Drug Repurposing: An Effective Tool in Modern Drug Discovery.

Drug repurposing is using an existing drug for a new treatment that was not indicated before. It has received immense attention during the COVID-19 pandemic emergency. Drug repurposing has become the need of time to fasten the drug discovery process and find quicker solutions to the over-exerted healthcare scenario and drug needs. Drug repurposing involves identifying the drug, evaluating its efficiency using preclinical models, and proceeding to phase II clinical trials. Identification of the drug candidate can be made through computational and experimental approaches. This approach usually utilizes public databases for drugs. Data from primary and translational research, clinical trials, anecdotal reports regarding off-label uses, and other published human data information available are included. Using artificial intelligence algorithms and other bioinformatics tools, investigators systematically try to identify the interaction between drugs and protein targets. It can be combined with genetic data, clinical analysis, structure (molecular docking), pathways, signatures, targets, phenotypes, binding assays, and artificial intelligence to get an optimum outcome in repurposing. This article describes the strategies involved in drug repurposing and enlists a series of repurposed drugs and their indications.

Design and synthesis of novel 2-(3-substituted propyl)-3-(2-methyl phenyl) quinazolin-4-(3H)-ones as a new class of H1-antihistaminic agents.

A series of novel 2-(3-substituted propyl)-3-(2-methyl phenyl) quinazolin-4-(3H)-ones were synthesized by the reaction of 2-(3-bromopropyl thio)-3-(2-methyl phenyl) quinazolin-4-(3H)-one with various amines. The starting material, 2-(3-bromopropyl thio)-3-(2-methyl phenyl) quinazolin-4-(3H)-one was synthesized from 2-methyl aniline. When tested for their in vivo H(1)-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. Compound 2-(3-(4-methylpiperazin-1-yl) propylthio)-3-(2-methyl phenyl) quinazolin-4(3H)-one (OT5) emerged as the most active compound (71.70% protection) of the series when compared to the reference standard chlorpheniramine maleate (70.09% protection). Compound OT5 shows negligible sedation (7%) compared to chlorpheniramine maleate (33%). Therefore, compound OT5 can serve as the leading molecule for further development into a new class of H(1)-antihistaminic agents.

Computational Search for Potential COVID-19 Drugs from Ayurvedic Medicinal Plants to Identify Potential Inhibitors against SARS-CoV-2 Targets.

BACKGROUND: To date, very few small drug molecules are used for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has been discovered since the epidemic commenced in November 2019. SARS-CoV-2 RdRp and spike protein are essential targets for drug development amidst whole variants of coronaviruses. OBJECTIVE: This study aims to discover and recognize the most effective and promising small molecules against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and spike protein targets through molecular docking screening of 39 phytochemicals from five different Ayurveda medicinal plants. METHODS: The phytochemicals were downloaded from PubChem, and SARS-CoV-2 RdRp and spike protein were taken from the protein data bank. The molecular interactions, binding energy, and ADMET properties were analyzed. RESULTS: Molecular docking analysis identified some phytochemicals, oleanolic acid, friedelin, serratagenic acid, uncinatone, clemaphenol A, sennosides B, trilobine and isotrilobine from ayurvedic medicinal plants possessing greater affinity against SARS-CoV-2-RdRp and spike protein targets. Two molecules, namely oleanolic acid and sennosides B, with low binding energies, were the most promising. Furthermore, based on the docking score, we carried out MD simulations for the oleanolic acid and sennosides B-protein complexes. CONCLUSION: Molecular ADMET profile estimation showed that the docked phytochemicals were safe. The present study suggested that active phytochemicals from medicinal plants could inhibit RdRp and spike protein of SARS-CoV-2.

Pharmacophore modelling-based drug repurposing approaches for monkeypox therapeutics.

Monkeypox is a zoonotic viral disease that mainly affects tropical rainforest regions of central and west Africa, with sporadic exportations to other places. Since there is no cure, treating monkeypox with an antiviral drug developed for smallpox is currently acceptable. Our study mainly focused on finding new therapeutics to target monkeypox from existing compounds or medications. It is a successful method for discovering or developing medicinal compounds with novel pharmacological or therapeutic applications. In this study, homology modelling developed the Monkeypox VarTMPK (IMNR) structure. Ligand-based pharmacophore was generated using the best docking pose of standard ticovirimat. Further, molecular docking analysis showed compounds, tetrahydroxycurcumin, procyanidin, rutin, vicenin-2, kaempferol 3-(6''-malonylglucoside) were the top five binding energy compounds against VarTMPK (1MNR). Furthermore, we carried out MD simulations for 100 ns for the six compounds, including reference based on the binding energies and interactions. MD studies revealed that as ticovirimat interacted with residues Lys17, Ser18, and Arg45, all the above five compounds interacted with the same amino acids at the active site during docking and simulation studies. Among all the compounds, ZINC4649679 (Tetrahydroxycurcumin) was shown to have the highest binding energy -9.7 kcal/mol and also observed stable protein-ligand complex during MD studies. ADMET profile estimation showed that the docked phytochemicals were safe. However, further biological assessment through a wet lab is essential to measure the efficacy and safety of the compounds.Communicated by Ramaswamy H. Sarma.

In Silico Screening of Some Active Phytochemicals to Identify Promising Inhibitors Against SARS-CoV-2 Targets.

BACKGROUND: There are very few small-molecule drug candidates developed against SARS-CoV-2 that have been revealed since the epidemic began in November 2019. The typical medicinal chemistry discovery approach requires more than a decade of the year of painstaking research and development and a significant financial guarantee, which is not feasible in the challenge of the current epidemic. OBJECTIVE: This current study proposes to find and identify the most effective and promising phytomolecules against SARS-CoV-2 in six essential proteins (3CL protease, Main protease, Papain- Like protease, N-protein RNA binding domain, RNA-dependent RNA polymerase, and Spike receptor binding domain target through in silico screening of 63 phytomolecules from six different Ayurveda medicinal plants. METHODS: The phytomolecules and SARS-CoV-2 proteins were taken from public domain databases such as PubChem and RCSB Protein Data Bank. For in silico screening, the molecular interactions, binding energy, and ADMET properties were investigated. RESULTS: The structure-based molecular docking reveals some molecules' greater affinity towards the target than the co-crystal ligand. Our results show that tannic acid, cyanidin-3-rutinoside, zeaxanthin, and carbolactone are phytomolecules capable of inhibiting SARS-CoV-2 target proteins in the least energy conformations. Tannic acid had the least binding energy of -8.8 kcal/mol, which is better than the binding energy of its corresponding co-crystal ligand (-7.5 kcal/mol) against 3 CL protease. Also, it has shown the least binding energy of -9.9 kcal/mol with a more significant number of conventional hydrogen bond interactions against the RdRp target. Cyanidin-3-rutinoside showed binding energy values of -8.8 and -7.6 kcal/mol against Main protease and Papain-like protease, respectively. Zeaxanthin was the top candidate in the N protein RBD with a binding score of - 8.4 kcal/mol, which is slightly better when compared to a co-crystal ligand (-8.2 kcal/mol). In the spike, carbolactone was the suitable candidate with the binding energy of -7.2 kcal/mol and formed a conventional hydrogen bond and two hydrophobic interactions. The best binding affinity-scored phytomolecules were selected for the MD simulations studies. CONCLUSION: The present in silico screening study suggested that active phytomolecules from medicinal plants could inhibit SARS-CoV-2 targets. The elite docked compounds with drug-like properties have a harmless ADMET profile, which may help to develop promising COVID-19 inhibitors.

An In silico Investigation to Identify Promising Inhibitors for SARS-CoV-2 Mpro Target.

BACKGROUND: A limited number of small molecules against SARS-CoV-2 has been discovered since the epidemic commenced in November 2019. The conventional medicinal chemistry approach demands more than a decade of the year of laborious research and development and a substantial financial commitment, which is not achievable in the face of the current epidemic. OBJECTIVE: This study aims to discover and recognize the most effective and promising small molecules by interacting SARS-CoV-2 Mpro target through computational screening of 39 phytochemicals from five different Ayurvedic medicinal plants. METHODS: The phytochemicals were downloaded from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) PubChem, and the SARS-CoV-2 protein (PDB ID: 6LU7; Mpro) was taken from the PDB. The molecular interactions, binding energy, and ADMET properties were analyzed. RESULTS: The binding affinities were studied using a structure-based drug design of molecular docking, divulging 21 molecules possessing greater to equal affinity towards the target than the reference standard. Molecular docking analysis identified 13 phytochemicals, sennoside-B (-9.5 kcal/mol), isotrilobine (-9.4 kcal/mol), trilobine (-9.0 kcal/mol), serratagenic acid (-8.1 kcal/mol), fistulin (-8.0 kcal/mol), friedelin (-7.9 kcal/mol), oleanolic acid (-7.9 kcal/mol), uncinatone (-7.8 kcal/mol), 3,4-di- O-caffeoylquinic acid (-7.4 kcal/mol), clemaphenol A (-7.3 kcal/mol), pectolinarigenin (-7.2 kcal/mol), leucocyanidin (-7.2 kcal/mol), and 28-acetyl botulin (-7.2 kcal/mol) from ayurvedic medicinal plants phytochemicals possess greater affinity than the reference standard Molnupiravir (-7.0 kcal/mol) against SARS-CoV-2-Mpro. CONCLUSION: Two molecules, namely sennoside-B, and isotrilobine with low binding energies, were predicted as most promising. Furthermore, we carried out molecular dynamics simulations for the sennoside-B protein complexes based on the docking score. ADMET properties prediction confirmed that the selected docked phytochemicals were optimal. These compounds can be investigated further and utilized as a parent core molecule to create novel lead molecules for preventing COVID-19.

Neurotransmitter metabolic enzymes and antioxidant status on Alzheimer's disease induced mice treated with Alpinia galanga (L.) Willd.

Amyloid ß25₋35 (Aß) peptide may be neurotoxic during the progression of Alzheimer's disease by eliciting reactive oxygen species. The use of folklore medicine is prevalent and plants which possess a rejuvenating property are a large source of natural antioxidants that might afford leads for the development of novel drugs in neurodegenerative disorders. The study was designed to investigate the effect of an ethanol extract of Alpinia galanga (L.) Willd (EAG) on oxidative stress induced Alzheimer's type amnesia in mice. Mice were treated with an experimental extract at 200 mg/kg and 400 mg/kg dose for 14 days and injected with neurotoxic Aß and the doses were continued for 21 days. Behavioural studies with open field, step-down inhibitory avoidance and a water maze after treatment indicated the acceleration in cognitive function. The elevated levels of acetylcholinesterase and monoamine oxidase enzymes in amnesia induced mice were attenuated by treatment with EAG. The generation of free radicals was decreased due increased activity of antioxidant enzymes after treatment with EAG. These findings suggested that EAG exerts an antiamnesiac effect in Aß induced neurodegeneration through an antioxidant property.

Neuroprotective potential of ethanolic extract of Pseudarthria viscida (L) Wight and Arn against beta-amyloid(25-35)-induced amnesia in mice.

The neuroprotective potential of ethanolic extract of roots of Pseudarthria viscida (L) Wight and Arn (EEPV) was investigated against beta-amyloid(25-35)-induced amnesia in mice which is a suitable animal model for Alzheimer's disease (AD). The senile plaques of beta-amyloid (Abeta) are major constituents accumulated during the progression of AD as a potent neurotoxicant. In our investigation, intracerebroventricular injection of Abeta(25-35) in mice induced the neurodegeneration, exhibited the increased time of escape latency in behavioral pattern using water maze and decreased the levels of antioxidants namley superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and vitamin C with elevated level of acetylcholinesterase enzyme (AChE). The neuroprotective potential of EEPV was determined by behavioral pattern using water maze and biochemical parameters such as SOD, CAT and GPx and vitamin C content as well as AChE. Mice were treated with EEPV at 200 and 400 mg/kg doses for 21 days. Except control, all animals received a single injection of neurotoxicant Abeta(25-35) on 14th day. In behavioural assessment, treatment with ethanolic extract improved the cognitive function in the water maze and attenuated the elevated levels of AChE with increase in antioxidant enzymes, indicating the neuroprotection with increased levels of vitamin C. These findings suggest that ethanolic extract of P. viscida exerts anti-amnesiac effects and enhances cognitive function.

4-(3-Methoxyphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones: new class of H1-antihistaminic agents.

A series of 1-substituted-4-(3-methoxyphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were synthesized by the cyclization of 2-hydrazino-3-(3-methoxyphenyl)-3H-quinazolin-4-one with various electrophile. The starting material 2-hydrazino-3-(3-methoxyphenyl)-3H-quinazolin-4-one was synthesized from 3-methoxy aniline by an innovative route. Title compounds were tested for their in vivo H1-antihistaminic activity on guinea pigs; all the tested compounds protected the animals from histamine induced bronchospasm significantly. Compound 1-methyl-4-(3-methoxyphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) emerged as the most active compound of the series and was more potent (72.76%) than the reference standard chlorpheniramine maleate (71%). Compound II showed negligible sedation (10%) when compared to chlorpheniramine maleate (25%). Hence it could serve as prototype molecule for further development as a new class of H1-antihistaminic agents.

Synthesis of 4-butyl-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as new class of H(1)-antihistaminic agents.

A series of novel 4-butyl-1-substituted-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones were synthesized by the cyclization of 3-butyl-2-hydrazino-3H-quinazolin-4-one with various one carbon donors. The starting material 3-butyl-2-hydrazino-3H-quinazolin-4-one was synthesized from butyl amine by a new innovative route. When tested for their in vivo H(1)-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. Compound 4-butyl-1-methyl-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-one (II) emerged as the most active compound of the series and it is equipotent (71.91% protection) when compared to the reference standard chlorpheniramine maleate (71% protection). Compound II show negligible sedation (9%) when compared to chlorpheniramine maleate (30%).

Synthesis of 3-(2-pyridyl)-2-substituted-quinazolin-4(3H)-ones as new analgesic and anti-inflammatory agents.

A new series of 3-(2-pyridyl)-2-substituted-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(2-pyridyl)-quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(2-pyridyl)-quinazolin-4(3H)-one was synthesized from 2-aminopyridine. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. While the test compounds exhibited significant activity, compound 2-(1-ethylpropylidene)-hydrazino-3-(2-pyridyl)-quinazolin-4(3H)-one (AS2) showed moderate analgesic activity and compound 2-(1-methylbutylidene)-hydrazino-3-(2-pyridyl)-quinazolin-4(3H)-one (AS3) showed realistic anti-inflammatory activity when compared to the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic side effect when compared to aspirin.

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

A series of novel 1-substituted-4-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were synthesized by the cyclization of 2-hydrazino-3-(2-methylphenyl)-3H-quinazolin-4-one with various one carbon donors. The starting material 2-hydrazino-3-(2-methylphenyl)-3H-quinazolin-4-one was synthesized from 2-methyl aniline by a novel innovative route. The title compounds were tested for their in vivo H(1)-antihistaminic activity on guinea pigs; all the tested compounds protected the animals from histamine-induced bronchospasm significantly. Compound 1-methyl-4-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) emerged as the most active compound of the series and it is more potent (72.45%) when compared to the reference standard chlorpheniramine maleate (71%). Compound II showed negligible sedation (11%) when compared to chlorpheniramine maleate (30%). Hence it could serve as the prototype molecule for further development as a new class of H(1)-antihistaminic agents.

Design and synthesis of 3-(4-ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones as a novel class of analgesic and anti-inflammatory agents.

A new series of 3-(4-ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-ethylphenyl)-3H-quinazolin-4-one from 4-ethyl aniline with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. The compound 2-(N'-3-pentylidene-hydrazino)-3-(4-ethylphenyl)-3H-quinazolin-4-one (AS2) emerged as the most active compound of the series and was moderately more potent than the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to aspirin.

An overview of quinazolines: Pharmacological significance and recent developments.

Most of the drugs and pharmacologically relevant molecules possess heterocyclic ring structures and presence of hetero atoms or groupings divulges privileged specificities in their pharmacological targets. Especially the heterocyclic systems, quinazoline is a biologically imperative scaffold known to be linked with several pharmacological activities. Some of the protuberant pharmacological responses attributed to this system are analgesic, anti-inflammatory, anti-convulsant, sedative-hypnotic, anti-histaminic, anti-hypertensive, anti-cancer, anti-microbial, anti-tubercular and anti-viral activities. This multiplicity in the pharmacological response contours of quinazoline has attracted the consideration of medicinal chemists to explore this system to its multiple potential against numerous activities. Several of these synthetic and pharmacological investigations have been successively studied for structure-activity relationship (SAR) to correlate the particular structural features for their pharmacological target. The emerging understanding of quinazoline derivatives on their pharmacological target offer opportunities for novel therapeutics. This review principally emphases on the medicinal chemistry aspects including drug design, structure-activity relationships (SARs), and mechanism of actions of quinazoline derivatives. This review gives detailed attention on in vitro and in vivo pharmacological activities of quinazoline and its analogs in the perspective of drug discovery and its development.

Synthesis of 2-mercapto-3-substituted-5,6-dimethylthieno[2,3-d] pyrimidin-4(3H)-ones as new analgesic, anti-inflammatory agents.

A new series of 2-mercapto-3-substituted-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-ones were synthesised by reacting 3-amino-2-mercapto-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one with different aldehydes and ketones. The starting material 3-amino-2-mercapto-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one was synthesised from 2-amino-3-carbethoxy-4,5-dimethyl thiophene by a novel innovative route. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. While the test compounds exhibited significant activity, among these compound AS1 showed more potent analgesic and anti-inflammatory activities and the compound AS3 showed equipotent analgesic and anti-inflammatory activities when compared to the reference standard diclofenac sodium.

Design and synthesis of 2-methylthio-3-substituted-5,6-dimethylthieno [2,3-d] pyrimidin-4(3H)-ones as analgesic, anti-inflammatory and antibacterial agents.

Pain and inflammation are simultaneous responses in bacterial infections. In current clinical practice, two groups of agents like antibacterial and non-steroidal anti-inflammatory drugs (NSAID's) are prescribed simultaneously. Regrettably, none of the drug possesses these activities in a single component. Exploiting the bioisosterism concept, we have documented that 2-phenyl-3-substituted quinazolines, 2,3-disubstituted quinazolines, 2-methyl-3-substituted quinazolin-4-(3H)-ones and 2-methylthio-3-substituted quinazolin-4-(3H)-ones exhibited good analgesic and anti-inflammatory activities. The present work is an extension of our ongoing efforts towards the development and identification of lead molecules by bioisostere concept, for which we designed some of 2-methylthio-3-substituted-5,6-dimethylthieno[2,3-d] pyrimidin-4(3H)-ones. The title compounds were investigated for analgesic, anti-inflammatory and antibacterial activities. While the test compounds exhibited significant activity, the compounds (6-9) showed more potent analgesic activity, and the compounds (8, 9) showed anti-inflammatory activity comparable to the reference standard diclofenac.

Synthesis, analgesic, anti-inflammatory, ulcerogenic index and antibacterial activities of novel 2-methylthio-3-substituted-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-4(3H)-ones.

A variety of novel 2-methylthio-3-substituted-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-4(3H)-ones have been synthesized by reacting (2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)dithiocarbamic acid methyl ester (5) with a variety of amines. The starting material dithiocarbamate (5) was synthesized from 2-amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo (b) thiophene (1) by a novel innovative route. The title compounds were investigated for analgesic, anti-inflammatory, ulcerogenicity index and antibacterial activities. While the test compounds exhibited significant activity, the compounds 1-methyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A1), 1-dimethyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A2), 1-diethyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A3) and 1-pyrrolidinyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A4) showed more potent analgesic activity and the compounds 1-dimethyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A2), 1-diethyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno-[2,3-d]pyrimidin-3-yl)thiourea (A3) and 1-pyrrolidinyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d] pyrimidin-3-yl)thiourea (A4) showed more potent anti-inflammatory activity than the reference standard diclofenac sodium.

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.

Bone mineral content determined by functional imaging.

Quantitation of bone mineral by photon absorptiometry is a simple and accurate method for determining changes in bone volume and mineral content in serial studies. An extension of the scintillation camera method for studying such changes in the calcaneous is described. This technique is applicable to large areas of bone, thereby minimizing the effect of repositioning errors. Using a 40-mCi 241Am sheet source, a 2.1% reproducibility in bone phantoms and a 2.4% reproducibility in normal patients was achieved. Several case studies are presented to illustrate sensitivity and clinical application of the method. Although bone mineral determinations are now performed in a limited number of health care facilities, the scintillation camera method described in this report could increase the availability of these determinations significantly.

Synthesis and pharmacological investigation of some novel 2-methyl-3-(substituted methylamino)-(3H)-quinazolin-4-ones as histamine H1-receptor blockers.

A series of 2-methyl-3-(substituted methylamino)-(3H)-quinazolin-4-ones were synthesized from 3-amino-2-methyl-(3H)-quinazolin-4-one. Their structures were confirmed by spectral data (IR, NMR and MS) and the purity was ascertained by microanalysis. When tested for H1-receptor blocking activity on isolated guinea pig ileum all the test compounds inhibited histamine induced contraction whereas compound 5 (IC50 0.22 x 10(3) ng/ml) was found to be four times more potent than chlorpheniramine maleate (IC50 1 x 10(3) ng/ml) and it showed lesser sedation (8%) than the standard (32%).