Design, synthesis, biological evaluation and molecular dynamics of some novel 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based compounds as anti-tubercular agents.

Decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1) is a druggable target which is being exploited for the development of new anti-TB agents. In the present work, we report developing a pharmacophore model and performing virtual screening of Asinex database using the developed pharmacophore model to get eight hits as potential DprE1 inhibitors. The hits were used as leads to design new 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based potential anti-TB agents. On the basis of the identified lead molecules, a total of 18 compounds were synthesized and evaluated for their anti-TB activity by using MABA. ADMET predictions for all the compounds revealed that these compounds have drug-like and lead-like properties. One of the final compounds was found to exhibit potent anti-TB activity against Mycobacterium bovis.Communicated by Ramaswamy H. Sarma.

Design, synthesis, and computational studies of phenylacetamides as antidepressant agents.

In the present work, a hit molecule obtained from zinc 'clean drug-like database' by systematically performed computational studies was modified chemically to obtain different derivatives (VS1-VS25). Structures of synthesized derivatives were confirmed by IR, 1H-NMR, 13C-NMR, 13C-DEPT, MS, and elemental analysis. All the synthesized compounds were biologically evaluated for their antidepressant activity by using tail suspension test and forced swimming test in albino mice. All these derivatives showed moderate to good antidepressant activity. The most potent compound (VS25) among the synthesized compounds showed better antidepressant potential than the standard drugs moclobemide, imipramine, and fluoxetine. To understand the time-dependent interactions of this most active compound with MAO-A molecular dynamics was carried out and reported here. Additionally, acute oral toxicity was performed for the most active compound as per OECD guidelines.

Design and synthesis of novel N-[3-(benzimidazol-2-ylamino)phenyl]amine and N-[3-(benzoxazol-2-ylamino)phenyl]amine derivatives as potential anticancer agents.

In this contribution, we report the design, synthesis and cytotoxicity studies of a series of N-[3-(benzimidazol-2-yl-amino)phenyl]amine and N-[3-(benzoxazol-2-ylamino)phenyl]amine derivatives. In vitro cytotoxicity assay of 26 selected compounds was carried out at National Cancer Institute (NCI), USA. Out of them, compounds 10e (NSC D-762842/1) and 11s (NSC D-764942/1) have shown remarkable cytotoxicity with GI50 values ranging between "0.589-14.3 µM" and "0.276-12.3 µM," respectively, in the representative nine subpanels of human tumor cell lines. Further, flow cytometry analysis demonstrated that compound 10e exerted cell cycle arrest at G2/M phase and showed dose-dependent enhancement in apoptosis in K-562 leukemia cancer cells.

Development of a credible 3D-QSAR CoMSIA model and docking studies for a series of triazoles and tetrazoles containing 11ß-HSD1 inhibitors.

Type 2 diabetes mellitus is described by insulin resistance and high fasting blood glucose. Increased levels of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme result in insulin resistance and metabolic syndrome. Inhibition of 11ß-HSD1 decreases glucose production and increases hepatic insulin sensitivity. Use of selective 11ß-HSD1 inhibitors could prove to be an effective strategy for the treatment of the disease. It was decided to identify the essential structural features required by any compound to possess 11ß-HSD1 inhibitory activity. A dataset of 139 triazoles and tetrazoles having 11ß-HSD1 inhibitory activity was used for the development of a 3D-QSAR model. The best comparative molecular field analysis (CoMFA) model was generated with databased alignment, which was further used for comparative molecular similarity indices analysis (CoMSIA). The optimal CoMSIA model showed [Formula: see text] = 0.809 with five components, [Formula: see text] = 0.931, SEE = 0.323 and F-value = 249.126. The CoMSIA model offered better prediction than the CoMFA model with [Formula: see text] = 0.522 and 0.439, respectively, indicating that the CoMSIA model appeared to be a better one for the prediction of activity for the newly designed 11ß-HSD1 inhibitors. The selectivity aspect of 11ß-HSD1 over 11ß-HSD2 was studied with the help of docking studies.

Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism.

Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type α1-blockers and AII-antagonists it was planned to develop dual α1- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual α1- and AII-antagonists on rat aortic strips for the blockade of known α1- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both α1- as well as AII-receptor antagonists.

Pyrido[1,2-a]pyrimidin-4-ones as antiplasmodial falcipain-2 inhibitors.

Plasmodium falciparum cysteine protease falcipain-2 (FP-2) is a promising target for antimalarial chemotherapy and inhibition of this protease affects the growth of parasite adversely. A series of pyrido[1,2-a]pyrimidin-4-ones were synthesized and evaluated for their in vitro FP-2 inhibitory potential. Compounds (14,17) showed excellent FP-2 inhibition and can serve as lead compounds for further development of potent FP-2 inhibitors as potential antimalarial drugs.

Assessment of antiplatelet activity of 2-aminopyrimidines.

A series of 4,6-diaryl-2-aminopyrimidines was developed as antiplatelet agents and their potency was evaluated by in vitro assay. Compound 14k was found to be two times more potent than aspirin. These encouraging results could be helpful for the development of new antiplatelet compounds.

Revelation on the potency of α(1) -blockers - parallel blockade of angiotensin II receptor: a new finding.

CONTEXT: The problem of hypertension has gained enormous proportions in the past decade. Multifactorial etiology and complex pathophysiology of the disease has rendered the treatment of the disease a hard task. Sympathetic nervous system and the renin-angiotensin-aldosterone system are primary contributors of blood pressure homeostasis. OBJECTIVE: Structural similarities were identified among AT(1) and α(1)-antagonists, initiating a speculation that α(1)-antagonists could possibly block the AT(1) receptor and vice-versa. METHODS: To corroborate this speculation, we screened prototypical α(1)-antagonists such as prazosin, doxazosin, and terazosin for antagonism of angiotensin II on rat aortic strips. We also examined the AT(1) antagonists losartan, valsartan, and olmesartan for their possible antagonistic effect, on contractions of rat aortic strips induced by phenylephrine. RESULTS: To our astonishment, we found that prazosin and its analogs which have been reported to have α(1)-antagonistic activity only, were able to shift concentration response curves of angiotensin II. CONCLUSION: Our findings suggest that the potent antihypertensive effect of prazosin-type α(1)-antagonists is not purely due to α(1)-receptor blocking activity of these compounds but also due to blockade of AT(1) receptors. This finding may lead to the development of more potent dual inhibitors which would prove to be of immense value in the control of the scourge of hypertension.

Gemini amphiphiles: a novel class of nonviral gene delivery vectors.

A number of carriers have been developed for the delivery of genes, but the search for a clinically successful ideal carrier is ongoing. Nonviral carriers, especially cationic liposomes, were developed to resolve issues related to the immunogenicity and oncogenicity of viral carriers. Many synthetic cationic amphiphiles have been synthesized and structurally modified to incorporate genes into vesicular carriers to enhance DNA transfection efficiency and to reduce carrier toxicity. Of these carriers, gemini amphiphiles have demonstrated the suitable physiochemical properties needed for promising and novel gene carriers. Moreover, three basic parts (head, spacer, and chain) in the structure of gemini amphiphiles provide ample opportunities to tailor them according to the needs of specific gene delivery. Initial studies have demonstrated the superiority of gemini amphiphiles in gene delivery efficiency over currently used carriers for gene delivery. This article critically reviews these studies and provides a balanced view to fellow scientists to carry out their efforts in filling in the technological gaps.

Synthesis, antileukemic and antiplatelet activities of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines.

The synthesis, antileukemic and antiplatelet activity evaluation of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines are described. In general, it was found that compound 17o showed moderate antileukemic activity against MOLT3 human leukemic cancer cell lines. An arachidonic acid induced platelet aggregation effect on washed rat platelets was studied. Compound 17i was found to be the most potent. The antiplatelet properties may be mediated by interference with the arachidonic acid pathway.

Current scenario of 1,4-diazepines as potent biomolecules--a mini review.

The aim of this review is precisely to give a comprehensive account of the large volume of work carried out on 1,4-diazepines regardless of the degree of unsaturation in the diazepine system. This review mainly emphasizes recent work on the diazepines also including earlier work.

Synthesis and pharmacological investigation of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as a new class of H1-antihistamine agents.

A series of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones was synthesized by the cyclization of 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one with various one-carbon donors. The starting material, 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one, was synthesized from 4-substituted aniline by a novel innovative route. When tested for in-vivo H1-antihistamine activity on conscious guinea-pigs, all the test compounds significantly protected the animals against histamine-induced bronchospasm. The compound 1-methyl-4-(4-chloro phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (VII) was more potent (72.71% protection), and 1-methyl-4-(4-methoxy phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) was equipotent (71% protection), when compared with the reference standard, chlorpheniramine maleate (71% protection). Compounds II and VII showed negligible sedation (5% and 8% respectively) when compared with chlorpheniramine maleate (25%). Compounds II and VII could serve as prototype molecules for further development as a new class of H1-antihistamines.

Understanding the antitumor activity of novel tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors using CoMFA and CoMSIA.

3D-QSAR studies of some tricyclicpiperazinyl derivatives as farnesyltransferase inhibitors were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy conformer of the template molecule 35, the most active and pharmacokinetically stable molecule of the series, was obtained by simulated annealing method and used to build structures of the molecules in the dataset. The CoMFA model obtained after the removal of outliers produced statistically significant results with cross-validated and conventional correlation coefficients of 0.550 and 0.969, respectively. The combination of steric, electrostatic, hydrogen bond acceptor and hydrophobic fields in CoMSIA gave the best results with cross-validated and conventional correlation coefficients of 0.611 and 0.986, respectively. The predictive ability of CoMFA and CoMSIA were determined using a test set of 24 tricyclicpiperazinyl derivatives giving predictive correlation coefficients of 0.543 and 0.663, respectively, indicating good predictive power. Further the robustness of the model was verified by bootstrapping analysis. Based on the CoMFA and CoMSIA analysis we have identified some key features in the tricyclicpiperazinyl series that are responsible for farnesyltransferase inhibitory activity that may be used to design more potent tricyclicpiperazinyl derivatives and predict their activity prior to synthesis.

Studies on the development of taste-masked suspension of chloroquine.

A non-bitter chloroquine suspension formulation for pediatric use was prepared in the form of an ion-pair of chloroquine with pamoic acid. Various parameters involved in the formulation of a stable and palatable suspension have been optimized. The suspension was characterized for particle size analysis, viscosity, physical and chemical stability and taste. Release of chloroquine from the ion-pair conducted as dissolution rate studies in simulated gastric media showed near to 100% release instantaneously. In-vivo bioavailability study conducted in albino rats indicated comparable bioavailability of chloroquine from the suspension with that of chloroquine phosphate syrup taken as standard. Stability study conducted over a period of 3 months showed the intactness of the ion-pair and the tasteless behavior of the suspension throughout the period of storage.

Chemical and pharmacological studies on fixed oil of Ocimum sanctum.

Gas liquid chromatographic analysis of fixed oil of O. sanctum revealed the presence of five fatty acids (stearic, palmitic, oleic, linoleic and linolenic acids). The triglyceride fraction of the oil showed higher protection compared to fixed oil against carrageenam-induced paw edema and acetic acid-induced writhings in rats and mice, respectively. The pharmacological activity of the fixed oil could be attributed to its triglyceride fraction or the fatty acids.

Heterosteroids and drug research.

PIP: This updated literature review on heterosteroids and drug research has information on chemical structure, pharmacology, and effects. It first discusses the anti-inflammatory heterosteroids, such as mometasone furoate and cortivazol. It also covers heterosteroidal antimineralocorticoids and anabolic hetero derivatives. The review discusses at length the 19-norsteroid, mifepristone (RU-486), which exhibits antiprogestational activity and is being used for fertility control in women. It also has antiglucocorticoid activity and shows promise as a treatment of diseases characterized by muscle atrophy. In vitro studies indicate that mifepristone inhibits growth of breast cancer cell lines and of endometrial cancer cell lines. It has already exhibited growth inhibitory effects in some breast cancer patients. Discussions of mifepristone's pharmacokinetics and structural modifications of mifepristone follow. Danazol is an antigonadotropin and is used to treat endometriosis, benign breast disease, precocious puberty, hereditary angioneurotic edema, menorrhagia, some types of infertility, and gynecomastia. Danazol effects considerable changes in lipid metabolism. Other hormonal, antihormonal, and/or antifertility heterosteroids and/or aspects include androgen antagonists (e.g., cyproterone acetate), estrogen activity, antiestrogens, STS-557, and oximinosteroids. Heterosteroidal inhibitors of steroid hormone biosynthesis discussed are aromatase inhibitors, 5 alpha-reductase inhibitors, and 3 beta-hydroxysteroid dehydrogenase inhibitors (trilostane, epostane, and azastene). Heterosteroids affect the cardiovascular system, including the cardiac glycosides, antiarrhythmic agents, and antilipemic agents. Some heterosteroids affect central nervous system activity (e.g., RU-5135 causes convulsions in rodents). Pancuronium analogues and chandonium and analogues are neuromuscular blocking azasteroids. In addition to danazol and RU-486, several other antineoplastic heterosteroids exist (e.g., estramustine phosphate sodium, a prostate cancer drug).^ieng