Kamal Ahmad

Synthesis, antiamoebic and molecular docking studies of furan-thiazolidinone hybrids.

In continuation of our previous work, a series of furan-thiazolidinone hybrids was prepared by Knoevenagel condensation of 3-(furan-2-ylmethyl)-2-(phenylimino)-1, 3-thiazolidin-4-one with different aryl aldehydes in presence of strong base. Some members of the series exhibited remarkable antiamoebic activity and cell viability. Three compounds (3, 6 and 11) showed excellent binding energy for Entamoeba histolytica O-acetyle-l-serine sulfohydrolase and Entamoeba histolytica thioredoxin reductase. These compounds demonstrated significant inhibition of O-acetyle-l-serine sulfohydrolase. The promising antiamoebic activity and enzymatic assay of 3, 6 and 11 make them promising molecules for further lead optimization in the development of novel antiamoebic agents.

Thienopyrimidine sulphonamide hybrids: design, synthesis, antiprotozoal activity and molecular docking studies

A series of hybrid compounds containing the thienopyrimidine scaffold as a DHFR inhibitor fused with a bioactive sulphonamide piperazine skeleton were synthesized and evaluated against the chloroquine and pyrimethamine resistant K1 strain of Plasmodium falciparum and the HM1:1MSS strain of Entamoeba histolytica, respectively. A few of the compounds showed better results than the standard drugs. The toxicity of the hybrids was measured on the Chinese hamster cell line. The majority of the compounds had low toxicity. The binding modes of the most potent antimalarial compounds (5, 6 and 8) were also investigated against PfDHFR using molecular docking and enzyme binding studies, whereby 5 and 6 were found to the most promising against PfDHFR. The present studies suggest that these hybrids might be possible antiprotozoal lead compounds worth further investigation.

Parasitic diarrheal disease: drug development and targets.

Diarrhea is the manifestation of gastrointestinal infection and is one of the major causes of mortality and morbidity specifically among the children of less than 5 years age worldwide. Moreover, in recent years there has been a rise in the number of reports of intestinal infections continuously in the industrialized world. These are largely related to waterborne and food borne outbreaks. These occur by the pathogenesis of both prokaryotic and eukaryotic organisms like bacteria and parasites. The parasitic intestinal infection has remained mostly unexplored and under assessed in terms of therapeutic development. The lack of new drugs and the risk of resistance have led us to carry out this review on drug development for parasitic diarrheal diseases. The major focus has been depicted on commercially available drugs, currently synthesized active heterocyclic compounds and unique drug targets, that are vital for the existence and growth of the parasites and can be further exploited for the search of therapeutically active anti-parasitic agents.

Fungicidal action of geraniol against Candida albicans is potentiated by abrogated CaCdr1p drug efflux and fluconazole synergism

Among the several mechanisms of multidrug resistance (MDR), overexpression of drug efflux pumps CaCdr1p and CaMdr1p belonging to ATP binding cassette (ABC) and major facilitator superfamily (MFS) respectively remain the predominant mechanisms of candidal infections. Therefore inhibiting or modulating the function of these transporters continues to draw attention as effective strategy to combat MDR. We have previously reported the antifungal potential of Geraniol (Ger), a natural monoterpenoid from Palmarosa oil, against Candida albicans. Herein, we explored the fungicidal nature of Ger. The Rhodamine 6G (R6G) and Nile red accumulation confirms the specific effect on CaCdr1p. Mechanistic insights with Candida cells overexpressing CaCdr1p and CaMdr1p revealed that Ger specifically modulates CaCdr1p activity. Kinetic studies further unraveled the competitive inhibition of Ger for R6G efflux as evident from increased apparent Km without affecting Vmax value. The effect of Ger on CaCdr1p was substantiated by molecular docking analyses, which depicted in-silico binding affinity of Ger with CaCdr1p and explored that Ger binds to the active site of CaCdr1p with higher binding energy. Although RT-PCR and western blot revealed no change in expressions of CDR1 and CaCdr1p, confocal microscopy images however depicted CaCdr1p mislocalization in presence of Ger. Interestingly, Ger was synergistic (FICI<0.5) with fluconazole (FLC) which is a well known antifungal drug. Furthermore, Ger sensitizes the FLC sensitive and resistant clinical matched pair of isolates Gu4/Gu5 and led to abrogated R6G efflux and depleted ergosterol. Furthermore, Rhodamine B labeling demonstrates altered mitochondrial potential with Ger which suggest possible linkage of dysfunctional mitochondria with CaCdr1p activity. We also estimated phenotypic virulence marker extracellular phospholipase activity which was considerably diminished along with inhibited cell adherence and biofilm biomass. Lastly, antifungal efficacy of Ger was demonstrated by enhanced survival of Caenorhabditis elegans model and negligible hemolytic activity (20%). Together, modulation of efflux pump activity by Ger and FLC synergism represent a promising approach for combinatorial treatment of candidiasis.

Antioxidant and apoptotic effects of Callistemon lanceolatus leaves and their compounds against human cancer cells

Callistemon lanceolatus (Myrtaceae) has been utilized in folk medicine and its pharmacological properties are widely studied. Phytochemicals are effectively recognized as bases of pharmacologically potent drugs for the development of anticancer therapeutics. The free radical scavenging potential of numerous extracts of C. lanceolatus leaves, Hexane leaf extract (HLE), Chloroform leaf extract (CLE), Ethyl acetate leaf extract (ELE), Methanol leaf extract (MLE), and Aqueous leaf extract (ALE)) were determined by Biochemical assay. We evaluated the anticancer activity of C. lanceolatus leaves extracts against different human cancer cell lines viz liver cancer cells (HepG2), breast cancer cells (MCF7), and normal human embryonic kidney (HEK 293) cell line. The ELE and MLE extracts of C. lanceolatus leaves showed potential antiproliferative effects on HepG2 cells. On the basis of free radical scavenging potential and cytotoxicity studies, ELE and MLE extracts of C. lanceolatus leaves are further evaluated in detail for numerous biological activities. ELE and MLE extracts reduced the cell growth, ROS generation, lowering the potential of cell migration and inhibits the metastatic activity in HepG2 cell lines. ELE and MLE extracts treated HepG2 cells showed down-regulation of STAT3 and up-regulation of p53 and inhibition of cdk2 and cyclin A activity. Phytochemicals analysis have shown that the ELE and MLE possess some anticancer compounds like 4-Fluoro-2-trifluoromethylbenzoic acid, neopentyl ester; fumaric acid, di(pent-4-en-2-yl) ester; 2,3-Dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one and 2-Furancarboxaldehyde,5-(hydroxymethyl). Molecular docking results demonstrate that interactions of compounds present in ELE and MLE extracts with the SH2 domain of STAT3, might be responsible for their inhibitory effects. We have further concluded that the ELE and MLE extracts of C. lanceolatus arrests the cells at S and G2/M phase and subsequently induced cell death by regulating the DNA damage in HepG2 cells.

New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5-14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC50 values (0.14-1.26μM) lower than the standard drug metronidazole (IC50 1.80μM). All nine compounds exhibited antimalarial activity (IC50 range: 1.42-19.62μM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC50 range: 14.67-81.24μM) than quinine (IC50: 275.6±16.46μM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae.