Design and synthesis of pyrazole-pyrazoline hybrids as cancer-associated selective COX-2 inhibitors.

In continuation of our previous work on cancer and inflammation, 15 novel pyrazole-pyrazoline hybrids (WSPP1-15) were synthesized and fully characterized. The formation of the pyrazoline ring was confirmed by the appearance of three doublets of doublets in 1 H nuclear magnetic resonance spectra exhibiting an AMX pattern for three protons (HA , HM , and HX ) of the pyrazoline ring. All the synthesized compounds were screened for their in vitro anticancer activity against five cell lines, that is, MCF-7, A549, SiHa, COLO205, and HepG2 cells, using the MTT growth inhibition assay. 5-Fluorouracil was taken as the positive control in the study. It was observed that, among them, WSPP11 was found to be active against A549, SiHa, COLO205, and HepG2 cells, with IC50 values of 4.94, 4.54, 4.86, and 2.09 µM. All the derivatives were also evaluated for their cytotoxicity against HaCaT cells. WSPP11 was also found to be nontoxic against normal cells (cell line HaCaT), with an IC50 value of more than 50 µM. The derivatives were also evaluated for their in vitro anti-inflammatory activity by the protein (egg albumin) denaturation assay and the red blood cell membrane stabilizing assay, using diclofenac sodium and celecoxib as standard. Compounds that showed significant anticancer and anti-inflammatory activities were further studied for COX-2 inhibition. The manifestation of a higher COX-2 selectivity index of WSPP11 as compared with other derivatives and an in vitro anticancer activity against four cell lines further established that compounds that were more selective toward COX-2 also exhibited a better spectrum of activity against various cancer cell lines.

Methylene-bearing sulfur-containing cyanopyrimidine derivatives for treatment of cancer: Part-II.

In continuation of our previous work on anticancer and anti-inflammatory agents, a series of 22 novel methylene-bearing sulfur-containing cyanopyrimidine derivatives was synthesized by Biginelli condensation reaction, which was followed by nucleophilic substitution of the chloro group with secondary or tertiary amines. Structural confirmation of these derivatives was attained through different spectral techniques. Then, anticancer evaluation of these compounds was done at the National Cancer Institute. Compounds 4g, 4j, 4k, and 4v demonstrated appreciable results against different cell lines. Among the synthesized compounds, 4g (NSC: 795475) exhibited a growth inhibition (GI) of 81.34% against the NCI-H460 lung cancer cell line, 72.64% against the ACHN renal cancer cell line, and 112.17% against the OVCAR-4 ovarian cancer cell line. Compound 4j (NSC: 795746) was active against U-251 CNS cancer, OVCAR-4 ovarian cancer, and 786-0 and ACHN renal cancer cell lines, with GI of 78.84%, 150.38%, 75.64%, and 86.45%, respectively. The literature supporting the association between cancer and underlying inflammation prompted us to evaluate the four compounds, 4g, 4j, 4k, and 4v, with appreciable anticancer activity for their in vitro anti-inflammatory activity. Cyclooxygenase (COX)-2 inhibition studies were also performed to study the molecular target. To validate the target study, molecular docking studies in the ligand-binding domain of COX-2 (PDB ID: 1CX2) were also performed. Compounds 4g, 4j, and 4k did not show cytotoxicity on RAW 264.7 cells up to 10 µM concentration; however, compound 4v showed cytotoxic effects at 10 µM concentration.

Combretastatin-based compounds with therapeutic characteristics: a patent review.

Introduction: Combretastatins represent a potent class of phenolic-stilbene natural products that function as colchicine binding site inhibitors of tubulin polymerization and have been advanced as promising anticancer lead compounds. Among them, combretastatin A-4 is the most potent lead molecule due to its broad spectrum cytotoxicity against a variety of tumors. However, low water solubility due to its high lipophilic nature and inter-conversion of olefinic double bond from more active cis to less active trans-conformation poses limitations to its clinical utility. However, different approaches including prodrugs, salt formations, structural modifications, prevention of inter-conversion of the olefinic bond and changes to the substitution pattern on the rings of combretastatin A-4 were investigated and successfully resulted in different combretastatin-based molecules that demonstrated varying levels of potency against different types of tumors during their in-vitro and in-vivo studies. Areas covered: This review covers the patents over a period of 2008-2018. Expert opinion: Molecular hybridization and prodrug designing imparted multi-targeted actions to combretastatin derivatives. Currently, various combretastatin derivatives are under clinical trials. These derivatives could be used to treat disorders other than cancer, due to their vascular disrupting action.

Malaria Hybrids: A Chronological Evolution.

Malaria, an upsetting malaise caused by a diverse class of Plasmodium species affects about 40% of the world's population. The distress associated with it has reached colossal scales owing to the development of resistance to most of the clinically available agents. Hence, the search for newer molecules for malaria treatment and cure is an incessant process. After the era of a single molecule for malaria treatment ended, there was an advent of combination therapy. However, lately there had been reports of the development of resistance to many of these agents as well. Subsequently, at present most of the peer groups working on malaria treatment aim to develop novel molecules, which may act on more than one biological processes of the parasite life cycle, and these scaffolds have been aptly termed as Hybrid Molecules or Double Drugs. These molecules may hold the key to hitherto unknown ways of showing a detrimental effect on the parasite. This review enlists a few of the recent advances made in malaria treatment by these hybrid molecules in a sequential manner.

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents.

Piperazine is one of the most sought heterocyclics for the development of new drug candidates. This ring can be traced in a number of well established, commercially available drugs. Wide array of pharmacological activities exhibited by piperazine derivatives have made them indispensable anchors for the development of novel therapeutic agents. The review herein highlights the therapeutic significance of piperazine derivatives. Various therapeutically active piperazine derivatives developed by several chemists are reported here.

Novel pyrazole-pyrazoline hybrids endowed with thioamide as antimalarial agents: their synthesis and 3D-QSAR studies.

One of the most viable options to tackle the growing resistance to the antimalarial drugs is hybrid molecules. It involves combination of different scaffolds in one frame that may lead to compounds with diverse biological profiles. In this context, new hybrids of three different scaffolds viz pyrazole, pyrazoline and thiosemicarbazone moiety were incorporated into one single compound and evaluated for their in vitro schizontocidal activity against the CQ-sensitive 3D7 strain of Plasmodium falciparum. Compounds with significant in vitro antimalarial activity were further evaluated for cytotoxicity against VERO cell lines. The best active compound 48 exhibited an IC50 of 1.13 µM. The in vitro results were further validated by quantitative structure-activity relationship (QSAR).

A review exploring biological activities of hydrazones.

The development of novel compounds, hydrazones has shown that they possess a wide variety of biological activities viz. antimicrobial, anticonvulsant, antidepressant, anti-inflammatory, analgesic, antiplatelet, antimalarial, anticancer, antifungal, antitubercular, antiviral, cardio protective etc., Hydrazones/azomethines/imines possess-NHN = CH- and constitute an important class of compounds for new drug development. A number of researchers have synthesized and evaluated the biological activities of hydrazones. This review aims at highlighting the diverse biological activities of hydrazones.

Malaria: hitches and hopes.

Malaria, a devastating infectious disease caused by parasites of Plasmodium genera is transmitted from person to person through bites of infected mosquitoes. It generally traps underdeveloped nations with poor infrastructure and high population density. It has attracted considerable attention from academic institutions, pharmaceutical industries and government agencies but the efforts to eradicate this threat face a number of technical, economic, financial and institutional hurdles. In the absence of clinically proven vaccines to combat malaria, chemotherapy continues to be the best available option, although it suffers from a big loophole of resistance. Emergence of resistance is associated with the two phases of Plasmodium's life cycle: asexual in humans and sexual in mosquito, which are intricate to target simultaneously. Consequently, the search for novel antimalarial agents is a never-ending task for scientists and chemists. This review aims at highlighting the currently used antimalarial agents, targets for the therapy and present scenario in the development of new antimalarial drugs to combat this global problem.

Quinoline: A versatile heterocyclic.

Quinoline or 1-aza-naphthalene is a weak tertiary base. Quinoline ring has been found to possess antimalarial, anti-bacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, and analgesic activity. Quinoline not only has a wide range of biological and pharmacological activities but there are several established protocols for the synthesis of this ring. The article aims at highlighting these very diversities of the ring.

Immunoinflammatory responses in gastrointestinal tract injury and recovery.

Inflammation is a non-specific immune response to infection, irritation or other injury, the key features being redness, warmth, swelling and pain. A number of mediators are released which alter the resistance of mucosa to injury induced by noxious substances. Oxidative stress is a unifying mechanism of injury in many types of disease processes, including gastrointestinal diseases. It has been defined as an imbalance in the activity of pro and antioxidants. Pro-oxidants favour free radical formation while antioxidants inhibit or retard the same. A number of markers of oxidative stress have been identified. This review provides an overview of various mediators of inflammation and oxidative stress, and diverse approaches for prevention and treatment of gastrointestinal inflammation.

Microwave assisted one pot synthesis of some pyrazole derivatives as a safer anti-inflammatory and analgesic agents.

A series of pyrazolo[3,4-b]quinolines have been synthesized using one-pot water mediated synthetic route under microwave irradiation involving the condensation of 2-chloroquinoline-3-carbaldehydes with semicarbazide or 2,4-dinitrophenyl hydrazine. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. The pharmacological evaluation showed that the compounds are good at inhibiting edema induced by carrageenan and also showed prominent analgesic activity with lesser GI toxicity as indicated by severity index and LPO values.

Pyrazolines: a biological review.

Pyrazoline is an important five membered nitrogen heterocycle, which has been extensively researched upon. The ring is quite stable and has inspired chemists to carry out various structural variations in the ring. This has propelled the development of distinct pyrazolines with an array of pharmacological activities viz. anti-inflammatory, analgesic, antimicrobial, anticancer, antidepressant etc. The review aims at highlighting this pharmacological diversity of pyrazolines. The review is a gist of latest work done describing the pharmacological aspects and potential of pyrazoline ring.

Recent updates on biological activities of oxadiazoles.

Among the plethora of heterocyclic nucleus discovered, the oxadiazoles have also been explored extensively. The oxadiazole structure has been demonstrated to bear important biological activities such as anti-cancer, antiinflammatory, anti-tuberculosis, anti-malarial and anti-schistosomiasis etc. The presence of oxadiazole motifs in diverse types of compounds proves its importance in the field of medicinal chemistry. This review is complementary to earlier reviews and covers recent updates of various pharmacological aspects of oxadiazoles. To help the reader better know the context for these approaches, a summary of various aspects of background of related topic is presented.

Anti-inflammatory and antimicrobial activity of 4,5-dihydropyrimidine-5-carbonitrile derivatives: their synthesis and spectral elucidation.

Thirteen new 6-(1-H-indole-2-yl)-4-oxo-2-[2-(substituted-benzylidene)-hydrazinyl]-4,5-dihydropy-rimidine-5-carbonitrile derivatives were synthesized. The title compounds, hydrazones, were synthesized by reaction of hydrazine group of 2-hydrazinyl-4-(1-H-indole-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (2) with different substituted aromatic aldehydes using a mixture (2:8, v/v) of glacial acetic acid and alcohol. The required intermediate compound 2 was synthesized from 2-mercapto-4-(1-H-indole-2-yl)-6-oxo-1,6-dihy-dropyrimidine-5-carbonitrile 1 upon nucleophilic attack by the hydrazine hydrate. Compound 1 was synthesized by modified Biginelli condensation method using indole-3-carbaldehyde, ethyl cyanoacetate and thiourea. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and antimicrobial actions. Among the newer derivatives, one compound i.e., 6-(1-H-indole-2-yl)-4-oxo-2-[2-(2,6-dichlorobenzylidene)-hydrazinyl]-4,5-dihydropyrimidine-5-carbonitrile (7) emerged as lead compound having 71.14% inhibition of edema and 12.5 microg/mL MIC against both bacterial and fungal strains.

Search for new pharmacophore as antimalarial agent: synthesis and antimalarial activity of some 2(3H)-furanones bearing quinoline moiety.

A series of substituted 3-[(substituted-2-chloroquinolin-3-yl)methylene]-5-(substituted-phenyl)-furan-2(3H)-ones (4a-p) have been synthesized and evaluated for their in vitro antimalarial activity against P. falciparum. The title compounds were synthesized by condensing 3-(substituted-benzoyl)propionic acids (3a-d) with substituted 2-chloroquinoline-3-carbaldehydes (2a-d) following modified Perkin's reaction. Compounds 3-[2-chloro-6-methylquinolin-3-yl)methylene]-5-(2,4-dimethyl-phenyl)-furan-2(3H)-one (4n) and 3-[2-chloro-6-methoxyquinolin-3-yl)methylene]-5-(2,4-dimethyl-phenyl)-furan-2(3H)-one (4p) showed promising antimalarial activity with MIC of 10 microg/mL.