Lipinski’s Rule of Five and Drug Likeness Scores

Lipinski’s Rule of Five and Drug Likeness Scores

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A series of new 10-(alkylamino)-8-methyl-2,6-dihydroimidazo[1,2-c]pyrimido[5,4-e]pyrimidine-5(3H)-thiones (4a-g) were subjected to molecular property prediction (drug-likeness, lipophilicity and solubility parameters) using Osiris Property Explorer, ALOGPS 2.1, Molinspiration and ACD/Chemsketch 12.0 software programmes. The calculated drug-related properties of the designed molecules were similar to those found in most marketed drugs. Amongst the proposed analogues, four promising candidates were chosen (4a-d) for synthesis on the basis of Lipinski’s ‘Rule of Five’ and drug likeness scores. The significant biological activity of the test compounds in two in vitro modes (isolated guinea pig tracheal chain preparation, isolated guinea pig ileum) supports the promise and accuracy of the prediction. Among them, 4a was the most potent antihistaminic [IC50 value of 30.2 µM; Standard, chlorpheniramine maleate -IC50 = 14.1 µM].

Key words: Antihistaminic, asthma, bronchodilator, drug likeness, property, pyrimidine
Asthma is primarily a complex, chronic inflammatory disease of the airways, which affects more than 300 million people worldwide, making it a serious global health problem [1]. It is characterized by recurrent reverse obstruction of the airways, airway inflammation and bronchial hyper responsiveness to stimuli which are not in themselves noxious and which do not affect non-asthmatic subjects [2]. Bronchial asthma results from a complex interplay between genetic and environmental factors [3]. An asthmatic subject suffers from intermittent attacks of dyspnoea (difficulty in breathing), wheezing and cough. Epidemiological studies show that its occurrence has been on a rise in children and young adults since early 1970’s, with the greatest incidence in more industrialized and urbanized societies, worldwide[4,5]. Nearly 7-10% of the world population suffers from bronchial asthma and India alone has an estimated burden of more than 15 million patients [6].

Currently bronchodilators (anticholinergics, selective β2-adrenergic agonists, methylxanthines, antihistaminics) and antiinflammatory agents (inhaled steroids, leukotriene antagonists, mast cell stabilizers etc) are used in the treatment of asthma[7]. Despite the availability of a wide range of drugs, asthma control is poor globally and especially in developing countries due to the underutilization of these agents in view of their cost and adverse drug reaction (ADR) profiles[8-10]. Moreover, the relief offered by these drugs is not only symptomatic but short-lived. Poorly controlled asthma is associated with significant morbidity, mortality and consequent socio-economic issues[11]. Hence, there is a dire need to search for new, effective and safer remedies to treat bronchial asthma.

While reviewing the recent perspectives in the design of antiasthmatic agents, we observed that different angularly fused heterocyclic ring systems like imidazoquinolines, imidazonaphthyridines, thienopyrimidines, triazolothienopyrimidines, benzimidazolo -quinazolines, imidazoquinazolines, benzimidazolopyridopyrimidines, imidazothienopyrimidines and triazinoquinazolines are potentially useful compounds[12,13].

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Among them, pyrimidopyrimidines, being annelated uracils, attracted considerable interest in recent years. Numerous reports have been patented[14] and have delineated the antiallergic, antiviral, antibacterial, antioxidant and hepatoprotective properties of fused pyrimidines[15,16]. Furthermore, imidazo[1,2-c]pyrimidines are also important structural moieties which are known to exhibit antiinflammatory, antiallergic, bronchodilatory, antimycobacterial and antiviral activities[17,18]. Thus, with an effort to capitalize the pharmacological potential of the above heterocyclic nuclei and to synthesize biologically potent compounds, an attempt has been made to bring such important molecular moieties into a single molecular framework and evaluate them for their possible bronchodilatory and H1-antihistaminic activities, and this communication is a part of such continued efforts.

In modern drug discovery the potential of a new compound is often investigated initially with virtual tools. The likelihood of a compound to exhibit useful therapeutic activity (sometimes called its ‘druglikeness’) is predicted from its molecular structure[19,20]. Prediction of bioavailability and bioavailability related properties, such as solubility, lipophilicity are important before actual synthesis. This could be the best way in order to avoid wastage of expensive chemicals, precious time and above all the likely environmental issues. In the present investigation, seven analogues were designed (4a-g) and were subjected to drug-like molecular properties prediction using Osiris Property Explorer[21], ALOGPS 2.1[22], Molinspiration[23] and ACD/Chemsketch 12.0[24] softwares to select the compounds for further synthesis and pharmacological evaluation.

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