Synthesis, biological evaluation and molecular modeling investigation of some new benzimidazole analogs as antiviral agents

A set of heterocyclic benzimidazole derivatives bearing 1,3,5-triazine group with different substituents at C-2 and C-5 of the benzimidazole ring have been synthesized and evaluated for their antiviral activities against HSV-1. The structures of these compounds have been established by analytical data, IR spectra, [1]H NMR, and mass spectra. Compounds 8a and 8b proved to be the most active antiherpetic agents in this study, at EC[50]% concentrations of 2.9, 3.4 mg/ml, respectively. Computational evaluation of the quantum chemical descriptors such as hydrophobicity [log P], HOMO and LUMO, and the gap energy, were calculated and correlated with the antiviral activity. The tested compounds showed proper degree of hydrophobicity [<0.5 - >5]. The HOMO-LUMO gap energy values of the tested compounds are comparable with the observed values for the antiviral drug, Acyclovir

Computational characteristics of valproic acid binding to histone deacetylase

Recently, the antiepileptic drug valproic acid [VPA] has also demonstrated efficacy in the management of cancer and bipolar disorders. These actions are largely mediated by inhibition of the HDAC enzyme/induction of certain genes. Relative to other HDAC inhibitors such as trichostatin-A [TSA], VPA offers higher selectivity on cancer cells with virtually no detrimental effects on normal cells. The molecular underpinnings of these biological profiles for VPA remain undefined. We currently propose for and attempt to identify differences in the binding of VPA and TSA to HDAC. In this paper, conformational changes and energy calculations have been derived. VPA had to accomplish conformational changes in its structure for best accommodation at the HDAC binding site. Energy computations showed that VPA has a lower binding affinity than TSA [-53.80 vs. -66.30 Kcal/mol]. These findings demonstrate that VPA binding to HDAC confers catalytic, conformational, and computational characteristics that are distinct from those of TSA. These findings for VPA are consistent with a moderate inhibition of HDAC, a low toxicity on normal cells, and a higher selectivity on cancer cells than TSA. Accordingly, these newly identified binding properties of VPA can state a framework strategy for the rational design of VPA-related anticancer drugs with superior cytodifferentiating- and/or safety-profiles

Resveratrol activates the kinase-G system in human coronary smooth muscle cells via a nongenomic, estrogen-independant mechanism

Resveratrol [RSVL], a polyphenolic phytoestrogen in grapes, confers multifaceted cardiovascular benefits. The cellular and molecular basis of RSVL actions has been largely undefined. Currently, in human coronary smooth muscle cells [HCSMCs], RSVL markedly [3.2 fold] enhanced cGMP formation [t1/2: 6.3 min, EC 50: 1.8 microM] and stimulated kinase-G activity [4 fold]. By contrast, RSVL had no effect on cAMP or PKA activity in these cells. The RSVL-enhanced cGMP/kinase-G activity was not abrogated by either of the phosphodiesterase-inhibitors [zaprinast, 10 microM, IBMX, 0.5mM], the nitric oxide synthase-inhibitor [L-NMMA, 10 microM], or the soluble guanylyl cyclase [sGC]-inhibitor [ODQ, 10 microM].In membrane preparations from HCSMCs, RSVL activated GC in the particulate-, but not in the soluble- membrane fraction. Similar effects were due to the specific particulate-GC [pGC] agonist atrial natriuretic peptide [ANP, 0.1-1 microM]. By contrast, the nitric oxide donor, SNAP [1-10 microM] stimulated GC only in the soluble fraction. Responses to RSVL were insensitive to the estrogen receptor blockers, tamoxifen and ICI-182,780. Conversely, pretreatment with the PKC activator, PMA [0.1 microM], a known desensitizer of pGC, markedly blunted the RSVL-enhanced GC-activity. These findings demonstrate that RSVL triggers a pGC-mediated stimulation of protein kinase-G in human coronary smooth muscle cells. This pathway appears to be independent of the conventional estrogen machinery and supports both vasodilatory and anti-atherogenic actions for RSVL