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.

New dimensions in the field of antimalarial research against malaria resurgence.

Malaria is a life threatening disease caused by microscopic parasites called Plasmodium that are transmitted to human beings by mosquitoes. Single celled Eukaryotic plasmodium parasite is responsible to cause malaria in human beings and is transmitted by bite of Anopheles species mosquitoes. Resurgence of malaria towards the end of 20th Century is due to failure of its eradication completely. Parasite recurrence occurs due to high densities of parasite, low immunity and non opimized drug concentration. The ineffective eradications strategies were due to indefinable complex life cycle of Plasmodium and emergence of drugs resistant strains of Plasmodium falciparum (Pf) including Artemisinin and Artemisinin based combination therapy (ACT). The vector of the disease i.e. mosquitoes became resistive towards Pyrethroids, which are only class of insecticides recommended for vector control. Artemisinin based combination therapy gained acceptance as an effective approach to counter the spread of disease resistance to chloroquine, sulfadoxine, pyrimethamine and other anti malarial drugs. Understanding the underlying molecular basis of the pathogenesis led to the development of some new diagnostic, drugs and insecticides. Reports on the use of new combination therapies reduced the burden of disease worldwide. Some of the new combination therapies are in clinical stage of development that have efficacy against drug resistant parasites and the potential to use in single dose regimens to improve compliance. The current review represents the recent anti-malarial research carried out globally especially in the class of synthesis of small molecule and natural product derivatives as potent anti-malarial drugs. The review also covers the advancement in the anti-malarial vaccine development although goal for vaccine development still remains elusive.