydrogenase release for lymphoma (BJAB) cells after 1 h incubation demonstrates that unspecific necrosis is negligible for the most active compounds 3 and 7. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72 h incubation and significant loss of the mitochondrial membrane potential in lymphoma cells indicates that the intrinsic pathway is involved.     

Diheteroarylmethyl substituted titanocenes: A novel class of possible anti-cancer drugs

From the reaction of tert-butyl lithium or n-butyl lithium with N-methylpyrrole (1a), furan (1b) or 2-bromo-thiophen (1c), 2-N-methylpyrrolyl lithium (2a), 2-furyl lithium (2b) or 2-thiophenyl lithium (2c), respectively, was obtained. When reacted with 6-(2-N-methylpyrrolyl) fulvene (3a), 6-(2-furyl) fulvene (3b) or 6-(2-thiophenyl) fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanocenes (5a-c) were obtained through transmetallation with titanium tetrachloride. When these titanocenes were tested against pig kidney epithelial (LLC-PK) cells, inhibitory concentrations (IC₅₀) of 32 μM, 140 μM, and 240 μM, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.     

A novel alkaloid, aristopyridinone A and anti-inflammatory phenanthrenes isolated from Aristolochia manshuriensis

A novel alkaloid, aristopyridinone A (1) and a new phenanthrene, aristolamide II (2), were isolated from Aristolochia manshuriensis (Guanmutong) together with eight known phenanthrenes (3-10). All structures were elucidated by spectroscopic methods. Compound 2 showed a selective inhibitory effect on elastase release by human neutrophils in response to fMLP with an IC₅₀ value of 4.11 μg/mL. Compound 7 exhibited significant inhibitory effects on superoxide anion generation and elastase release with IC₅₀ values of 0.12 and 0.20 μg/mL, respectively.     

Dioxovanadium(V) and μ-oxo bis[oxovanadium(V)] complexes containing thiosemicarbazone based ONS donor set and their antiamoebic activity

Neutral dioxovanadium (V) complexes [VO₂(HL)] (H₂L = I: 1, H₂L = II: 2 and H₂L = III: 3; H₂L are the thiosemicarbazones H₂pydx-tsc (I), H₂pydx-chtsc (II) and H₂pydx-clbtsc (III); pydx = pyridoxal, tsc = thiosemicarbazide, chtsc = N₄-cyclohexylthiosemicarbazide, clbtsc = N₄-(2-chloro)benzylthiosemicarbazide) have been isolated and characterised on the basis of elemental and electrochemical analyses, spectroscopic (IR, UV-Vis, ¹H and ⁵¹V NMR) data, thermogravimetric studies and reactivity patterns. These complexes are stable in solution at ambient temperature but heating of the methanolic solutions yields the μ-oxo binuclear complexes [(VOL)₂μ-O] (H₂L = I: 4, H₂L = II: 5, H₂L = III: 6). Treatments of dioxo species with H₂O₂ yield oxoperoxo species, the formations of which have been established spectrophotometrically. Similarly, the formations of oxohydroxo species, an intermediate proposed during the catalytic action of haloperoxidases, have also been established in solution by treating 1, 2 and 3 with a methanolic solution of HCl. The antiamoebic activities were carried out to ascertain the effectiveness of dioxovanadium(V) and μ-oxobis(oxovanadium(V)) complexes in comparison to their corresponding thiosemicarbazones. These complexes possess noteworthy potencies against HM1:1MSS strain of Entamoeba histolytica. Complexes 2, 3, 5 and 6 showed less IC₅₀ values than metronidazole, indicating that these metal thiosemicarbazones may be the lead molecules to inhibit the growth of E. histolytica. Within the series, complex 5 showed the most promising amoebicidal activity (IC₅₀ = 0.5 μM versus IC₅₀ = 1.8 of metronidazole).     

Synthesis and structural characterization of new chiral mixed phosphine phosphoramidite complexes of ruthenium

New phosphoramidite complexes of ruthenium chiral at the metal were synthesized, structurally characterized and their electrochemical and catalytic properties were studied. Reaction of the known chiral phosphoramidites (R = naphthyl, R′ = CH₃, 1a; R = naphthyl, R′ = benzyl, 1b; R = octahydronaphthyl, R′ = benzyl, 1c) with CpRu(PPh₃)₂Cl afforded the title compounds CpRu(PPh₃)(1a-c)(Cl) (2a-c) in 46-74% isolated yields. Fractional crystallization of 2b and 2c afforded the corresponding diastereopure complexes which are chiral both at the metal and at the ligand. The molecular structures of 2b and 2c were determined, revealing a pseudo octahedral coordination geometry about the ruthenium center. Electrochemical studies by cyclic voltammetry showed reversible electrochemical behavior of the metal complexes 2a-c. The new metal complexes are catalytically active in the Mukaiyama aldol reaction (24 h, room temperature, 31-53% yield), but almost no enantiomeric excesses for the products were obtained.     

Design of novel N-phenylnicotinamides as selective cyclooxygenase-1 inhibitors

A series of N-phenylnicotinamides (1-40) were designed and evaluated in vitro for their COX inhibitory activities. Most of the synthesized compounds were proved to be potent and selective inhibitors of COX-1. Compound 28 showed the most potent COX-1 inhibitory activity (COX-1 IC₅₀ = 0.68 ± 0.07 μM) and good selectivity (COX-2 IC₅₀ >100 μM). This compound may be useful as a lead compound for superior COX-1 inhibitors. On the basis of the biological results, structure-activity relationships for the COX-1-inhibitory activities of the synthesized N-phenylnicotinamides were discussed concisely.     

Design of potent and selective GPR119 agonists for type II diabetes

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC₅₀ = 3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).     

Synthesis and structural characterizations of para-bis(dialkyl/diarylphosphino)phenylenes built around tetrahalogenated benzene cores

Double deprotonation of 1,2-dibromo-4,5-difluorobenzene and 1-bromo-2-chloro-4,5-difluorobenzene by lithium diisopropylamide (LDA) in ethereal solutions is facile at very low temperatures (T < −90 °C). The organo-dilithium intermediates thus generated react readily with chlorophosphines ClPR₂ (R = Ph and/or ⁱPr), producing 1,2-dibromo-3,6-bis(diphenylphosphino)-4,5-difluorobenzene (1a), 1,2-dibromo-3,6-bis(diisopropylphosphino)-4,5-difluorobenzene (1b) and 1-bromo-2-chloro-3,6-bis(diphenylphosphino)-4,5-difluorobenzene (1c). Corresponding P-oxides 2a-c are obtained by oxidation of 1a-c with H₂O₂. Analogous reactions of 1,2-dibromo-4,5-difluorobenzene and 1-bromo-2-chloro-4,5-difluorobenzene with only 1 equiv. of LDA do not result in selective monodeprotonations, as 1a and 1c are formed preferentially after ClPPh₂ quench. All of the isolated new compounds were fully characterized by multinuclear NMR spectroscopy, elemental analysis and/or mass-spectrometry. In addition, 1a, 1c, 2a, and 2b were characterized by single crystal X-ray diffraction methods.