Medicinal Chemistry

A series of 5-(substituted aldehyde)-2-imino-7-methyl-3-oxo-N-phenyl-1,2,3,5-tetrahydroimidazo [1,2-a]pyrimidine-6-carboxamide derivatives was synthesized and their chemical structures were confirmed by 1H-NMR, FT-IR and elemental analysis studies. The synthesized derivatives were evaluated for their in vitro antimicrobial potential and validated by UV visible spectroscopy at absorbance 272 nm and comparable with lamivudine as standard. These compounds validated as per International Conference on Harmonization (ICH) guideline in the range of 2-20 μg/ml. Validation study indicated that, compounds 1, 2 and 3 exhibited good percentage purity at absorbance 272 nm and there is no interference of diluents at 272 nm. Antimicrobial results indicated that compound 2 was found to be most active against microbial species (bacterial and fungal).

The target compounds 1-(4-(1H-indol-3-yl)-6-(4-methoxyphenyl)pyrimidin-2-yl)hydrazine (5) was synthesized by reacting 6-(1H-Indol-3-yl)-4-(4-methoxyphenyl)pyrimidine-2(1H)-thione 4 with hydrazine hydrate. Compound 5 was used as a precursor for the synthesis of new pyrazolo pyrimidine derivatives 6-9. Moreover, the 5-amino-1H-pyrazole-4-carbonitrile derivative 6 was then converted into another set of novel compounds 10-14. On the other hand a series of transformations were carried out using the newly synthesized 1-(4-(1H-indol-3-yl)-6-(4-methoxyphenyl) pyrimidin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (11) to afford the pyrazolo pyrimidine derivatives 15-18. Antiproliferatve activities for some of the newly synthesized compounds were evaluated.

Invasion is a crucial step of metastasis process that has a complex mechanism and inducible various cellular signalling pathway (SMADs, JAK/STATs, PI3K/Akt and MAP kinases). In among these pathways, Pl3K (phosphatidylinositol-3-OH kinase)/Akt/NF-ĸB (nuclear factor-ĸB) signalling pathway is an important on cellular invasion and its constitutively active in various human cancer, including non-small cell lung cancer (NSCLC). PI3K/Akt/NF-ĸB pathway has been associated with multiple cellular function; migration, apoptosis, proliferation, survival, and also differentiation. Thus, this signalling pathway plays a major role not only in tumorigenesis but also in a potential target for cancer treatment. It has been investigated that there are lots of observation about Pl3K/Akt signalling pathway on many cancers, especially NSCLC. But, it is not enough to completely understanding the molecular mechanism of NSCLC invasion. In this review, we will briefly discuss the molecular mechanism of PI3K/Akt/NF-ĸB signalling pathway in NSCLC invasion.

The aporphine alkaloids are known to have affinities as the dopaminergic, adrenergic and serotonergic receptor system. Hence the aporphine template can be considered as a privileged scaffold for the design of selective monopotent as well as multi-potent Central Nervous System (CNS) ligands. This review attempts to summarize the recent Structure Activity Relationship (SAR) studies of aporphine alkaloids specifically at the serotonin receptor system. Based on the obtained SAR information it can be concluded that aporphines have great potential to be developed as potent serotonergic ligands.

Current use of Dimethylsulfoxide (DMSO) in dermatology and in topical formulations is scarce despite its potential as a skin penetration enhancer and as a pharmacological active itself. The aim of this work is to develop and characterize a new type of semisolid formulation of Soybean Phosphatidylcholine (SPC) - DMSO deformable nanovesicles for topical application. Tretinoin is used in this work as a model substance. The formulation presents a non-newtonian pseudoplastic behaviour and a pH compatible with the skin. Stability-on-storage at different temperatures indicate an excellent physical and chemical stability and SPC-DMSO vesicles show high deformability when forced to pass through pores much smaller than their own size. These new nanovesicles show a high Tretinoin yield. Calorimetric analysis indicates a possible interaction between Tretinoin and DMSO in the lipid vesicle bilayer and vesicles formulation exhibit low cytotoxic effect below 1.25% SPC. Moreover, these vesicles once applied on the skin do not cause irritation. This study presents a new opportunity in dermal delivery for a controversial molecule such as DMSO. SPC-DMSO vesicles have plenty of advantages for topical application and future studies should confirm their superiority as drug carriers for topical application as well as for clinical evaluations in managing skin disorders.

Some new sulfonamide and amide derivatives containing piperazine ring and imidazo[1,2-b]pyridazine moiety have been synthesized by the reaction of 6-chloro-2-substituted aryl(or alkyl)imidazo[1,2-b]pyridazine derivatives [obtained by the reaction of 3-amino-6-chloro pyridazine with 2-bromo-1-substituted aryl(or alkyl)ethanone] with homopiperazine in NMP and followed by reaction with alkyl (or substituted aryl) acid chloride or sulfonyl chloride in presence of triethyl amine and dichloromethane. All the synthesized compounds were characterized by elemental analysis, 1H NMR and LCMS. These were screened for in vitro antimicrobial activity against two gram positive (Bacillus subtilis and Staphylococcus aureus) and two gram negative bacteria (Pseudomonas fluorescens and Escherichia coli), as well as for antifungal and antimalarial activity.

A new 3-(5-alkyl-2-phenyl-2H-1,2,4-triazol-3-yl)thiazolidin-4-ones derivatives were obtained by condensation of 5-amino-1,2,4-triazoles, mercaptoacetic acid with aromatic aldehydes and catalyzed by Sm(SO3CF3)3 using microwave irradiation. The prepared compounds were tested for their antioxidant, antibacterial and antifungal proprieties. Some of these compounds displayed significant activities. Among them, compound 2e exhibited remarkable activity against a broad spectrum of Gram positive, negative bacteria and pathogenic fungal strains with low MIC values. The investigation of the mode of action of the most potent antifungal compounds on the fungus Pythium phanidermatum showed a membrane alteration and distortions of hyphal morphology. The newly synthesized compounds exhibited also promising radical scavenging activity.

Amyloidosis is a general name for a group of rare diseases, which may end up with progressive organ damage and death as a result of the accumulation of the low-molecular-weight subgroups of normal serum proteins, after their precipitation in the extracellular tissues in the form of cross-ß-folded fibrillar aggregates, which are resistant to proteolysis. More than 30,000 different proteins are produced in human cells. The first product of the protein synthesis is a linear amino acid chain (primary structure). AL amyloidosis, which is also called primary amyloidosis, is the most common and most aggressive type of systemic amyloidosis with an annual incidence of 8.9/1,000,000 in Western countries. The common signs and symptoms of AL amyloidosis are fatigue, weight loss, syncope, peripheral edema, dyspnea, diarrhea or constipation. The clinical suspicion is the first and the most important step for the diagnosis of amyloidosis. All patients with a visceral amyloid syndrome need therapy in AL amyloidosis. The goals of the current treatment approach of systemic AL amyloidosis includes rapidly reduction in the supply of the monoclonal amyloidogenic light chain by eradicating the plasma cell or B cell clone to prevent the new amyloid formation and facilitate the clearance of the existing amyloid deposits and, also supportive care to sustain the function of the organ involved and maintaining the quality of life.

Thiazolidinones is the special class of heterocyclic compounds with a broad spectrum of biological activities such as anti-inflammatory, antiproliferative, antihistaminic, anti-HIV, hypnotic, anaesthetic, antifungal, anthelmintic and antiviral agents as well as CNS stimulants. Therefore researchers have synthesized these condensed heterocycles through different complex pathways as target structures for biological studies. This review focuses on the various strategies followed for the convenient synthesis of thiazolidinone based heterocyclic derivatives. The steps included condensation followed by cyclization of Schiff’s bases, either in a step-wise manner or in one pot under different conditions. Mercaptoacetic acid, thiolactic acid, chloroacetyl chloride, potassium thiocyanate, ethylchloro acetate and ammonium thiocyanate are the most common reagents used for the synthesis thiazolidinone appended on different heterocyclic skeletons.