Medicinal Chemistry

In the present study, a series of N-pyridin-2-yl substituted [4-methylphenylsulphonamido] acetamides have been synthesized. The reaction of 4-methylphenyl sulphonyl chloride 1 with various amino acids 2a-e in basic medium yielded [4-methylphenylsulphonamido] alkanoic acids 3a-e which on chlorination with thionyl chloride gave the acid chloride derivatives of [4-methylphenylsulphonamido] alkanoic acid in situ. The acid chloride derivatives on condensation with 2-aminopyridine 4, gave the corresponding acetamides 5a-e in good to excellent yield. The compounds were characterized by FTIR, 1H-NMR and 13C-NMR and screened for antifungal activities against Candida albican and Aspergillus niger. The results revealed that the compounds had betterantifungal activity than fluconazole the reference drug. Compound 5d was most active against Candida albicans with MIC of 0.224 mg/mL and compound 2b most active against Aspergillus niger with MIC of 0.190 mg/mL.

This study investigated the anti-oxidant activities of both the stem and root bark of Sterculia tragacantha, isolated its active compounds and characterised the isolated compounds.

The plant parts and the isolated compounds were screened for anti-oxidant activity by Thin Layer Chromatography technique using 2, 2-diphenyl-1-dipicrylhydrazyl (DPPH). Extracts were fractionated using Medium Pressure Liquid Chromatography guided by bioautography to isolate active substances. The isolated compounds were characterised using Nuclear Magnetic Resonance spectroscopy and by comparison of spectroscopic data with literature values.

The results revealed that the crude extracts and two compounds possess strong anti-oxidant activity and antibacterial activity. Epicatechin was isolated from both the stem and the root bark while Procyanidin B2, C4-C8 dimer of epicatechin, was isolated from the stem bark.

In conclusion, this study suggests that the crude extracts, epicatechin and procyanidin B2 which demonstrated strong anti-oxidant activities can provide efficient antioxidant protection by complementary mechanism, such as free radical scavenging and metal ions reduction.

There is a long history for the bioorganic and biomedical use of N-methyl-pyrrole-derived polyamides (PAs) that are higher homologs of natural products such as distamycin A and netropsin. This work has been pursued by many groups, with the Dervan and Sugiyama groups responsible for many breakthroughs. We have studied PAs since about 1999, partly in industry and partly in academia. Early in this program, we reported methods to control cellular uptake of polyamides in cancer cell lines and other cells likely to have multidrug resistance efflux pumps induced. We went on to discover antiviral polyamides active against HPV31, where SAR showed that a minimum binding size of about 10 bp of DNA was necessary for activity. Subsequently we discovered polyamides active against two additional high-risk HPVs, HPV16 and 18, a subset of which showed broad spectrum activity against HPV16, 18 and 31. Aspects of our results presented here are incompatible with reported DNA recognition rules. For example, molecules with the same cognate DNA recognition properties varied from active to inactive against HPVs. We have since pursued the mechanism of action of antiviral polyamides, and polyamides in general, with collaborators at NanoVir, the University of Missouri-St. Louis, and Georgia State University. We describe dramatic consequences of β-alanine positioning even in relatively small, 8-ring polyamides; these results contrast sharply with prior reports. This paper was originally presented by JKB as a Keynote Lecture in the 2nd International Conference on Medicinal Chemistry and Computer Aided Drug Design Conference in Las Vegas, NV, October 2013.

Diabetes mellitus is a chronic metabolism disorder characterized by hyperglycemia due to insulin deficiency or insulin resistance. Associated complications include Myocardial infarction, cardiomyopathy, retinopathy, neuropathy, nephropathy, etc.

Cinnamic acid analogs (SSPC0-SSPC20) containing different amino acids were designed and docked into crystal structure of AMPK and PPARs. Among the 20 designed compounds five compounds namely SSPC5, SSPC8, SSPC11, SSPC14, SSPC15 showed good docking scores using Glide 5.0 Maestro program and were subjected to ADME prediction by using software Quickprop version 3.1. These were then selected for synthesis, characterized and antidiabetic activity carried out using Alloxan induced diabetic rat model by measuring blood glucose levels using glucometer at 0, 1, 2, 4, 6, 8 and 24 hrs through the tail vein puncture method. SSPC5, SSPC8, SSPC11, SSPC14 showed % reduction in blood glucose of 23.02%, 37.02%, 14.04% and 15.96% as compared to standard with 33.53% reduction.

As SSPC14 had good and comparable docking scores in both AMPK and PPAR γ receptor, so it was subjected for the Diabetic as well as diabetic cardiomyopathy activity by recording the electrocardiogram of both diabetic and control rat. It was found to be very efficient at low dose and had a prolong duration of action on the heart (Up to 54 hrs). Thus this study indicated that such hybrid antidiabetic drug with dual action on hyperglycemia and cardiac function is desirable and cost effective.

A new syntheses of novel series of 2,3-dihydroquinazolin-4(1H)-one and benzotriazepin- 5(2H)-one derivatives, starting from the same intermediate (IIa-g). By varying the substituent on the benzamide moiety of the key intermediate (IIa-g) or the conditions of the reactions utilized in this syntheses, the reaction gives rise either quinazolin-4(1H)-one or benzotriazepine-5(2H)-one. The intermediate; 2-methylamino-N-(substituted benzoyl)benzohydrazide (IIa-g); was prepared by condensation of N-methyl-isatoic anhydride with different benzoic acid hydrazides. Constructing the intermediates (IIa-g) on different cyclo-condensation reactions; either with ethylchloroformate /potassium hydroxide or carbon disulfide/potassium hydroxide, yielded a new series of benzotriazepin-5(2H)-one (IIIa-b, IVa-d) and a new series of quinazolin4(1H)-one (Va-c, VI a-d). Pharmacological screening of the new benzotriazepinone derivatives revealed that the compounds (VI a-b, IVc-d) exhibited strong CNS depressant activity over clozapine while compounds (VIa,IVc) showed the same antipsychotic activity as clozapine with an observed neurotoxicity.